1. Chapter 41
Thromboembolic Disease in Pregnancy
Charles J. Lockwood, MD
Venous thromboembolism (VTE) is the leading cause of maternal centrations at term.5 Thus, pregnancy is associated with increased
mortality in the United States, accounting for almost 20% of preg- thrombin-generating potential, decreased endogenous anticoagulant
nancy-related deaths in the past decade.1 A retrospective cohort study effects, and impaired fibrinolysis.
of 268,525 patients over a 19-year period reported a prevalence of VTE The occurrence of VTE in pregnancy is also promoted by venous
of 1 per 1627 births; of these cases, 77% were deep venous thromboses stasis in the lower extremities resulting from compression of the infe-
(DVTs), and 23% were acute pulmonary emboli (PE).2 No antecedent rior vena cava and pelvic veins by the enlarging uterus, compression
history of VTE was present in 86% of these patients. Moreover, among of the left common iliac vein by the right iliac artery,8 and increases in
nonpregnant adults who have a fatal PE, 65% (95% confidence inter- deep vein capacitance caused by increased circulating levels of proges-
vals [CI], 40.8% to 84.6%) die within 1 hour after onset.3 These find- terone and local endothelial production of prostacyclin and nitric
ings underscore the need for a high index of suspicion, a sensitive and oxide.9,10
rapid diagnostic algorithm, and expeditious initiation of treatment in
pregnant women with suspected VTE.
Among pregnant women, 98.4% of DVTs are localized to the lower
Risk Factors Not Specific
extremities, with the left leg affected in 82% of cases.2 The occurrence to Pregnancy
of DVT is more common in the antepartum than in the postpartum Additional risk factors for VTE that may be more common in preg-
period (74% versus 26%; P < .001), with a mean gestational age at nancy include trauma, infection, obesity, severe proteinuria, and pro-
diagnosis of 16.8 ± 2.4 weeks. Nearly 50% of antepartum DVTs are longed bed rest. Maternal age greater than 35 years doubles the risk of
detected by 15 weeks, 38% between 16 and 30 weeks, and only 12% VTE in pregnancy.11 One study found that, among patients undergo-
after 30 weeks. In contrast, most PEs are diagnosed in the postpartum ing cesarean delivery who developed a PE, 36% were older than
period (60.5%) and are strongly associated with cesarean delivery 35 years of age, and 55% were obese (body mass index >29).12
(relative risk [RR], 30.3; P < .001).2 Antiphospholipid antibody (APA) syndrome is associated with a
1% to 5% risk of VTE in pregnancy and the puerperium despite
thromboprophylaxis.13,14 In a case-control study of 30 pregnant women
with VTE versus matched controls who were subsequently analyzed
Risk Factors for APA, the prevalence of these antibodies was substantially increased
in cases compared with controls (27% versus 3%; P = .026).15
Pregnancy Is a Prothrombotic State The presence of an inherited thrombophilic disorder also increases
Normally, VTE is a disease of aging, occurring in fewer than 1 of every the risk of VTE during pregnancy, particularly in the setting of a per-
10,000 healthy women before 40 years of age.4 However, the risk of sonal or strong family history. For example, the factor V Leiden (FVL)
VTE is increased sixfold in pregnancy. Pregnancy induces this pro- mutation is present in 40% of pregnant patients with VTE.16,17 However,
thrombotic state in a number of ways. Compared to nonpregnant because the prevalence of VTE in pregnancy is low (1/1600) and the
women of reproductive age, pregnancy is associated with increases of incidence of heterozygosity for FVL in European populations is high
20% to 1000% in plasma concentrations of fibrinogen; factors VII, (5%), the actual risk of VTE among gravidas who are without a per-
VIII, IX, X, and XII; and von Willebrand factor.5 In addition, activity sonal history of VTE or an affected first-degree relative is less than
of the anticoagulant factor, protein S, declines, on average, to 39% of 0.2% to 0.3%.16,17 With such a history, the risk of VTE in the antepar-
normal in the second trimester and 31% of normal in the third trimes- tum or postpartum period is greater than 10%. Similar observations
ter.6 As a consequence, pregnancy is associated with an increase in have been made for the other common inherited thrombophilias (see
resistance to activated protein C. The net effect of these changes is an Chapter 40 and Table 41-1).
