CHAPTER 52: Thromboembolic Disorders

During the past century, the frequency of venous thromboembolism (VTE) during the puerperium decreased remarkably as early ambulation became more widely practiced. Despite this and other advances in prevention and treatment, however, thromboembolism remains a leading cause of maternal morbidity and mortality. Indeed, thrombotic pulmonary embolism accounted for 9.2 percent of pregnancy-related deaths in the United States between 2011 and 2013 (Creanga, 2017).

The absolute incidence of VTE during pregnancy is low—1 or 2 cases per 1000 pregnancies. However, the risk is approximately five times higher than that among women who are not pregnant (Greer, 2015). Approximately equal numbers of cases are identified antepartum and in the puerperium. Deep-vein thrombosis alone is more frequent antepartum, and pulmonary embolism is more common in the first 6 weeks postpartum (Jacobsen, 2008). During the puerperium, the estimated incidence of a thromboembolic complication is 22 events per 100,000 deliveries. Although still elevated, the risk falls to approximately 3 cases per 100,000 deliveries during the second 6-week postpartum period (Kamel, 2014).

Rudolf Virchow (1856) postulated that stasis, local trauma to the vessel wall, and hypercoagulability predisposed to venous thrombosis. During normal pregnancy, the risk for each of these rises. Compression of the pelvic veins and inferior vena cava by the enlarging uterus renders the lower extremity venous system particularly vulnerable to stasis. From their review, Marik and Plante (2008) cite a 50-percent reduction in venous flow velocity in the legs that lasts from the early third trimester until 6 weeks postpartum. This stasis is the most constant predisposing risk factor for venous thrombosis. Venous stasis and delivery may also contribute to endothelial cell injury. Last, as listed in the Appendix (Serum and Blood Constituents), the synthesis of most clotting factors is markedly enhanced during pregnancy and favors coagulation.

Characteristics for developing thromboembolism during pregnancy are shown in Table 52-1. The most important of these is a personal history of thrombosis. Specifically, 15 to 25 percent of all VTE cases during pregnancy are recurrent events (American College of Obstetricians and Gynecologists, 2017b). In one study, the magnitude of other risks was estimated from 7177 VTE cases during pregnancy and 7158 events during the postpartum period (James, 2006). Calculated risks for thromboembolism were approximately doubled in women with multifetal gestation, anemia, hyperemesis, hemorrhage, and cesarean delivery. The risk was even greater in pregnancies complicated by postpartum infection. Waldman and associates (2013) found that the risk of VTE was slightly higher in women with advanced maternal age and approximately doubled in women with great parity, a hypertensive disorder, cesarean delivery, or obesity. Risks were significantly higher among women who had a stillbirth or who underwent peripartum hysterectomy.

The next most important individual risk factor is a genetically determined thrombophilia. An estimated 20 to 50 percent of women who develop a venous thrombosis during pregnancy or postpartum have an identifiable underlying genetic disorder (American College of Obstetricians and Gynecologists, 2017b).

Several important regulatory proteins act as inhibitors in the coagulation cascade (Fig. 52-1). Normal values for many of these proteins during pregnancy are found in the Appendix (Serum and Blood Constituents). Inherited or acquired deficiencies of these inhibitory proteins are collectively referred to as thrombophilias. These can lead to hypercoagulability and recurrent VTE (Connors, 2017). Although these disorders are collectively present in approximately 15 percent of white European populations, they are responsible for approximately 50 percent of all thromboembolic events during pregnancy (Lockwood, 2002; Pierangeli, 2011). Some aspects of the more common inherited thrombophilias are summarized in Table 52-2.

Inherited Thrombophilias

Patients with inherited thrombophilic disorders often have a family history of thrombosis. Inherited thrombophilias are also found in up to half of all patients who present with VTE before the age of 45 years, particularly in those whose event occurred in the absence of well-recognized risk factors. Of greatest significance is a family history of sudden death due to pulmonary embolism or a history of multiple family members requiring long-term anticoagulation therapy because of recurrent thrombosis (Anderson, 2011).

Antithrombin Deficiency

Synthesized in the liver, antithrombin is one of the most important inhibitors of thrombin and inactivates thrombin and factor Xa (Rhéaume, 2016). Notably, the rate of antithrombin interaction with its target is accelerated by heparin (Anderson, 2011). Antithrombin deficiency may result from hundreds of different mutations that are almost always autosomal dominant. Type I deficiency results from reduced synthesis of biologically normal antithrombin, and type II deficiency is characterized by normal levels of antithrombin with reduced functional activity (Anderson, 2011). Homozygous antithrombin deficiency is lethal.

Antithrombin deficiency is rare—it affects approximately 1 in 500 to 5000 individuals (Ilonczai, 2015; Rhéaume, 2016). It is the most thrombogenic of the heritable coagulopathies. Indeed, antithrombin deficiency is associated with a 25- to 50-fold higher relative risk of VTE in the general population and a sixfold increased risk of thromboembolic complications during pregnancy (Ilonczai, 2015). Those affected have approximately a 50-percent lifetime risk of VTE (Duhl, 2007).

Sabadell and associates (2010) studied the outcomes of 18 pregnancies complicated by antithrombin deficiency. Twelve of these women were treated with therapeutic doses of low-molecular-weight heparin (LMWH), and six were not treated because antithrombin deficiency had not yet been diagnosed. Three of the untreated patients suffered a thromboembolic episode compared with none in the treated group. Untreated women also had a 50-percent risk of stillbirth and fetal-growth restriction. By comparison, none of the treated women had a stillbirth, but a fourth developed fetal-growth restriction. Similar results were reported by Ilonczai and colleagues (2015). García-Botella and associates (2016) described a mesenteric vein thrombosis in a pregnant woman with antithrombin deficiency. In one review of outcomes in 23 newborns with antithrombin deficiency, there were 11 cases of thrombosis and 10 infant deaths (Seguin, 1994).

Given such risk, affected women are treated during pregnancy with heparin regardless of whether they have had a prior thrombosis. When anticoagulation is necessarily withheld, such as during surgery or delivery, Paidas and colleagues (2016) found that treatment with recombinant human antithrombin protected against VTE development. Sharpe and associates (2011) described successful use of antithrombin concentrate infusions plus therapeutic anticoagulation in a pregnant woman with antithrombin deficiency who developed a thrombosis during the third trimester despite therapeutic LMWH.

Protein C Deficiency

When thrombin is bound to thrombomodulin on endothelial cells of small vessels, its procoagulant activities are neutralized. This binding also activates protein C, a natural anticoagulant that in the presence of protein S controls thrombin generation, in part, by inactivating factors Va and VIIIa (see Fig. 52-1). Protein C activity increases modestly but significantly throughout the first half of pregnancy, and some have speculated that this augmentation may play a role in maintaining early pregnancy through both anticoagulant and inflammatory regulatory pathways (Said, 2010b).

More than 160 different autosomal dominant mutations for the protein C gene have been described (Louis-Jacques, 2016). The prevalence of protein C deficiency is 2 to 3 per 1000, but many of these individuals do not have a thrombosis history because the phenotypic expression is highly variable (Anderson, 2011). These prevalence estimates correspond with functional activity threshold values of 50 to 60 percent, which are used by most laboratories and which are associated with a six- to 12-fold higher risk for VTE (Lockwood, 2012).

