Williams Manual of Pregnancy Complications, 23 ed.

CHAPTER 52. Thromboembolic Disease

Pregnancy and the puerperium are considered as one of the highest risks for otherwise healthy women to develop venous thrombosis and pulmonary embolism. Indeed, thrombotic pulmonary embolism caused nearly 9 percent of the almost 623 pregnancy-related deaths in the United States during 2005.

The incidence of all thromboembolism (deep venous thrombosis or pulmonary embolism) is approximately 1 per 1000 pregnancies. About half are identified antepartum and the other half in the puerperium. Stasis is probably the strongest single predisposing event to deep venous thrombosis, the frequency of which has decreased remarkably during the puerperium as early ambulation has become widely practiced.

THROMBOPHILIAS

A number of isolated deficiencies of proteins involved either in coagulation inhibition or in the fibrinolytic system—collectively referred to as thrombophilias—can lead to hypercoagulability and recurrent venous thromboembolism. Thrombophilias are discussed in Chapter 53.

DEEP VENOUS THROMBOSIS

The signs and symptoms of deep venous thrombosis (DVT) involving the lower extremity vary greatly, depending upon the degree of occlusion and the intensity of the inflammatory response. Classical puerperal thrombophlebitis involving the lower extremity is abrupt in onset, with severe pain and edema of the leg and thigh. The thrombus typically is left sided and involves much of the deep venous system from the foot to the iliofemoral region. Occasionally, reflex arterial spasm causes a pale, cool extremity with diminished pulsations—so called phlegmasia alba dolens or milk leg. More likely, there may be appreciable volume of clot yet little reaction in the form of pain, heat, or swelling. Importantly, calf pain, either spontaneous or in response to squeezing, or to stretching the Achilles tendon (Homan sign), may be caused by thrombosis or a strained muscle or a contusion. The latter may be common during the early puerperium as the consequence of inappropriate contact between the calf and the delivery table leg holders.

Diagnosis

Although venography remains the standard for confirmation of DVT, noninvasive methods have largely replaced these tests to confirm the clinical diagnosis. Compression ultrasonography, used along with duplex and color Doppler ultrasound, is the primary test currently used to detect proximal DVT. Importantly, normal venous ultrasonography results do not necessarily rule out pulmonary embolism, because the thrombosis may have already embolized or it arose from deep pelvic veins inaccessible to ultrasound evaluation. In pregnant women, thrombosis associated with pulmonary embolism frequently originates in the iliac veins.

Magnetic resonance imaging is reserved for specific cases in which the ultrasound findings are equivocal, or with negative ultrasound findings but strong clinical suspicion. This technique allows for excellent delineation of anatomical detail above the inguinal ligament, and phase images can be used to diagnose the presence or absence of pelvic vein flow (Figure 52-1). An additional advantage is the ability to image in coronal and sagittal planes. Furthermore, in those patients without DVT, nonthrombotic conditions are often demonstrated that explain the clinical findings that originally suggest venous thrombosis. Some examples include cellulitis, edema, hematomas, and superficial phlebitis.

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FIGURE 52-1 Magnetic resonance image through the pelvis of a 26-week pregnant woman who presented with symptoms of pulmonary embolism but without clinically apparent deep venous thrombosis of the lower extremities. The T1-weighted image shows occlusion of left common iliac vein. There is normal absence of signal in the right iliac vein and both iliac arteries.

Computed tomographic scanning may also be used to assess the lower extremities. It is widely available but requires contrast agents and ionizing radiation. As discussed in Appendix C, radiation exposure to the fetus is negligible unless the pelvic veins are imaged.

Superficial Venous Thrombosis

Thrombosis limited strictly to the superficial veins of the saphenous system is differentiated from DVT and treated with analgesia, elastic support, and rest. If it does not soon subside, or if deep venous involvement is suspected, appropriate diagnostic measures are taken; and heparin is given if deep vein involvement is confirmed. Superficial thrombophlebitis is typically seen in association with superficial varicosities or as a sequela to intravenous catheterization.

Management

Treatment of DVT consists of anticoagulation, limited activity, and analgesia. For all women, during either pregnancy or postpartum, initial anticoagulation is with either unfractionated heparin or with low-molecular-weight heparin. For women during pregnancy, heparin therapy is continued, and for those postpartum, warfarin therapy is given.

Most often, pain is promptly relieved by these measures. After symptoms have completely abated, graded ambulation should be started with the legs fitted with elastic stockings, and anticoagulation continued. Recovery to this stage usually takes about 7 to 10 days.