increase in thrombin generation, as measured by increased levels of The presence of a thrombophilia can also affect the recurrence risk
fibrinopeptide A and the thrombin-antithrombin complex.7 Protein S for VTE among pregnant women. Brill-Edwards and colleagues pro-
levels drop even further after cesarean delivery or infection, helping to spectively followed 125 pregnant women with a prior VTE, 95 of
account for the high prevalence of PE after cesarean deliveries. Levels whom were tested for thrombophilias, including FVL; the prothrom-
of plasminogen activator inhibitor 1 (PAI-1), which inhibits clot lysis, bin G20210A gene mutation (PGM); protein C, protein S, and anti-
increase threefold to fourfold during pregnancy, whereas plasma thrombin deficiencies; and the APAs, anticardiolipin antibodies, and
PAI-2 values, which are negligible before pregnancy, reach high con- lupus anticoagulant.23 The authors withheld antepartum thrombopro-

2. 856 CHAPTER 41 Thromboembolic Disease in Pregnancy
TABLE 41-1 INHERITED THROMBOPHILIAS AND THEIR ASSOCIATION WITH VENOUS
THROMBOEMBOLISM IN PREGNANCY
Probability of VTE Probability of VTE
% Thrombophilia Relative Risk in Patients without with a Personal or
% VTE in in European or Odds Ratio Personal or Family Strong Family
Thrombophilia Pregnancy Populations (95% CI) History of VTE (%) History of VTE (%) References
FVL (homozygous) <1 0.06+ 25.4 [8.8-66] 1.5 17 16-19
FVL (heterozygous) 40-44 5 6.9 [3.3-15.2] 0.26 10 16,17
PGM (homozygous) <1 0.02+ NA 2.8 >17 18
PGM (heterozygous) 17 3 9.5 [2.1-66.7] 0.37 >10 16,17
FVL/PGM (compound <1 0.15 84 [19-369] 4.7 NA 16,17
heterozygous)
Antithrombin 1-8 0.04 119 3.0-7.2 >40 16-21
deficiency
Protein S deficiency 12.4 0.03-0.13 2.4 [0.8-7.9] <1 6.6 16-18, 21
Protein C deficiency <10 0.2-0.3 6.5-12.5 0.8-1.7 NA 16,18, 22
+, calculated based on a Hardy-Weinberg equilibrium; CI, confidence interval; FVL, factor V Leiden; NA, not applicable; PGM, prothrombin G20210A
gene mutation; VTE, venous thromboembolism.
phylaxis but employed it in the postpartum period. They noted an TABLE 41-2 DVT CLINICAL CHARACTERISTIC
overall antepartum recurrence rate of 2.4% (CI, 0.2% to 6.9%) but no SCORE
recurrences in the 44 women without a detectable thrombophilia
whose previous VTE was associated with a temporary risk factor Item No. Description Score
(among which the authors included pregnancy itself). In contrast, the
1 Immobilization due to cast or paresis +1
recurrence risk for VTE among the 25 thrombophilic patients was 16%
2 Bed rest for >3 days or major surgery +1
(4 patients) (odds ratio [OR], 6.5; CI, 0.8 to 56.3). Therefore, it would within 12 wk requiring general or regional
appear prudent to test pregnant patients who have a history of a VTE anesthesia
associated with a transient risk factor (e.g., fracture) for thrombophil- 3 Localized tenderness along deep venous +1
ias. Similarly, consideration should be given to screening pregnant system
women who have a strong family history (i.e., affected first-degree 4 Entire leg swollen +1
relative) of VTE, particularly if they are likely to be exposed to other 5 Asymmetric calf swelling >3 cm measured +1
risk factors such as prolonged mobilization or cesarean delivery. 10 cm below tibial tuberosity
6 Pitting edema only in symptomatic leg +1
7 Collateral nonvaricose superficial veins +1
+1
Diagnosis and Evaluation of 8
9
Active cancer
Prior documented DVT +1
Venous Thromboembolism 10 Alternative diagnosis at least as likely as
DVT
−2
in Pregnancy *Patients with a score <2 are considered unlikely, and those with a
score ≥2 are considered likely, to have deep venous thrombosis (DVT).