Protein S Deficiency

This circulating anticoagulant is activated by protein C, which enhances the capacity of protein S to inactivate factors Va and VIIIa (see Fig. 52-1). Protein S deficiency may be caused by more than 130 different mutations, with an aggregate prevalence of approximately 0.3 to 1.3 per 1000 individuals (Louis-Jacques, 2016). Protein S deficiency may be measured by antigenically determined free, functional, and total S levels. All three decline substantively during normal gestation (Appendix, Serum and Blood Constituents). Thus, the diagnosis in pregnant women—as well as in those taking certain oral contraceptives—is difficult (Archer, 1999). If screening during pregnancy is necessary, threshold values for free protein S antigen levels in the second and third trimesters have been identified at <30 percent and <24 percent, respectively. Among those with a positive family history, the VTE risk in pregnancy is 6 to 7 percent (American College of Obstetricians and Gynecologists, 2017c).

Conard and coworkers (1990) described thrombosis in five of 29 pregnant women with protein S deficiency. They, as well as Burneo and colleagues (2002), reported maternal cerebral vein thrombosis. Neonatal homozygous protein C or S deficiency is usually associated with a fatal clinical phenotype known as purpura fulminans (Shanbhag, 2015).

Activated Protein C Resistance—Factor V Leiden Mutation

This is the most prevalent of the known thrombophilia syndromes and is characterized by resistance of plasma to the anticoagulant effects of activated protein C. There are several mutations that create this resistance, but the most common is the factor V Leiden mutation, which was named after the city in which it was described. This missense mutation in the factor V gene results from a substitution of glutamine for arginine at position 506 in the factor V polypeptide. As a result of this mutation, activated factor V is neutralized approximately tenfold more slowly by activated protein C (see Fig. 52-1). This leads to enhanced thrombin generation (MacCallum, 2014).

Heterozygous inheritance of factor V Leiden is the most common heritable thrombophilia. Found in 3 to 15 percent of select European populations and 3 percent of African Americans, it is virtually absent in African blacks and Asians (Lockwood, 2012). One theory for its relatively high prevalence suggests that the heterozygous state may confer a survival advantage, possibly because of reduced bleeding with childbirth or trauma (MacCallum, 2014).

Women who are heterozygous for factor V Leiden account for approximately 40 percent of VTE cases during pregnancy. However, the actual risk among pregnant women who are heterozygous and who do not have a personal history or a first-degree relative with a thrombotic episode before age 50 years is 5 to 12 events per 1000 gravidas (see Table 52-2). In contrast, this risk rises to at least 10 percent among pregnant women with a personal or family history. Pregnant women who are homozygous without a personal or family history have a 1- to 4-percent risk for VTE, whereas those with such a history have an approximately 17-percent risk (American College of Obstetricians and Gynecologists, 2017c).

Diagnosis during pregnancy is performed by DNA analysis for the mutant factor V gene. Bioassay is not used because of the normal resistance that develops after early pregnancy from alterations in other coagulation protein concentrations (Walker, 1997). Of note, activated protein C resistance can also be caused by antiphospholipid syndrome, which is described in Acquired Thrombophilias and also detailed in Chapter 59, Antiphospholipid Syndrome.

To assess the prognostic significance of maternal factor V Leiden mutation during pregnancy, Kjellberg and colleagues (2010) compared the outcomes of 491 carriers with those of 1055 controls. All three of the thromboembolic events occurred among the carriers. But, preterm birth rates, birthweights, or hypertensive complication rates did not differ between the two groups. In a prospective observational study of approximately 5000 women conducted by the Maternal-Fetal Medicine Units Network, the heterozygous mutant gene incidence was 2.7 percent (Dizon-Townson, 2005). Of three pulmonary emboli and one deep-vein thrombosis cases—a rate of 0.8 per 1000 pregnancies—none were among these carriers. Moreover, in the heterozygous women, the risks of preeclampsia, placental abruption, fetal-growth restriction, or pregnancy loss were not elevated. The investigators concluded that universal prenatal screening for the Leiden mutation and prophylaxis for carriers without a prior VTE is not indicated.

Prothrombin G20210A Mutation

This missense mutation in the prothrombin gene leads to excessive accumulation of prothrombin, which then may be converted to thrombin. Prothrombin levels are increased approximately 30 percent in heterozygotes and 70 percent in homozygotes (MacCallum, 2014). As with factor V Leiden, a personal or family history of VTE in a first-degree relative before age 50 years raises the risk of VTE during pregnancy (see Table 52-2). For a heterozygous carrier with such a history, the risk exceeds 10 percent. Without such a history, heterozygous carriers of the mutation have less than a 1-percent risk of VTE during pregnancy (American College of Obstetricians and Gynecologists, 2017c).

Silver and coworkers (2010) tested nearly 4200 women for the prothrombin G20210A mutation. A total of 157—or 3.8 percent—of the women carried the mutation, and only one of these was homozygous. Carriers had similar rates of pregnancy loss, preeclampsia, fetal-growth restriction, and placental abruption compared with noncarriers. Three thromboembolic events occurred in women who tested negative for the mutation.

Homozygous patients, or those who coinherit a G20210A mutation with a factor V Leiden mutation, have a greater thromboembolism risk than heterozygous carriers (Connors, 2017). Lim and associates (2016) have provided detailed information on pregnancy outcomes in women with such rare compound thrombophilias.

Hyperhomocysteinemia

The most common cause of elevated homocysteine is the C667T thermolabile mutation of the 5,10-methylene-tetrahydrofolate reductase (MTHFR) enzyme. Inheritance is autosomal recessive. Elevated homocysteine levels may also result from deficiency of one of several enzymes involved in methionine metabolism and from correctible nutritional deficiencies of folic acid, vitamin B₆, or vitamin B₁₂ (Hague, 2003). During normal pregnancy, mean homocysteine plasma concentrations decline (López-Quesada, 2003). Thus, to make a diagnosis during pregnancy, Lockwood (2002) recommends a fasting threshold >12 μmol/L to define hyperhomocysteinemia.

In an interesting metaanalysis, Den Heijer and associates (2005) found that international studies of MTHFR polymorphisms were collectively associated with slightly greater risks for thrombosis. In contrast, studies conducted in North America collectively demonstrated no such association. The authors speculated that folic acid supplementation could explain the difference. Recall that folic acid serves as a cofactor in the remethylation reaction of homocysteine to methionine. Similarly, the American College of Chest Physicians concluded that the lack of an association with thromboembolism could reflect the physiological reductions in homocysteine levels associated with pregnancy and the effects of widespread prenatal folic acid supplementation (Bates, 2012). The American College of Obstetricians and Gynecologists (2017c) has concluded that there is insufficient evidence to support assessment of MTHFR polymorphisms or measurement of fasting homocysteine levels in the evaluation for VTE.

Other Thrombophilia Mutations

Potentially thrombophilic polymorphisms are being discovered at an ever-increasing rate. Unfortunately, information regarding the prognostic significance of such newly discovered mutations is limited. For example, protein Z is a vitamin K-dependent protein that serves as a cofactor in factor Xa inactivation. Studies have found that low protein Z levels are associated with an elevated thromboembolism risk in nonpregnant patients and may be implicated in the pathogenesis of poor pregnancy outcomes (Almawi, 2013). Similarly, plasminogen activator inhibitor type 1 (PAI-1) is an important regulator of fibrinolysis. Certain polymorphisms in the gene promoter have been associated with slightly greater VTE risks. Although these thrombophilias may exacerbate risk among patients when coinherited with other thrombophilias, the American College of Obstetricians and Gynecologists (2017c) has concluded that evidence to recommend screening is insufficient.