Heparin

Treatment of thromboembolism during pregnancy begins with an intravenous heparin bolus followed by continuous infusion titrated to achieve full anticoagulation. There are a number of protocols to accomplish this, and the one used at Parkland Hospital is shown in Table 52-1. Intravenous anticoagulation should be maintained for at least 5 to 7 days, after which treatment is converted to subcutaneous heparin. Injections are given every 8 hours to prolong the partial thromboplastin time (PTT) to a least 1.5 to 2.5 times control throughout the dosing interval. Treatment is continued for at least 3 months after the acute event. If the woman is still pregnant at this juncture, it is not known whether it is better to continue with a therapeutic or a prophylactic dose of anticoagulate for the remainder of pregnancy.

TABLE 52-1. Parkland Hospital Protocol for Continuous Heparin Infusion for Patients with Venous Thromboembolism

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Complications of heparin therapy include thrombocytopenia, osteoporosis, and hemorrhage. There are two types of thrombocytopenia associated with heparin use. The most common type of heparin-induced thrombocytopenia (commonly referred to as HIT) is a nonimmune, benign, reversible form that occurs within the first few days of therapy and resolves in 5 days without cessation of therapy. The more severe form of HIT results from an immunereaction involving IgG antibodies directed against complexes of platelet factor 4 and heparin. Osteoporosis develops with long-term administration and is more prevalent in cigarette smokers. In an attempt to avoid severe osteoporosis, women treated with heparin should be encouraged to take supplemental calcium and vitamin D.

Low-Molecular-Weight Heparin

This is a family of derivatives of unfractionated heparin, and their molecular weights average 4000 to 5000 daltons compared with about 12,000 to 16,000 daltons for conventional heparin. Like standard heparin, low-molecular-weight heparins do not cross the placenta.

In 2002, the manufacturer of Lovenox warned that its use in pregnancy had been associated with congenital anomalies and as increased risk of hemorrhage. After its own extensive review, the American College of Obstetricians and Gynecologists (Safety of Lovenox in pregnancy. Committee Opinion No. 276, October 2002) concluded that these risks were rare, that the incidence was not higher than expected, and that no cause-and-effect relationship has been established. The committee further concluded that enoxaparin and dalteparin could be given safely during pregnancy.

One caveat is that low-molecular-weight heparins should not be used in patients with prosthetic heart valves because of reports of valvular thrombosis. Their use may increase the risk of spinal hematoma associated with regional analgesia. Finally, when given within 2 hours of cesarean delivery, these agents increase the risk of wound hematoma.

Warfarin

Anticoagulation with warfarin derivatives is generally contraindicated during pregnancy. These drugs readily cross the placenta and cause fetal death and malformations from hemorrhages. They are safe, however, when ingested while breastfeeding (American Academy of Pediatrics and American College of Obstetricians and Gynecologist, 2004). Postpartum venous thrombosis can be treated with intravenous heparin and oral warfarin initiated simultaneously, and heparin can usually be discontinued after 5 days. Postpartum women have been shown to require a significantly larger median total dose of warfarin compared to nonpregnant controls (45 vs. 24 mg), and a longer time (7 vs. 4 days), to achieve the target international normalized ratio (INR). After delivery, most women are anticoagulated with warfarin for at least 6 weeks.

PULMONARY EMBOLISM

Although it causes about 10 percent of maternal deaths, pulmonary embolism is relatively uncommon during pregnancy and the puerperium. The incidence averages about 1 in 7,000 pregnancies with an almost equal prevalence for antepartum and postpartum embolism. Clinical evidence for DVT of the legs precedes pulmonary embolization in about 70 percent of cases. In others, especially those that arise from deep pelvic iliac veins, the woman usually is asymptomatic until symptoms of embolization develop (Table 52-2).

TABLE 52-2. The Most Common Symptoms Associated with Pulmonary Embolism

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Physical signs associated with pulmonary embolism may include an accentuated pulmonic closure sound, rales, or friction rub. Right-axis deviation may or may not be evident on the electrocardiogram. Even with massive pulmonary embolism, signs, symptoms, and laboratory data to support the diagnosis may be deceivingly nonspecific.

Diagnosis

As with deep venous thrombosis, the diagnosis of pulmonary embolism requires an initial high index of suspicion followed by objective testing. Shown in Figure 52-2 is an algorithm for the evaluation of suspected pulmonary embolism in pregnancy. A chest radiograph should be performed if there is underlying suspicion for other diagnoses. In many centers, spiral computed tomography has replaced the more cumbersome ventilation–perfusion lung scan.