The clinical signs and symptoms of VTE are neither sensitive nor spe-
Adapted from Wells PS, Anderson DR, Rodger M, et al: Evaluation of
cific. Indeed, three quarters of patients in whom the diagnosis of either D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J
DVT or PE is suspected are unaffected.24 Conversely, many of those Med 349:1227-1235, 2003.
ultimately diagnosed with VTE do not have classic features. To make
an early diagnosis, clinicians must exercise a high index of suspicion
and approach the diagnosis in a systematic fashion. Wells and associates introduced and validated a simple model in non-
pregnant patients (Table 41-2).26 In the Wells model, 46% of nonpreg-
nant patients were categorized as likely to have a DVT (score = 2), and,
Deep Venous Thrombosis of these patients, 28% (CI, 24% to 32%) were found to have either
proximal DVT or PE. In contrast, of the 54% who were categorized as
Clinical Presentation unlikely to have a DVT, only 6% (CI, 4% to 8%) proved to have a
Only a third of patients with unilateral lower extremity edema, ery- proximal DVT or PE. Therefore, the first step in diagnosing DVT is
thema, warmth, pain, tenderness, and a positive Homan sign—the risk ascertainment.
traditional hallmarks of DVT—prove to have the diagnosis when
objective diagnostic tests are performed.25 Differential diagnoses Venous Ultrasonography
include a ruptured or strained muscle or tendon, cellulitis, knee joint Venous ultrasonography (VUS) with or without color Doppler imaging
injury, Baker cyst, cutaneous vasculitis, superficial thrombophlebitis, has become the primary diagnostic modality for evaluating pregnant
and lymphedema. The positive predictive value of these signs and patients who are at risk for DVT. The test is performed by placing the
symptoms increases substantially in patients at increased risk. However, ultrasound transducer over the common femoral vein, beginning at
there is no risk assessment model that has been validated in pregnancy. the inguinal ligament, and then moving down the leg to sequentially

3. CHAPTER 41 Thromboembolic Disease in Pregnancy 857
image the greater saphenous vein, the superficial femoral vein, and mography (IPG), two clinically useful patterns emerged in 70% of
then the popliteal vein to its trifurcation with the deep veins of the calf. at-risk patients.33 The first pattern was a normal IPG and a negative
Calf veins are then insonated. Pressure is applied with the probe to D-dimer assay, which had a negative predictive value for DVT of 97%
determine whether the vein under examination is compressible. The overall and 99% for proximal vein DVT. The second pattern was the
most accurate ultrasonic criterion for diagnosing DVT is noncom- combination of a positive D-dimer and an abnormal IPG, which had
pressibility of the venous lumen in a transverse plane under gentle a positive predictive value of 93% for any DVT and 90% for proximal
probe pressure using duplex and color flow Doppler.25 The sensitivity DVT. However, if the D-dimer and IPG results were discordant, it was
and specificity of VUS are reported to be 90% to 100% for proximal not possible to reliably exclude or diagnose DVT, and such discordant
vein thromboses.27 Meta-analysis suggests that VUS is also effective at results occurred in 28% of patients. Extrapolation of these findings to
screening for calf vein DVT, with a sensitivity of 92.5% (CI, 81.8% to pregnancy is difficult, not only because of the high “false-positive” rate
97.9%) and a specificity of 98.7% (CI, 95.5% to 99.9%), yielding an of D-dimer testing (>50%)34 but because IPG is rarely performed
overall accuracy of 97.2% (CI, 93.9% to 99.0%).28 Even though there anymore.
is a paucity of data on the performance of VUS in pregnancy, it has A number of investigators have argued that, given the high rate of
become the gold standard for DVT detection in the nonpregnant false-positive results on D-dimer testing in pregnancy, it can be used
state.29 as a screening test in low-risk patients, because a negative D-dimer
result in a pregnant woman would have an exceedingly high negative
Magnetic Resonance Venography predictive value. Morse measured D-dimer values in 48 women, aged
It appears that magnetic resonance (MR) imaging may be superior to 17 to 36 years, at 16, 26, and 34 weeks of gestation and compared these
VUS, and perhaps the equivalent of contrast venography, for diagnos- values to those of 34 healthy, nonpregnant controls.34 Morse found a
ing DVT. The sensitivity of MR imaging for the diagnosis of proximal progressive increase in D-dimer concentrations across gestation (191
leg vein DVT has been reported to be 100% (CI, 87% to 100%); the ± 25 ng/mL at 16 weeks, 393 ± 72 ng/mL at 26 weeks, and 544 ± 96 ng/
specificity, 100% (CI, 92% to 100%); and the overall accuracy, 96% mL at 34 weeks), all of which were significantly higher than the values
(CI, 89% to 99%).30 Moreover, MR venography is significantly more in nonpregnant women (140 ± 58 ng/mL). Because the cutoff value for
sensitive and more accurate than sonography for the detection of normal D-dimer levels at the author’s hospital was 280 ng/mL, most
pelvic and calf DVT. The published literature suggests that the range pregnant patients would be considered positive. The author recom-
of sensitivity for MR imaging in the diagnosis of DVT is 80% to 100%, mended new threshold ranges for 16 to 26 weeks (<465 ng/mL) and
and its specificity is 90% to 100%, with median published rates of for 27 to 34 weeks (<640 ng/mL) of gestation.