As an interesting aside, Galanaud and coworkers (2010) hypothesized that a paternal thrombophilia could increase the risk of maternal thromboembolism. Specifically, these investigators found that a paternal thrombophilia—the PROCR 6936G allele—affects the endothelial protein C receptor. This receptor is expressed by villous trophoblast and thus is exposed to maternal blood. Although this research is preliminary, it could help explain the pathogenesis of recurrent idiopathic thromboses in pregnant women.

Acquired Thrombophilias

Some examples of acquired hypercoagulable states include antiphospholipid syndrome (APS), heparin-induced thrombocytopenia (Newer Agents), and cancer.

Antiphospholipid Syndrome

This prothrombotic disorder can affect both the venous and arterial circulations. The deeper veins of the lower limbs and the cerebral arterial circulation are the most frequent sites of venous and arterial thrombosis, respectively (Connors, 2017; Giannakopoulos, 2013). Besides thrombosis, the other major clinical manifestations of the APS are obstetrical (Table 18-5). Criteria include: (1) at least one otherwise unexplained fetal death at or beyond 10 weeks; (2) at least one preterm birth before 34 weeks’ gestation because of eclampsia, severe preeclampsia, or placental insufficiency; or (3) at least three unexplained consecutive spontaneous abortions before 10 weeks.

Once one of the above clinical criteria—thrombosis or obstetrical—is met, antiphospholipid antibody testing should be performed to diagnose APS. These patients should be tested for the presence of three factors: (1) lupus anticoagulant, (2) anticardiolipin immunoglobulin G and M (IgG and IgM) antibodies, and (3) anti-β₂-glycoprotein I IgG and IgM antibodies. If any of these laboratory test results are positive, a confirmatory test is performed 12 weeks later (Connors, 2017).

Based on their study of 750 singleton pregnancies complicated by APS, Saccone and associates (2017) found that anticardiolipin antibody is the most common sole antiphospholipid antibody present; but anti-β₂-glycoprotein I is associated with the lowest live birth rate and highest incidences of preeclampsia, fetal-growth restriction, and stillbirth compared with anticardiolipin antibodies or lupus anticoagulant alone. These investigators also observed that despite therapy with low-dose aspirin and prophylactic LMWH heparin, the chance of a liveborn neonate was only 30 percent for women with positive test results for all three antibodies.

The thrombosis risk rises significantly during pregnancy in women with APS. Indeed, up to 25 percent of thrombotic events in women with APS occur during pregnancy or in the puerperium. Looking at this a different way, women with APS have a 5- to 12-percent risk of thrombosis during pregnancy or the puerperium (American College of Obstetricians and Gynecologists, 2017a). This syndrome is discussed in more detail in Chapter 59 (Antiphospholipid Syndrome).

Thrombophilias and Pregnancy Complications

Attention has been directed toward possible relationships between inherited thrombophilias and pregnancy complications other than thromboses. Summarized in Table 52-3 are the findings of 25 studies systematically reviewed by Robertson and associates (2005) and incorporated into the recommendations of the American College of Chest Physicians (Bates, 2012). Importantly, the considerable heterogeneity and wide confidence intervals illustrate the uncertainty of these associations.

Other investigations underscore the heterogeneity of results. For example, Kahn and coworkers (2009) found no higher risk for early-onset or severe preeclampsia in women with factor V Leiden mutation, prothrombin G20210A mutation, MTHFR C677T polymorphism, or hyperhomocysteinemia. Said and associates (2010a) prospectively screened more than 2000 healthy nulliparous women for factor V Leiden, prothrombin gene mutation, MTHFR C677T, MTHFR A1298C, and thrombomodulin polymorphism. Women who carried the prothrombin gene mutation had a 3.6-fold greater risk of adverse pregnancy outcome, including severe preeclampsia, fetal-growth restriction, placental abruption, or stillbirth. But, none of the other polymorphisms conferred an elevated risk of these adverse outcomes. From the Stillbirth Collaborative Research Network, Silver and associates (2016) found a weak association between maternal factor V Leiden and stillbirth. There was no association between stillbirth and the other inherited thrombophilias. Based on their prospective study of 750 pregnancies complicated by stillbirth, Korteweg and colleagues (2010) concluded that routine thrombophilia testing after fetal death is inadvisable.

The American College of Obstetricians and Gynecologists (2017c) notes that a definitive causal link cannot be made between inherited thrombophilias and adverse pregnancy outcomes. Moreover, in one randomized trial, Rodger and associates (2014) found that antepartum prophylactic LMWH did not reduce a composite outcome of pregnancy loss, severe or early-onset preeclampsia, small-for-gestational age neonates, and VTE in thrombophilic women.

Thus, because of uncertainties in the magnitude of risk and in the benefits of prophylaxis given to prevent pregnancy complications in women with heritable thrombophilias, it remains unproven that universal screening is indicated (Louis-Jacques, 2016). In contrast, the association between APS and adverse pregnancy outcomes—including fetal loss, recurrent pregnancy loss, and preeclampsia—is much stronger.

Thrombophilia Screening

Given the relatively high incidence of thrombophilia in the population and the low incidence of VTE, universal screening during pregnancy is not cost effective (Carbone, 2010). Thus, a selective screening strategy is required. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) recommend that thrombophilia screening be considered in the following clinical circumstances: (1) a personal history of VTE that was associated with a nonrecurrent risk factor such as fractures, surgery, and/or prolonged immobilization; and (2) a first-degree relative (parent or sibling) with a history of high-risk thrombophilia or VTE before age 50 years in the absence of other risk factors.

The American College of Obstetricians and Gynecologists (2017c) notes that testing for inherited thrombophilias in women who have experienced recurrent fetal loss or placental abruption is not recommended because clinical evidence that antepartum heparin prophylaxis prevents recurrence is insufficient. Similarly, testing is not recommended for women with a history of fetal-growth restriction or preeclampsia. The American College of Chest Physicians also recommends against screening women with prior pregnancy complications (Bates, 2012). However, screening for antiphospholipid antibodies may be appropriate in women who have experienced a fetal loss or early-onset preeclampsia (Berks, 2015).

Methods of screening for the more common inherited thrombophilias are shown in Table 52-4. Whenever possible, laboratory testing is performed at least 6 weeks after the thrombotic event, while the patient is not pregnant, and when she is not receiving anticoagulation or hormonal therapy. Screening for hyperhomocysteinemia is not recommended (American College of Obstetricians and Gynecologists, 2017c).

Clinical Presentation

During pregnancy, most venous thromboses are confined to the deep veins of the lower extremity. Approximately 70 percent of cases are located in the iliofemoral veins without involvement of the calf veins. Isolated iliac vein and calf vein thromboses occur in approximately 17 and 6 percent of cases, respectively (Chan, 2010). In contrast, in the general population, more than 80 percent of deep-vein thromboses involve calf veins, and iliofemoral or isolated iliac vein thromboses are uncommon (Huisman, 2015).

The signs and symptoms vary greatly and depend on the degree of occlusion and the intensity of the inflammatory response. Ginsberg and coworkers (1992) reported that 58 of 60 antepartum women—97 percent—had left leg thromboses. Blanco-Molina and coworkers (2007) reported left-leg involvement in 78 percent. Greer (2003) hypothesizes that this results from compression of the left iliac vein by the right iliac and ovarian artery, both of which cross the vein only on the left side. Yet, as described in Chapter 53 (Urinary Tract Infections), the ureter is compressed more on the right side.

Classically, thrombosis involving the lower extremity is abrupt in onset, and there is pain and edema of the leg and thigh. The thrombus typically involves much of the deep-venous system to the iliofemoral region. Occasionally, reflex arterial spasm causes a pale, cool extremity with diminished pulsations. Alternatively, there may be appreciable clot, yet little pain, heat, or swelling. Importantly, calf pain, either spontaneous or in response to squeezing or to Achilles tendon stretching—Homans sign—may be caused by a strained muscle or contusion. Between 30 and 60 percent of women with a confirmed lower-extremity acute deep-vein thrombosis have an asymptomatic pulmonary embolism (Superficial Venous Thrombophlebitis).