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FIGURE 52-2 Evaluation of suspected pulmonary embolism during pregnancy. The decision to begin with helical computer tomography (CT) ventilation/perfusion (V/Q) scan, or bilateral CUS depends on local availability and expertise. CTA, CT angiography; CUS, compression ultrasonography; MRA, magnetic resonance angiography; PE, pulmonary embolism. See text (p. 1025) for discussion. Nondiagnostic results are those that indicate an intermediate or low probability of pulmonary embolism, or that do not indicate a high probability. (Reproduced, with permission, from Cunningham FG, Leveno KJ, Bloom SL, et al (eds). Williams Obstetrics. 23rd ed. New York, NY: McGraw-Hill; 2010. Adapted from Nijkeuter M, Ginsberg JS, Huisman MV: Diagnosis of deep vein thrombosis and pulmonary embolism in pregnancy: A systematic review. J Thromb Haemost 4:496, 2006; Tapson VF: Acute pulmonary embolism. N Engl J Med 358:1037, 2008.)

These scans utilize a small dose of a radioactive agent, usually 99mTc-macro-aggregated albumin, which is administered intravenously. There is negligible fetal radiation exposure (see Appendix C). The scan may not provide a definite diagnosis because many other conditions—for example, pneumonia or local bronchospasm—can cause perfusion defects. Ventilation scans with inhaled 133Xe or 99mTc are added to perfusion scans in the hope that ventilation will be abnormal, but perfusion normal, in areas of pneumonia or hypoventilation. Thus, although ventilation scanning increases the probability of an accurate diagnosis of pulmonary embolus in patients with large perfusion defects and ventilation mismatches, normal ventilation–perfusion does not rule out pulmonary embolism.

Spiral Computed Tomography

Helical computed tomography (CT), or spiral CT, allows rapid imaging from the main pulmonary arteries to at least the segmental and possibly the subsegmental branches. Fetal radiation exposure with standard single-detector spiral CT is less than with V/Q lung scanning. The sensitivity and specificity for spiral CT scanning are similar to that for V/Q scanning.

We now use multidetector spiral CT as first-line evaluation of pregnant women at Parkland Hospital. Although the technique has many advantages, we have found that the better resolution allows detection of previously inaccessible small distal emboli that have uncertain clinical significance.

Management

Treatment for pulmonary embolism is similar to that for DVT. In general, heparin is given initially in a fashion similar to that for DVT.

In nonpregnant patients, the most common cause of death is recurrent pulmonary embolism. To prevent this, most recommend therapeutic anticoagulation for 4 to 6 months. For women who develop thromboembolism postpartum, or for those who were given heparin antepartum and are now delivered, warfarin therapy is usually given.

Vena Caval Filters

Routine placement of a vena caval filter has no added advantage over heparin given alone to prevent pulmonary embolism in patients with DVT. In the very infrequent circumstances in which heparin therapy fails to prevent recurrent pulmonary embolism from the pelvis or legs, or when embolism develops from these sites despite heparin given for their treatment, then a vena-caval filter is indicated. The device is inserted through either the jugular or the femoral vein. Some recommend suprarenal placement during pregnancy.

Anticoagulation and Delivery

The most serious complication with any of these heparin regimens is hemorrhage, which is more likely if there has been recent surgery or lacerations, such as with vaginal or cesarean delivery. The effects on blood loss at delivery will depend upon a number of variables, including the following:

1. Dose, route, and time of administration of heparin.

2. Magnitude of incisions and lacerations.

3. Intensity of postpartum myometrial contraction and retraction.

4. Presence of other coagulation defects.

In general, heparin therapy should be stopped during the time of labor and delivery. If the uterus is well contracted and there has been negligible trauma to the lower genital tract, it can be restarted within several hours. Otherwise, a delay of 1 or 2 days may be prudent. Protamine sulfate administered slowly intravenously will generally promptly reverse the effect of heparin. Protamine sulfate should not be given in excess of the amount needed to neutralize the heparin, because it has an anticoagulant effect.

The woman who has very recently suffered a pulmonary embolism and who must be delivered by cesarean presents a serious problem. Reversal of anticoagulation may be followed by another embolus, and surgery while she is fully anticoagulated frequently results in life-threatening hemorrhage or troublesome hematomas. In this situation, consideration should be given before surgery for placement of a vena caval filter.

Serious bleeding is likely when heparin in usual therapeutic doses is administered to a woman who has undergone cesarean delivery within the previous 48 to 72 hours.

THROMBOEMBOLISM ANTEDATING PREGNANCY

Optimal management of women with firm evidence of a prior thromboembolism is unclear. Our practice at Parkland Hospital for many years for women with a history of prior thromboembolism has been to administer subcutaneous heparin, 5000 to 7500 units two to three times daily. With this regimen, the recurrence of documented deep venous thrombosis embolization has been rare. More recently, we have successfully used 40-mg enoxaparin given subcutaneously daily.


For further reading in Williams Obstetrics, 23rd ed.,

see Chapter 47, “Thromboembolic Disorders.”