100% for both.31 There is preliminary evidence that the combination of VUS and
D-dimer values measured by the SimpliRED D-dimer test may be
Contrast Venography useful in diagnosing DVT in pregnancy.35 Based on the initial VUS and
Before improvements in sonographic imaging technology and the D-dimer results, women were categorized into one of four groups and
introduction of MR venography, contrast venography was the gold managed accordingly. Group 1 (VUS normal, D-dimer normal) com-
standard for the diagnosis of DVT. The procedure involved injecting a prised 31 patients who had routine follow-up until 6 weeks postpar-
contrast agent into a superficial vein on the dorsum of the foot and tum; none of these patients developed objectively diagnosed VTE (CI,
allowing it to circulate into the deep venous system while radiographic 0% to 9.2%). In group 2 (VUS normal, D-dimer abnormal), 4 (22%)
images were obtained of the lower leg, thigh, and pelvis. The diagnosis of 18 women were diagnosed with DVT on serial VUS at 3 and 7 days,
required intraluminal filling defects observed on two or more views or and, of the 14 (78%) with negative serial VUS, none developed VTE
an abrupt cutoff of contrast material. It was the most sensitive test for during follow-up (CI, 0% to 19.3%). In patients for whom VUS was
calf vein DVTs. Although accurate, it was expensive, invasive, and equivocal (group 3), venography was performed. If the VUS result was
painful and risked radiation exposure. In addition, the contrast positive (group 4), DVT was diagnosed. The authors concluded that
medium could potentially induce renal compromise and chemical the finding of a normal VUS together with a normal D-dimer result
phlebitis. or an abnormal D-dimer result coupled with reassuring serial VUS
findings allows the safe exclusion of DVT in pregnant patients, but that
D-dimer Assays larger confirmatory studies were needed.
Laboratory evaluation of D-dimer concentrations has been advocated
as an exclusionary test for DVT in low-risk nonpregnant women. A Testing Algorithms for Deep Venous
D-dimer study is very likely to be positive in a patient with DVT, but Thrombosis in Pregnancy
it is also commonly positive in patients with uncomplicated pregnan- The cornerstone of the evaluation of pregnant patients for possible
cies. Conversely, if a D-dimer assay is negative in a pregnant patient DVT is a VUS. However, D-dimer assessment can be employed either
with suspected DVT, the diagnosis is even less likely than with a com- as an initial screen in low-risk patients or as an adjunct to VUS. Figure
parable negative finding in the nonpregnant state. Recently developed 41-1 outlines a diagnostic paradigm which assumes the availability of
D-dimer assays include two rapid enzyme-linked immunosorbent a sensitive D-dimer assay and clinical risk assessment. In this para-
assays (ELISAs) (Instant-IA D-Dimer, Stago, Asnières, France, and digm, low-risk patients are given a D-dimer test. If the result is nega-
VIDAS DD, bioMérieux, Marcy-l’Etoile, France) and a rapid whole tive, they are discharged for routine follow-up. If the D-dimer test is
blood assay (SimpliRED D-Dimer, Agen Biomedical, Brisbane, Austra- positive, they undergo a VUS. Patients with moderate or high risk on
lia). In nonpregnant patients, the sensitivity of the rapid ELISAs is clinical assessment proceed directly to VUS. If the VUS result is posi-
greater than 95% and that of the SimpliRED D-dimer assay is report- tive, DVT is diagnosed and the patient is treated. If it is negative and
edly 85%.32 In nonpregnant patients, there appears to be utility in the patient remains symptomatic, serial VUS testing can be performed
combining a sensitive D-dimer assay with a noninvasive imaging test. in 3 days, 7 days, or both. If the repeat VUS findings are positive, the
Wells and associates reported that, when the whole blood assay for D- patient is treated. If both VUS studies are negative, the patient has
dimer (SimpliRED) was used in combination with impedance plethys- routine follow-up. In particularly high-risk settings (e.g., known

4. 858 CHAPTER 41 Thromboembolic Disease in Pregnancy
Assess patient risk VUS
Low Moderate Positive Negative
or high
Treat Assess
Assess ( ) VUS for DVT risk
D-dimer
( ) ( )
( )
High Low
( ) D/C Consider serial VUS, Treat
patient MR venogram, or
( ) ( )
contrast venography
( ) Serial VUS, Discharge
MR venogram, or
FIGURE 41-1 Testing algorithm for deep venous thrombosis contrast venography
in pregnancy, assuming availability of D-dimer test and clinical
assessment. D/C, discharge patient; MR, magnetic resonance;
VUS, venous ultrasonography. FIGURE 41-2 Testing algorithm for deep venous thrombosis
(DVT) in pregnancy with venous ultrasonography (VUS) as the
initial test. MR, magnetic resonance.