Diagnosis

Clinical diagnosis of deep-vein thrombosis is difficult, and in an earlier study of pregnant women, the clinical diagnosis was confirmed in only 10 percent (Hull, 1990). Another challenge is that many of the common diagnostic tests that have been investigated extensively in nonpregnant patients have not been validated appropriately in pregnancy (Huisman, 2015). Shown in Figure 52-2 is one diagnostic algorithm recommended by the American College of Chest Physicians that can be used for evaluation of pregnant women (Guyatt, 2012). With a few modifications, we follow a similar evaluation at Parkland Hospital.

Compression Ultrasonography

In pregnant women with suspected deep-vein thrombosis, the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) recommend compression ultrasonography of the proximal veins as the initial diagnostic test. According to the American College of Chest Physicians, this noninvasive technique is currently the most-used first-line test to detect deep-vein thrombosis (Guyatt, 2012). The diagnosis is based on the noncompressibility and typical echoarchitecture of a thrombosed vein.

For nonpregnant patients with suspected thrombosis, the safety of withholding anticoagulation for 1 week has been established for those who have a compression ultrasound examination that is initially normal (Birdwell, 1998; Heijboer, 1993). Serial compression examinations are then performed because isolated undetected calf thromboses that ultimately extend into the proximal veins will do so within 1 to 2 weeks of presentation in approximately a fourth of patients.

In pregnant women, the important caveat is that normal findings with venous ultrasonography do not always exclude a pulmonary embolism. This is because the thrombosis may have already embolized or because it arose from iliac or other deep-pelvic veins, which are less accessible to ultrasound evaluation (Goldhaber, 2004). As discussed, thrombosis associated with pulmonary embolism during pregnancy commonly originates in the iliac veins.

The results of two studies are helpful for evaluating the need for serial examinations in pregnant women suspected of having a deep-vein thrombosis but who have a negative initial compression ultrasound examination. The combined results are depicted in Figure 52-3. Chan and coworkers (2013) studied 221 pregnant and postpartum women presenting with a suspected deep-vein thrombosis. The 205 women with a negative initial study result underwent serial testing, which was negative in all cases. Of these, one woman with normal serial testing had a pulmonary embolism 7 weeks later. Le Gal and colleagues (2012) studied 210 pregnant and postpartum women with a suspected deep-vein thrombosis. Of these, 177 women without a deep-vein thrombosis were not anticoagulated and did not undergo serial testing. Two had an objectively confirmed thrombosis diagnosed within 3 months. In sum, these preliminary data suggest that a negative single complete compression ultrasonography study may safely exclude the diagnosis of deep-vein thrombosis in most pregnant women.

Magnetic Resonance Imaging

This imaging technique allows excellent delineation of anatomical detail above the inguinal ligament. Thus, in many cases, magnetic resonance (MR) imaging is immensely useful for diagnosis of iliofemoral and pelvic vein thrombosis. The venous system can also be reconstructed using MR venography (Chap. 46, Imaging During Pregnancy). Erdman and associates (1990) reported that MR imaging was 100-percent sensitive and 90-percent specific for detection of venographically proven deep-vein thrombosis in nonpregnant patients. Importantly, almost half of those without deep-vein thrombosis were found to have nonthrombotic conditions that included cellulitis, myositis, edema, hematomas, and superficial phlebitis.

Khalil and coworkers (2012) used MR venography to study the natural history of pelvic vein thrombosis after vaginal delivery. Among the 30 asymptomatic patients who were all within four days of delivery, 30 percent had a definitive thrombosis in either the iliac or ovarian veins, and another 37 percent had a suspected thrombosis. Our experiences with hundreds of postpartum MR scans do not support these findings. Thus, although the clinical significance of their findings is uncertain, it seems clear that some degree of pelvic vein intraluminal filling defect may be a normal finding.

d-Dimer Screening Tests

These specific fibrin degradation products are generated when fibrinolysin degrades fibrin, as occurs in thromboembolism (Chap. 41, Pregnancy-Induced Coagulation Changes). Their measurement is frequently incorporated into diagnostic algorithms for VTE in nonpregnant patients (Wells, 2003). Screening with the d-dimer test in pregnancy, however, is problematic for several reasons. As shown in the Appendix (Serum and Blood Constituents), depending on assay sensitivity, d-dimer serum levels rise with gestational age along with substantively elevated plasma fibrinogen concentrations (Murphy, 2015). Levels are also affected by multifetal gestation and cesarean delivery (Morikawa, 2011). d-Dimer concentrations can also be elevated in certain pregnancy complications such as placental abruption, preeclampsia, and sepsis syndrome. Moreover, higher levels have been observed in sickle-cell carriers and in women of African and South Asian racial origin (Grossman, 2016). For all these reasons, their use during pregnancy remains uncertain, but a negative d-dimer test should be considered reassuring (Lockwood, 2012; Marik, 2008).

Management

Optimal management of VTE during pregnancy has not undergone major clinical study to provide evidence-based practices. There is, however, consensus for treatment with anticoagulation and limited activity. If thrombophilia testing is performed, it is done before anticoagulation. Heparin induces a decline in antithrombin levels, and warfarin lowers protein C and S concentrations. The results of these tests do not change treatment (Connors, 2017).

Anticoagulation is initiated with either unfractionated heparin (UFH) or LMWH. Although either type is acceptable, most recommend one of the LMWHs (Bates, 2016; Kearon, 2016). For example, the American College of Chest Physicians suggests preferential use of LMWH during pregnancy because of better bioavailability, longer plasma half-life, more predictable dose response, reduced risks of osteoporosis and thrombocytopenia, and less frequent dosing (Bates, 2012). Dosages are shown in Table 52-5.

During pregnancy, heparin therapy is continued, and for postpartum women, anticoagulation is begun simultaneously with warfarin. Recall that pulmonary embolism develops in as many as 60 percent of patients with untreated venous thrombosis, and anticoagulation decreases this risk to less than 5 percent. In nonpregnant patients, the mortality rate with a pulmonary embolism approximates 1 percent (Douketis, 1998; Pollack, 2011).

Over several days, leg pain dissipates. After symptoms have abated, graded ambulation is begun. Elastic stockings are fitted, and anticoagulation is continued. Recovery to this stage usually takes 7 to 10 days. Graduated compression stockings are continued for 2 years after the diagnosis to reduce the incidence of postthrombotic syndrome (Brandjes, 1997). This syndrome can include chronic leg paresthesias or pain, intractable edema, skin changes, and leg ulcers.

Unfractionated Heparin

This agent should be considered for the initial treatment of thromboembolism and in situations in which delivery, surgery, or thrombolysis may be necessary (American College of Obstetricians and Gynecologists, 2017b). Unfractionated heparin can be administered by one of two alternatives: (1) initial intravenous therapy followed by adjusted-dose subcutaneous UFH given every 12 hours; or (2) twice-daily, adjusted-dose subcutaneous UFH with doses adjusted to prolong the activated partial thromboplastin time (aPTT) into the therapeutic range 6 hours postinjection (Bates, 2012). As shown in Table 52-5, the therapeutic dose for subcutaneous UFH is usually 10,000 units or more every 12 hours.