thrombophilia, suspected iliac vein thrombus), more definitive diag-
nostic tests can be performed, such as an MR or contrast venogram if
the D-dimer is positive and the initial VUS is negative. The problem Assess VUS and D-dimer
with this approach is that, as noted previously, the majority of preg-
nant women after 16 weeks’ gestation will have a positive D-dimer
assay if a nonpregnant threshold is used. Moreover, there has been no VUS ( ) and VUS ( )
validation of higher D-dimer thresholds in pregnancy, and there are D-dimer ( )
no validated risk scoring systems. Importantly, the Wells criteria may VUS ( ) but
not be appropriate in pregnancy, which is intrinsically a high-risk D-dimer ( )
state. ( ) D/C
patient
Figure 41-2 assumes the use of a VUS as the initial test, with patients
subsequently triaged based on the VUS result or clinical risk assess-
ment determining the need for additional evaluations. A positive VUS ( ) Consider serial VUS, ( )
MR venogram, or Treat
result prompts treatment. Follow-up of a negative VUS result depends contrast venography
on the patient’s risk category. If it is low, the patient is discharged to
routine follow-up. If it is moderate or high, she undergoes serial VUS
FIGURE 41-3 Testing algorithm for deep venous thrombosis in
or, if the index of suspicion is high enough, MR or contrast
pregnancy, using venous ultrasonography (VUS) and D-dimer
venography.
testing without formal clinical risk assessment. D/C, discharge;
The diagnostic scheme in Figure 41-3 utilizes VUS and D-dimer MR, magnetic resonance.
testing without formal clinical risk assessment to triage patients. The
combination of a negative D-dimer result and a negative VUS study is
associated with a very low risk of DVT, and such patients are dis- negative D-dimer finding would be very reassuring, whereas observa-
charged to routine follow-up. A positive VUS, which is virtually always tion of an intraluminal filling defect on MR or contrast venography
associated with a positive D-dimer test, prompts treatment. However, would be diagnostic of recurrent DVT.32
a negative VUS result combined with a positive D-dimer test is fol-
lowed with either serial VUS or MR or contrast venography, depending
on the clinician’s index of suspicion. It should be noted that D-dimer Acute Pulmonary Embolus
testing is likely to be completely irrelevant in puerperal and postopera-
tive patients, because these patients have very high false-positive Clinical Findings
rates.36,37 The diagnostic approach outlined in Figure 41-2 should be In nonpregnant women, the classic presentation of PE includes tachy-
employed in those settings. pnea (>20 breaths/min) and tachycardia (>100 beats/min), either of
The diagnosis of recurrent DVT in pregnancy presents a diagnostic which is present in 90% of cases.39 Additional common symptoms
challenge, because VUS findings remain abnormal after an initial include dyspnea and pleuritic chest pain. In contrast, lightheadedness
thrombus for up to 1 year in as many as 50% of patients.32 In this and syncope are rare and are indicative of massive emboli.40 In the
setting, an increase of more than 4 mm in the compressed diameter of nonpregnant state, the nonspecific nature of these signs and symptoms
a previously involved vein has been reported to provide strong evi- is a result of the common comorbidities found in older patients, includ-
dence of recurrent thrombosis, but this observation requires confirma- ing viral and bacterial pneumonia, postoperative atelectasis, pneumo-
tion.38 In such cases, strong consideration should be given to D-dimer thorax, exacerbation of chronic obstructive lung disease, congestive
assessment and adjunct imaging with MR or contrast venography. A heart failure, lung cancer, musculoskeletal chest wall pain, esophageal

5. CHAPTER 41 Thromboembolic Disease in Pregnancy 859
TABLE 41-3 PULMONARY EMBOLISM RISK right bundle branch block, P-wave pulmonale, or right axis deviation)
SCORE* and therefore are rare.42 Moreover, such changes are not universal, even
among critically ill patients. Constantini and associates reported
Scoring Factor Points changes characteristic of right ventricular strain including an S1Q3
pattern in 67% of such patients, with a “septal embolic pattern” in 53%,
Clinical signs and symptoms of DVT +3.0
and either anterior lead T-wave inversion or new right bundle branch
Alternative diagnosis deemed less likely than PE +3.0
Heart rate >100 beats/min +1.5 block in only 16%.43 However, there are no data on ECG changes in
Immobilization or surgery in previous 4 wk +1.5 pregnant women with PE. Moreover, pregnancy-induced physiologic
Prior VTE +1.5 changes mimic left heart strain (e.g., T inversions in the left precordial
Hemoptysis +1.0 leads) and, therefore, may mask PE-induced right heart strain changes.