For intravenous therapy, several protocols are acceptable. In general, if UFH is used, it is initiated with a bolus intravenous dose of 70 to 100 U/kg, which is 5000 to 10,000 U. This is followed by continuous intravenous infusions beginning at 1000 U/hr or 15 to 20 U/kg/hr. This infusion rate is titrated to achieve an aPTT 1.5 to 2.5 times control values (Brown, 2010; Linnemann, 2016). Intravenous anticoagulation is maintained for at least 5 to 7 days, after which treatment is converted to subcutaneous heparin to maintain the aPTT to at least 1.5 to 2.5 times control throughout the dosing interval. For women with lupus anticoagulant, aPTT does not accurately assess heparin anticoagulation, and thus anti-factor Xa levels are preferred.

The duration of full anticoagulation varies, and no studies have defined the optimal duration for pregnancy-related thromboembolism. In nonpregnant patients with VTE, evidence supports a minimum treatment duration of 3 months (Kearon, 2012). For pregnant patients, the American College of Chest Physicians recommends anticoagulation throughout pregnancy and postpartum for a minimum total duration of 3 months (Bates, 2012). Lockwood (2012) recommends that full anticoagulation be continued for at least 20 weeks followed by prophylactic doses if the woman is still pregnant. Prophylactic doses of subcutaneous UFH can range from 5000 to 10,000 U every 12 hours titrated to maintain an anti-factor Xa level of 0.1 to 0.2 U/mL, measured 6 hours after the last injection. If the VTE occurs during the postpartum period, Lockwood (2012) recommends a minimum of 6 months of anticoagulation treatment.

Low-Molecular-Weight Heparin

This is a family of derivatives of unfractionated heparin, and their molecular weights average 4000 to 5000 daltons compared with 12,000 to 16,000 daltons for conventional heparin. None of these heparins cross the placenta, and all exert their anticoagulant activity by activating antithrombin. The primary difference is their relative inhibitory activity against factor Xa and thrombin. Specifically, UFH has equivalent activity against factor Xa and thrombin, but LMWHs have greater activity against factor Xa than against thrombin. They also have a more predictable anticoagulant response and fewer bleeding complications than UFH because of their better bioavailability, longer half-life, dose-independent clearance, and decreased interference with platelets (Tapson, 2008). These LMWH compounds are cleared by the kidneys and must be used cautiously when there is renal dysfunction.

Several studies have shown that VTE is treated effectively with LMWH (Quinlan, 2004; Tapson, 2008). Using serial venograms, Breddin and associates (2001) observed that these compounds were more effective than UFH in reducing thrombus size without increasing mortality rates or major bleeding complications. Several different treatment regimens using adjusted-dose LMWH for treatment of acute VTE are recommended by the American College of Obstetricians and Gynecologists (2017b,c) and are listed in Table 52-5.

Pharmacokinetics in Pregnancy

LMWHs available for use in pregnancy include enoxaparin, tinzaparin, and dalteparin. Enoxaparin (Lovenox) pharmacokinetics were studied in 36 women with VTE during pregnancy or immediately postpartum (Rodie, 2002). The dose was approximately 1 mg/kg given twice daily based on early pregnancy weight. Treatment was monitored by peak anti-factor Xa activity at 3 hours postinjection, with a target therapeutic range of 0.4 to 1.0 U/mL. In 33 women, enoxaparin provided satisfactory anticoagulation. In the other three women, dose reduction was necessary. None developed recurrent thromboembolism or bleeding complications. In postcesarean women with a body mass index (BMI) ≥35, Stephenson and associates (2016) found that weight-based dosing of enoxaparin 0.5 mg/kg twice daily more effectively achieved prophylactic peak anti-Xa levels between 0.2 to 0.6 U/mL than a fixed dose of 40 mg daily. Similar findings were reported by Overcash and colleagues (2015).

For tinzaparin (Innohep), a dosage of 75 to 175 U/kg/d was necessary to achieve peak anti-factor Xa levels of 0.1 to 1.0 U/mL (Smith, 2004). In studies of dalteparin (Fragmin) pharmacokinetics, conventional starting doses of dalteparin—100 U/kg every 12 hours—were likely insufficient to maintain full anticoagulation (Barbour, 2004; Jacobsen, 2003). Thus, slightly higher doses than that shown in Table 52-5 may be required.

Dosing and Monitoring

Standard prophylactic and therapeutic dosages recommended by the American College of Obstetricians and Gynecologists (2017b) for various LMWHs are listed in Table 52-5. Whether such dosages require adjustments during the course of pregnancy is controversial (Berresheim, 2014; Cutts, 2013). Some suggest periodic measurement of anti-factor Xa levels 4 to 6 hours after an injection with dose adjustment to maintain a therapeutic level. Large studies using clinical end points that demonstrate an optimal therapeutic range or show that dose adjustments increase therapy safety or efficacy are lacking. Accordingly, the American College of Chest Physicians and others note that routine monitoring with anti-Xa levels is difficult to justify (Bates, 2012; McDonnell, 2017).

Safety in Pregnancy

Early reviews concluded that LMWHs were safe and effective (Lepercq, 2001; Sanson, 1999). Despite this, in 2002, the manufacturer of Lovenox warned that its use in pregnancy had been associated with congenital anomalies and a higher risk of hemorrhage. After its own extensive review, the American College of Obstetricians and Gynecologists (2017b) concluded that these risks were rare, that their incidence was not higher than expected, and that no cause-and-effect relationship had been established. It further concluded that enoxaparin and dalteparin could be given safely during pregnancy. Other reports confirm their safety (Andersen, 2010; Bates, 2012; Galambosi, 2012).

Nelson-Piercy and coworkers (2011) assessed the safety of tinzaparin through a comprehensive study of 1267 treated pregnant women. There were no maternal deaths or complications from regional analgesia. Although thrombocytopenia developed in 1.8 percent, there were no cases of heparin-induced thrombocytopenia (Newer Agents). The allergy incidence was 1.3 percent. Osteoporotic fractures in three women (0.2 percent) were judged to be related to tinzaparin (Newer Agents). A total of 43 women (3.4 percent) required medical intervention for bleeding. Of 15 stillbirths, four were judged as possibly being related to tinzaparin use. But, none of the neonatal deaths or congenital abnormalities was attributed to tinzaparin. The authors concluded that tinzaparin during pregnancy was safe for mother and fetus. LMWHs are also safe during breastfeeding (Lim, 2010).

However, LMWHs should be avoided in women with renal failure. Moreover, when given within 2 hours of cesarean delivery, these agents raise the risk of wound hematoma (van Wijk, 2002).

Labor and Delivery

Women receiving either therapeutic or prophylactic anticoagulation should be converted from LMWH to the shorter half-life UFH in the last month of pregnancy or sooner if delivery appears imminent. The purpose of conversion to UFH has less to do with any risk of maternal bleeding at the time of delivery, but rather with neuraxial blockade complicated by an epidural or spinal hematoma (Chap. 25, Safety). The American College of Chest Physicians recommends that women scheduled for a planned delivery who are receiving twice-daily adjusted-dose subcutaneous UFH or LMWH discontinue their heparin 24 hours before labor induction or cesarean delivery (Bates, 2012). Patients receiving once-daily LMWH should take only 50 percent of their normal dose on the morning of the day before delivery. The American College of Obstetricians and Gynecologists (2017c) advises that adjusted-dose subcutaneous LMWH or UFH can be discontinued 24 to 36 hours before an induction of labor or scheduled cesarean delivery. The American Society of Regional Anesthesia and Pain Medicine advises withholding neuraxial blockade for 10 to 12 hours after the last prophylactic dose of LMWH or 24 hours after the last therapeutic dose (Horlocker, 2010).

If a woman begins labor while taking UFH, clearance can be verified by an aPTT. Reversal of heparin with protamine sulfate is rarely required and is not indicated with a prophylactic dose of heparin. For women in whom anticoagulation therapy has temporarily been discontinued, pneumatic compression devices are recommended.

Anticoagulation with Warfarin Compounds

Vitamin K antagonists are generally contraindicated because they readily cross the placenta and may cause fetal death and malformations from hemorrhages (Chap. 12, Warfarin). They do not accumulate in breast milk and are thus safe during breastfeeding.

Postpartum venous thrombosis is usually treated with intravenous heparin and oral warfarin initiated simultaneously. The initial dose of warfarin is usually 5 to 10 mg for the first 2 days. Subsequent doses are titrated to achieve an international normalized ratio (INR) of 2 to 3. To avoid paradoxical thrombosis and skin necrosis from the early anti-protein C effect of warfarin, these women are maintained on therapeutic doses of UFH or LMWH for 5 days and until the INR is in a therapeutic range for 2 consecutive days (American College of Obstetricians and Gynecologists, 2017c; Stewart, 2010).

Treatment in the puerperium may require larger doses of anticoagulant. Brooks and colleagues (2002) compared anticoagulation in postpartum women with that of age-matched nonpregnant controls. The former required a significantly larger median total dose of warfarin—45 versus 24 mg—and a longer time—7 versus 4 days—to achieve the target INR.

Newer Agents

Of newer oral anticoagulants, dabigatran (Pradaxal) inhibits thrombin. Rivaroxaban (Xarelto) and apixaban (Eliquis) inhibit factor Xa. Currently, very few reports address these newer agents during pregnancy, and thus the human reproductive risks are essentially unknown (Bates, 2012). Dabigatran crosses the human placenta (Bapat, 2014). However, it is unknown whether any of these agents are excreted in breast milk. Because of the potential for infant harm, a decision should be made to either avoid breastfeeding or use an alternative anticoagulant, such as warfarin, in postpartum women (Burnett, 2016).

Complications of Anticoagulation

Three significant complications associated with anticoagulation are hemorrhage, thrombocytopenia, and osteoporosis. The latter two are unique to heparin, and their risk may be reduced with LMWHs. The most serious complication is hemorrhage, which is more likely if there has been recent surgery or lacerations. Troublesome bleeding also is more likely if the heparin dosage is excessive. Unfortunately, management schemes using laboratory testing to identify when a heparin dosage is sufficient to inhibit further thrombosis, yet not cause serious hemorrhage, have been discouraging.

Heparin-Induced Thrombocytopenia

There are two types—the most common is a nonimmune, benign, reversible thrombocytopenia that develops within the first few days of therapy and resolves in approximately 5 days without therapy cessation. The second is the severe form of heparin-induced thrombocytopenia (HIT), which results from an immune reaction involving IgG antibodies directed against complexes of platelet factor 4 and heparin. The diagnosis of HIT is based on a drop in the platelet count of more than 50 percent or thrombosis beginning 5 to 10 days after the start of heparin in association with the appearance of platelet-activating HIT antibodies. The fall in platelet count in HIT occurs rapidly—over a period of 1 to 3 days—and is assessed relative to the highest platelet count after the start of heparin. The typical nadir is 40,000 to 80,000 platelets per microliter (Greinacher, 2015).

Although the incidence of HIT is approximately 3 to 5 percent in nonpregnant individuals, it is <0.1 percent in obstetrical patients (Linkins, 2012). Fausett and coworkers (2001) reported no cases among 244 heparin-treated gravidas compared with 10 among 244 nonpregnant patients. Accordingly, the American College of Chest Physicians recommends against platelet count monitoring when the risk of HIT is considered to be less than 1 percent. In others, they suggest monitoring every 2 or 3 days from day 4 until day 14 (Linkins, 2012).

When HIT is diagnosed, heparin therapy is stopped and alternative anticoagulation initiated. Platelet transfusions are avoided (Greinacher, 2015). LMWH may not be entirely safe because it has some cross reactivity with UFH. The American College of Chest Physicians recommends danaparoid (Orgaran)—a sulfated glycosaminoglycan heparinoid (Bates, 2012; Linkins, 2012). In a review of nearly 50 pregnant women with either HIT or a skin rash, Lindhoff-Last and associates (2005) concluded that danaparoid was a reasonable alternative. However, they reported two fatal maternal hemorrhages and three fetal deaths. Magnani (2010) reviewed case reports of 83 pregnant women treated with danaparoid. Although it was generally effective, two patients died related to bleeding, three patients suffered nonfatal major bleeds, and three women developed thromboembolic events unresponsive to danaparoid. The drug has been removed from the U.S. market.

Other agents are fondaparinux (Arixtra)—a pentasaccharide factor Xa inhibitor and argatroban (Novastan)—a direct thrombin inhibitor (Kelton, 2013; Linkins, 2012). Successful use in pregnancy has been reported (Elsaigh, 2015; Knol, 2010). Tanimura and coworkers (2012) successfully used argatroban, and later fondaparinux, to manage HIT in a pregnant woman with hereditary antithrombin deficiency.

Heparin-Induced Osteoporosis

Bone loss may develop with long-term heparin administration—usually 6 months or longer—and is more prevalent in cigarette smokers. UFH can cause osteopenia, and this is less likely with LMWHs (Deruelle, 2007). Women treated with any heparin should be encouraged to take an oral daily 1500-mg calcium supplement (Cunningham, 2005; Lockwood, 2012). In one study, Rodger and colleagues (2007) found that long-term use of dalteparin for a mean of 212 days was not associated with a significant decline in bone mineral density.

Anticoagulation and Abortion

The treatment of deep-vein thrombosis with heparin does not preclude pregnancy termination by careful curettage. After the products are removed without trauma to the reproductive tract, full-dose heparin can be restarted in several hours.

Anticoagulation and Delivery

The effects of heparin on blood loss at delivery depend on several variables: (1) dose, route, and timing of administration; (2) number and depth of incisions and lacerations; (3) intensity of postpartum myometrial contractions; and (4) presence of other coagulation defects. Blood loss should not be greatly increased with vaginal delivery if the episiotomy is modest in depth, there are no lacerations, and the uterus promptly contracts. Unfortunately, such ideal circumstances do not always prevail. For example, Mueller and Lebherz (1969) described 10 women with antepartum thrombophlebitis treated with heparin. Three women who continued to receive heparin during labor and delivery bled remarkably and developed large hematomas. Thus, heparin therapy generally is stopped during labor and delivery. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) recommend restarting UFH or LMWH no sooner than 4 to 6 hours after vaginal delivery or 6 to 12 hours after cesarean delivery. We wait at least 24 hours to restart therapy after cesarean delivery or after vaginal delivery with significant lacerations.

Slow intravenous administration of protamine sulfate generally reverses the effect of heparin promptly and effectively. It should not be given in excess of the amount needed to neutralize the heparin, because it also has an anticoagulant effect.

Thrombosis limited strictly to the superficial veins of the saphenous system is treated with analgesia, elastic support, heat, and rest. If it does not soon subside or if deep-vein involvement is suspected, appropriate diagnostic measures are performed. Superficial vein thrombosis raises the risk of deep-vein thrombosis four- to sixfold. Heparin is given if deep-vein involvement is confirmed (Roach, 2013). Superficial thrombophlebitis is typically seen in association with varicosities or as a sequela of an indwelling intravenous catheter.