Active cancer +1.0 Conversely, some physiologic changes may simulate PE changes (e.g.,
physiologic Q waves in leads 3 and aVF), leading to false-positive
*Clinical probability of PE is low with a cumulative score <2.0,
results. For these reasons, the screening value of ECG in the setting
intermediate with a score of 2.0-6.0, and high with a score >6.0.
DVT, deep venous thrombosis; PE, pulmonary embolism; VTE, venous of maternal acute PE is probably low. However, assessment of the
thromboembolism. maternal ECG may have utility in making decisions about how
Adapted from Fedullo PF, Tapson VF: Clinical practice: The evaluation aggressively to pursue secondary diagnostic studies (see Testing
of suspected pulmonary embolism. N Engl J Med 349:1247-1256, 2003. Algorithms for Pulmonary Embolism, later).
ARTERIAL BLOOD GASES
spasm, pericarditis, pleuritis, and anxiety. Although these comorbidi- In young, nonpregnant patients, assessments of arterial blood gases
ties are far less common in otherwise young and healthy pregnant and oxygen saturation are of limited value in the setting of acute PE,
women, pregnancy itself can be associated with dyspnea, tachycardia, because PO2 values higher than 80 mm Hg are found in 29% of such
lightheadedness, orthostatic presyncope, and various chest wall com- patients who are younger than 40 years of age.44 Given that PO2 levels
plaints. Therefore, a high index of suspicion is required. are even higher in pregnant women, the test is likely to produce even
The initial step in the evaluation of any patient is risk assessment. more false-negative results in pregnancy. However, as was the case with
Table 41-3 outlines one scoring system used in nonpregnant patients, maternal ECG, assessment of maternal oxygen saturation may have
in which patients in the low-probability group had a prevalence of PE utility in making decisions about how aggressively to pursue secondary
of 10% or less, those in the intermediate group had a prevalence of diagnostic studies (see Testing Algorithms for Pulmonary Embolism,
about 30%, and those in the high-probability group had a prevalence later).
of PE of 70% or more.40 This system has not been validated in pregnant
patients. Furthermore, given the thrombogenic nature of pregnancy ECHOCARDIOGRAPHY
and the puerperal state, particularly after cesarean delivery, it may be More than 80% of nonpregnant patients with acute PE have echo-
prudent to consider all pregnant patients as being at high risk. cardiographic or Doppler abnormalities, including dilated and hypo-
kinetic right ventricle and tricuspid regurgitation.45,46 Because young,
Nonspecific Diagnostic Tests pregnant women are unlikely to have cardiorespiratory comorbidities
CHEST RADIOGRAPHY that can mimic these findings (e.g., chronic obstructive pulmonary
Chest radiographs can play an important role in the evaluation of disease), maternal echocardiography may be useful in pregnant women
pregnant patients with suspected PE. Given concerns about excess with suspected PE. Optimal screening requires transesophageal echo-
breast irradiation during computed tomographic pulmonary angiog- cardiography with or without contrast enhancement.47 Indeed, there is
raphy (CTPA), and because ventilation-perfusion (V/Q) studies have a report in which intraoperative transesophageal echocardiography
exceptionally high negative predictive values in otherwise healthy was used to diagnose a right atrial thrombus during a cesarean
pregnant women, some investigators have advocated obtaining an delivery.48
initial chest radiograph to triage patients to either CTPA or V/Q scan.41
If the radiograph is normal, a V/Q scan is obtained; if it is abnormal Specific Diagnostic Tests