Although it causes approximately 10 percent of maternal deaths, pulmonary embolism is relatively uncommon during pregnancy and the puerperium. The incidence averages 1 in 7000 pregnancies. According to Marik and Plante (2008), 70 percent of gravidas presenting with a pulmonary embolism have associated clinical evidence of deep-vein thrombosis. And recall that between 30 and 60 percent of women with a deep-vein thrombosis will have a coexisting silent pulmonary embolism.

Clinical Presentation

In almost 2500 nonpregnant patients with a proven pulmonary embolism, symptoms included dyspnea in 82 percent, chest pain in 49 percent, cough in 20 percent, syncope in 14 percent, and hemoptysis in 7 percent (Goldhaber, 1999). Pollack and coworkers (2011) found similar symptoms. Other predominant clinical findings typically include tachypnea, apprehension, and tachycardia. In some cases, an accentuated pulmonic closure sound, rales, and/or friction rub is heard.

Right axis deviation and T-wave inversion in the anterior chest leads may be evident on the electrocardiogram. In at least 40 percent, chest radiography results are normal. In others, nonspecific findings may include atelectasis, an infiltrate, cardiomegaly, or an effusion (Pollack, 2011). Vascular markings in the lung region supplied by the obstructed artery can be lost. Although most women are hypoxemic, a normal arterial blood gas analysis does not exclude pulmonary embolism. Approximately a third of young patients have Po₂ values >80 mm Hg. Thus, the alveolar-arterial oxygen tension difference is a more useful indicator of disease. More than 86 percent of patients with acute pulmonary embolism will have an alveolar-arterial difference >20 mm Hg (Lockwood, 2012). Even with massive pulmonary embolism, signs, symptoms, and laboratory data to support the diagnosis may be deceptively nonspecific.

Massive Pulmonary Embolism

This is defined as embolism causing hemodynamic instability (Tapson, 2008). Acute mechanical obstruction of the pulmonary vasculature causes increased vascular resistance and pulmonary hypertension followed by acute right ventricular dilation. In otherwise healthy patients, significant pulmonary hypertension does not develop until 60 to 75 percent of the pulmonary vascular tree is occluded (Guyton, 1954). Moreover, circulatory collapse requires 75- to 80-percent obstruction. This is depicted schematically in Figure 52-4 and emphasizes that most acutely symptomatic emboli are large and likely a saddle embolism. These are suspected when the pulmonary artery pressure is substantively increased as estimated by echocardiography.

If there is evidence of right ventricular dysfunction, the mortality rate approaches 25 percent. This compares with a 1-percent rate without such dysfunction (Kinane, 2008). It is important in these cases to infuse crystalloids carefully and to support blood pressure with vasopressors. As discussed in Management, oxygen treatment, endotracheal intubation, and mechanical ventilation are completed preparatory to thrombolysis, filter placement, or embolectomy (Tapson, 2008).

Diagnosis

In most cases, recognition of a pulmonary embolism requires a high index of suspicion that prompts objective evaluation. Exposure of the mother and fetus to ionizing radiation is a concern when investigating a suspected pulmonary embolism during pregnancy. However, this concern is largely overruled by the hazards of missing a potentially fatal diagnosis. Moveover, erroneously assigning a diagnosis of pulmonary embolism to a pregnant woman is also fraught with problems. It unnecessarily exposes the mother and fetus to the risks of anticoagulation treatment and will impact delivery plans, future contraception, and thromboprophylaxis during subsequent pregnancies. Therefore, investigations should aim at diagnostic certainty (Konstantinides, 2014).

In 2011, the American Thoracic Society and the Society of Thoracic Radiology developed an algorithm—shown in Figure 52-5 for the diagnosis of pulmonary embolism during pregnancy (Leung, 2011). In addition to compression ultrasonography, which was previously discussed (Deep-Vein Thrombosis), the algorithm includes computed-tomographic pulmonary angiography (CTPA) and ventilation-perfusion scintigraphy.

Computed Tomographic Pulmonary Angiography

Multidetector computed tomography with pulmonary angiography is currently the most commonly employed technique used for pulmonary embolism diagnosis in nonpregnant patients (Bourjeily, 2012; Pollack, 2011). The technique is described further in Chapter 46 (Computed Tomography), and an imaging example is shown in Figure 52-6. The estimated fetal radiation exposure averages 0.45 to 0.6 mGy. The estimated maternal breast dose is 10 to 70 mGy (Waksmonski, 2014).

Bourjeily and colleagues (2012) performed a follow-up study of 318 pregnant women who had a negative CTPA performed for a suspected pulmonary embolism. All were seen 3 months following their initial presentation or at 6 weeks postpartum. None of these women were subsequently diagnosed with a thromboembolism.

CTPA has many advantages, but we find that the higher resolution allows detection of previously inaccessible smaller distal emboli that have uncertain clinical significance. Similar observations have been reported by others (Anderson, 2007; Hall, 2009). Also, the hyperdynamic circulation and augmented plasma volume associated with pregnancy leads to a higher number of nondiagnostic studies compared with nonpregnant patients (Ridge, 2011; Scarsbrook, 2006).

Ventilation–Perfusion Scintigraphy—Lung Scan

This technique involves a small dose of radiotracer such as intravenously administered technetium-99m–macroaggregated albumin. There is negligible fetal and maternal breast radiation exposure—0.1 to 0.4 mGy. The scan may not provide a definite diagnosis because many other conditions can cause perfusion defects. Examples are pneumonia or local bronchospasm. Chan and coworkers (2002) found that a fourth of ventilation-perfusion scans in pregnant women were nondiagnostic. In these instances, CTPA is preferred (Tromeur, 2017).

To compare the performance of lung scintigraphy and CTPA, Revel and colleagues (2011) evaluated 137 pregnant women with suspected pulmonary embolism. The two modalities performed comparably and had no significant differences between the proportions of positive, negative, or indeterminate results. Specifically, the proportion of indeterminate results for both approximated 20 percent. By way of comparison, about a fourth of the nonpregnant population had indeterminate studies. The investigators attributed this difference to the younger age of the pregnant patients. Similarly, one systematic review concluded that both CTPA and lung scintigraphy seem appropriate for exclusion of pulmonary embolism during pregnancy (van Mens, 2017).

Intravascular Pulmonary Angiography

This requires catheterization of the right side of the heart and is considered the reference test for pulmonary embolism. With newer generation multidetector CT scanners, however, the role of invasive pulmonary angiography has been questioned. This is especially true given the higher radiation exposure for the fetus (Konstantinides, 2014; Kuriakose, 2010). Other detractions are that it can be time consuming, uncomfortable, and associated with dye-induced allergy and renal failure. Indeed, the procedure-related mortality rate approximates 1 in 200 (Stein, 1992). It is reserved for confirmation when less invasive tests are equivocal.

Management

Immediate treatment for pulmonary embolism is full anticoagulation similar to that for deep-vein thrombosis as discussed in Unfractionated Heparin. Several complementary procedures may be indicated.

Vena Caval Filters

The woman who has very recently suffered a pulmonary embolism and who must undergo cesarean delivery presents a particularly serious problem. Reversal of anticoagulation may be followed by another embolus, and surgery while fully anticoagulated frequently results in life-threatening hemorrhage or troublesome hematomas. In these cases, placement of a vena caval filter should be considered before surgery (Marik, 2008). Moreover, 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 treatment, a vena caval filter may also be indicated. Such filters can also be used following massive emboli in patients who are not candidates for thrombolysis (Deshpande, 2002).

The device is inserted through either the jugular or femoral vein and can be inserted during labor (Jamjute, 2006). Routine filter placement has no added advantage to heparin given alone (Decousus, 1998). Retrievable filters may be used as short-term protection and then removed 1 to 2 weeks later (Liu, 2012). From their systematic review, Harris and associates (2016) found that complication rates in pregnant women with vena caval filters are comparable to those in nonpregnant patients.