(e.g., infiltrates, which could compromise the V/Q study by causing VENTILATION-PERFUSION SCANNING
matched ventilation-perfusion abnormalities), a CTPA is ordered. In nonpregnant adults, V/Q scanning has largely been replaced by
Abnormal findings on radiography may also be consistent with a PE. CTPA. In younger, otherwise healthy, pregnant women, V/Q scans have
Such findings, which include pleural effusion, pulmonary infiltrates, superior PE diagnostic characteristics compared with their use in older,
atelectasis, and elevated hemidiaphragm, underscore the need for nongravid patients, who frequently have cardiorespiratory comorbidi-
CTPA, because it can diagnose a broad range of lung pathology. ties.41 Because of this improved accuracy in pregnancy, and given con-
However, chest radiography is rarely directly diagnostic of a PE, because cerns about the extent of maternal breast irradiation with CTPA, V/Q
the classic radiographic findings of pulmonary infarction, such as scans may still have a limited role in ruling out PE in select pregnant
Hampton’s hump or decreased vascularity (Westermark sign), are and puerperal patients.41 The perfusion component of a V/Q scan
rarely seen.31 requires injecting human albumin macroaggregates labeled
with radioactive isotopes (e.g., technetium 99m) into the bloodstream,
ELECTROCARDIOGRAPHY where they are deposited in the pulmonary capillary bed and imaged
In nonpregnant patients, electrocardiographic (ECG) changes are by a photoscanner. The ventilation component requires inhalation of
present in 87% of patients with documented PE who are otherwise radiolabeled (e.g., xenon 133) aerosols whose distribution in the alveo-
without underlying cardiopulmonary disease.42 However, truly charac- lar space is assessed by a gamma camera. Comparison of the perfusion
teristic ECG changes usually reflect the hemodynamic sequelae of and ventilation scans produces characteristic patterns that can be used
acute cor pulmonale characteristic of a massive PE (i.e., S1Q3T3 pattern, to assign diagnostic probabilities.

6. 860 CHAPTER 41 Thromboembolic Disease in Pregnancy
The chief limitation of V/Q scanning in nonpregnant patients is contrast pulmonary angiogram and a negative (normal or near-
that only 30% to 40% of older patients with preexisting lung disease normal) V/Q scan.
who have large matched V/Q defects are subsequently shown to have It had been argued that CTPA is less accurate with small, isolated
a PE, leading to false-positive results.25 Fortunately, pregnant patients subsegmental, peripheral vessels and horizontally oriented vessels in
are generally free of chronic lung disease. Moreover, as noted earlier, the right middle lobe. However, newer technology using spiral com-
the proportion of nondiagnostic V/Q scans can be further reduced by puted tomographic scanners with multiple detector rows and 1-mm
obtaining an initial chest radiograph and triaging pregnant patients slices appears to improve the accuracy of CTPA for diagnosing subseg-
with an abnormal result to CTPA.41 Furthermore, although fetal radia- mental infarcts and may reduce false-negative results to 5%.54 In addi-
tion exposure is higher with V/Q scanning than with CTPA (0.11 to tion, traditional contrast pulmonary angiograms have relatively poor
0.22 mGy versus 0.003 to 0.08 mGy),49 all of these exposures are interobserver agreement (45% to 66%) for diagnosis of subsegmental
exceedingly low, and the risk of subsequent leukemogenesis is esti- PE.55,56 Therefore, CTPA appears to be of comparable or superior effi-
mated at 1 case per 16,000 fetuses exposed to 1 mGy of radiation. cacy to contrast angiography.