Thrombolysis

Compared with heparin, thrombolytic agents provide more rapid lysis of pulmonary clots and improvement of pulmonary hypertension (Tapson, 2008). Konstantinides and coworkers (2002) studied 256 nonpregnant patients receiving heparin for an acute submassive pulmonary embolism. They also were randomly assigned to a placebo or the recombinant tissue plasminogen activator alteplase. Those given the placebo had a threefold greater risk of death or treatment escalation compared with those given alteplase. Agnelli and associates (2002) performed a metaanalysis of trials involving 461 nonpregnant patients. They reported that the risk of recurrence or death was significantly lower in patients given thrombolytic agents and heparin compared with those given heparin alone—10 versus 17 percent. Importantly, however, there were five—2 percent—fatal bleeding episodes in the thrombolysis group and none in the heparin-only group.

In their review, Leonhardt and colleagues (2006) identified 28 reports of tissue plasminogen activator use during pregnancy. Ten cases were for thromboembolism. Complication rates were similar to those in nonpregnant patients, and the authors concluded that such therapy should not be withheld during pregnancy if indicated. However, Akazawa and Nishida (2017) reviewed 13 cases of systemic thrombolytic therapy administered during the first 48 hours after delivery. Blood transfusion was required in five of the eight cesarean deliveries, including three cases of hysterectomy and two cases of hematoma removal.

Embolectomy

Given the efficacy of thrombolysis and filters, surgical embolectomy is uncommonly indicated. Published experience with emergency embolectomy during pregnancy is limited to case reports (Colombier, 2015; Saeed, 2014). From their review, Ahearn and associates (2002) found that although the operative risk to the mother is reasonable, the stillbirth rate is 20 to 40 percent.

Most recommendations regarding thromboprophylaxis during pregnancy stem from consensus guidelines. In one review of guidelines for thromboprophylaxis in pregnancy, the authors concluded that there is a lack of overall agreement about which women should be offered thromboprophylaxis or offered testing for thrombophilias (Okoroh, 2012). Bates and associates (2016) also conducted a review of guidelines for obstetrically associated VTE. They summarized that evidence-based recommendations are based largely on observational studies and extrapolated from data in nonpregnant patients. Similarly, a Cochrane review concluded that evidence is insufficient for firm recommendations regarding thromboprophylaxis during pregnancy (Bain, 2014).

The confusion that has ensued has provided fertile ground for litigators. Cleary-Goldman and associates (2007) surveyed 151 fellows of the American College of Obstetricians and Gynecologists and reported that intervention without a clear indication is common. Table 52-6 lists several consensus recommendations for thromboprophylaxis. In some cases, more than one option is listed, thus illustrating the confusion that currently reigns.

Prior Venous Thromboembolism

In general, either antepartum surveillance or heparin prophylaxis is recommended for women with prior VTE but without a recurrent risk factor, including no known thrombophilia. The study by Tengborn and coworkers (1989), however, suggested that such management may not be effective. They reported outcomes in 87 pregnant Swedish women who had prior thromboembolic disease and were not tested for thrombophilias. Despite unfractionated heparin prophylaxis, which was usually 5000 U twice daily, three of 20 women (15 percent) developed antepartum recurrence. This compared with eight of 67 women (12 percent) not given heparin.

Brill-Edwards and colleagues (2000) prospectively studied 125 pregnant women with a single prior VTE. Antepartum heparin was not given, but anticoagulant therapy was given for 4 to 6 weeks postpartum. Six women had a recurrent venous thrombosis—three antepartum and three postpartum. There were no recurrences in the 44 women without a known thrombophilia or whose prior thrombosis was associated with a temporary risk factor. These findings imply that prophylactic heparin may not be required for these two groups of women. In contrast, and as shown in Table 52-6, women with a prior thrombosis in association with a thrombophilia or in the absence of a temporary risk factor generally should be given both antepartum and postpartum prophylaxis (Connors, 2017).

De Stefano and coworkers (2006) studied 1104 nonpregnant women who had a first-episode VTE before the age of 40 years. After excluding those with antiphospholipid antibodies, 88 women were identified who subsequently had a total of 155 pregnancies and who were not given antithrombotic prophylaxis. There were 19 women (22 percent) who had a subsequent pregnancy- or puerperium-related VTE. Of 20 women whose original thrombosis was associated with a transient risk factor—not including pregnancy or oral contraceptive use—there were no recurrences during pregnancy, but two during the puerperium. These data also suggest that for women with a prior VTE, antithrombotic prophylaxis during pregnancy could be tailored according to the circumstances of the original event.

It is important to emphasize that VTE may recur despite antithrombotic prophylaxis. Galambosi and associates (2014) studied 270 women during 369 pregnancies who had at least one previous VTE. A total of 28 women (10.4 percent) suffered a recurrent VTE. Twelve of these recurrences occurred early in pregnancy before the initiation of antithrombotic prophylaxis, and 16 occurred despite prophylactic use of LMWH.

Our practice at Parkland Hospital for many years for women with a history of prior VTE was to administer subcutaneous UFH, 5000 to 7500 units two to three times daily. With this regimen, the recurrence of documented deep-vein thrombosis embolization was rare. Beginning approximately 10 years ago, we have successfully used 40 mg enoxaparin given subcutaneously daily for thromboprophylaxis.

Cesarean Delivery

The risk for deep-vein thrombosis and especially for fatal thromboembolism rises manyfold in women following cesarean compared with that after vaginal delivery. When considering that a third of women giving birth in the United States yearly undergo cesarean delivery, pulmonary embolism is understandably a major cause of maternal mortality (Creanga, 2017). That said, the “lack of high quality data” described earlier by Bates and colleagues (2016) creates considerable variation in the current recommendations promulgated by the American College of Obstetricians and Gynecologists, the Royal College of Obstetricians, and the American College of Chest Physicians (Palmerola, 2016).

In 2011, the American College of Obstetricians and Gynecologists (2017b) recommended placement of pneumatic compression devices before cesarean delivery for all women not already receiving thromboprophylaxis. This recommendation was based primarily on consensus and expert opinion. For patients undergoing cesarean delivery with additional risk factors for thromboembolism, both pneumatic compression devices and UFH or LMWH may be recommended. The College stipulated that cesarean delivery in an emergency setting should not be delayed because of the time necessary to implement thromboprophylaxis. Implementation of this strategy by the Hospital Corporation of America, the largest for-profit obstetrical health care delivery system in the United States, was associated with a reduction in deaths from pulmonary embolism from 7 of 458,097 cesarean births to 1 of 465,880 cesarean births (Clark, 2011, 2014).

In 2016, the National Partnership for Maternal Safety published several consensus recommendations for the prevention of maternal VTE (D’Alton, 2016). These recommendations included expanded use of antenatal prophylaxis for women hospitalized 3 days or longer, expanded use of prophylaxis during and after vaginal delivery, and expanded use of pharmacological prophylaxis to most women after cesarean delivery. In response, Sibai and Rouse (2016) expressed concern that these new recommendations derive from sparse data of questionable applicability to obstetrical patients. They called for better quality evidence to measure the benefits, harms, and costs of increased pharmacological thromboprophylaxis. As aptly expressed by Macones (2017), “an intervention, such as increased postcesarean pharmacologic thromboprophylaxis, where there are legitimate concerns about efficacy and safety, requires a much higher degree of evidence before a national guideline is implemented.” We agree with these sentiments.