Moreover, half-dose perfusion scans can be employed in young, healthy,
pregnant women. Such half-doses result in breast irradiation levels of MAGNETIC RESONANCE ARTERIOGRAPHY
0.25 mGy, which is 140-fold lower than the exposure from CTPA (i.e., Meaney and colleagues compared standard conventional intrave-
35 mGy per breast).41 nous contrast pulmonary angiography with magnetic resonance angi-
The diagnostic efficacy of V/Q scanning for PE was assessed by the ography (MRA) during the pulmonary arterial phase of the cardiac
multicenter Prospective Investigation of Pulmonary Embolism Diag- cycle after an intravenous bolus of gadolinium and observed that MRA
nosis (PIOPED) in 931 nonpregnant adults.50 In this study, patients had an overall sensitivity of 100%, a specificity of 95% (CI, 87% to
with high-probability scans were found by definitive testing (e.g., pul- 100%), and positive and negative predictive values of 87% (CI, 74%
monary contrast angiography) to have PE in 87% of cases, but only to 100%) and 100%, respectively.57 Oudkerk and associates conducted
41% of patients with PE had high-probability scans (sensitivity, 41%; a prospective study of MRA in which conventional contrast pulmonary
specificity, 97%). In contrast, 33% of patients with intermediate- angiography results were available for 118 patients at risk for PE.58 The
probability scans had a PE, and PE was present in only 14% of patients prevalence of PE was 30%, and MRA identified 27 of 35 patients with
with low-probability scans and 4% of those with negative scans. Inves- angiographically confirmed PE (sensitivity, 77%; CI, 61% to 90%). The
tigators also found that PE can be present in a substantial percentage sensitivity of MRA for isolated subsegmental, segmental, and central
of high-risk patients with nondiagnostic V/Q scans. One study found or lobar PE was 40%, 84%, and 100%, respectively. In fact, MRA identi-
that, among high-risk women, the prevalence of PE in those with low fied PE in two patients with normal angiograms. Given its lack of
and intermediate probability on V/Q scanning was 40% and 66%, radiation exposure, and if its efficacy is confirmed by larger studies,
respectively.31 Conversely, 44% of low-risk patients with a high- MRA may become the primary diagnostic test, where it is available, for
probability V/Q scan did not have a PE. These findings underscore the ruling out PE in pregnancy.
value of first determining the patient’s clinical risk category if V/Q
scanning is to be used as a first-line screening method. This is prob- CONVENTIONAL CONTRAST
lematic in pregnancy, because there are no validated risk scoring PULMONARY ARTERIOGRAPHY
systems. Pulmonary arteriography was long considered the gold standard
The efficacy of V/Q scanning in pregnancy was assessed by Chan for the diagnosis of PE, with sensitivities and specificities of 100%
and coworkers.51 They evaluated 120 consecutive pregnant women by definition. However, as noted earlier, interobserver agreement
having 121 V/Q scans for suspected PE. All V/Q results were reinter- decreases with smaller peripheral lesions. To perform the study, a
preted by two independent experts. Eight of the patients (6.6%) were catheter is usually placed in the right femoral, basilic, or right internal
already receiving treatment for VTE before their V/Q scan. Of the jugular vein. A PE is diagnosed by the finding of an intraluminal filling
remaining 113 scans, 83 (73.5%) were interpreted as normal, 28 defect on two views of a pulmonary artery. The procedure has a 0.5%
(24.8%) as nondiagnostic, and 2 (1.8%) as high-probability. None of mortality rate and a complication rate of 3%, including sequelae of
the 104 women who did not receive treatment because of a reassuring contrast injections and catheter placement such as respiratory failure
scan (i.e., 80 with normal and 24 with nondiagnostic results) had a (0.4%), renal failure (0.3%), cardiac perforation (1%), and groin
subsequent VTE over a follow-up period of more than 20 months. This hematoma requiring transfusion (0.2%). In light of these risks, pul-
study suggested that the negative predictive value of V/Q scanning is monary arteriography has fallen out of favor given the relative safety
higher in pregnancy than among older, nonpregnant patients. and efficacy of the other available tests.40,59,60 Moreover, contrast pul-
monary arteriography is relatively contraindicated in the presence of
COMPUTED TOMOGRAPHIC a significant hemorrhagic risk (e.g., disseminated intravascular coagu-
PULMONARY ANGIOGRAPHY lation, thrombocytopenia) and in patients with renal insufficiency. Left
CTPA has become the gold standard for the diagnosis of PE in bundle branch blocks require the use of a temporary pacemaker during
nonpregnant patients.41 Cross and colleagues compared CTPA to V/Q the procedure to avoid induction of complete heart block.31
scans for the initial investigation of patients with suspected PE and Pulmonary arteriography from the brachial vein route generates
observed that definitive diagnoses of various etiologies were more fre- 0.5 mGy (0.05 rad) of fetal exposure, whereas the femoral vein approach
quent with CTPA (90% versus 54%; P < .001).52 However, although generates 2.2 to 3.3 mGy (0.22 to 0.33 rad) of fetal exposure, making
CTPA more often demonstrated nonembolic lesions responsible for the former the preferable route in pregnancy.61 Concerns also exist
the patients’ symptoms, there was no difference in the detection rate regarding the development of fetal goiter after maternal exposure to
of PE between the two groups. Meta-analysis of 23 studies demon- iodinated contrast material. Therefore, the fetal heart rate should be
strated very low 3-month rates of subsequent VTE (1.4%; CI, 1.1% to assessed biweekly to rule out hypothyroidism, and, if delivery occurs
1.8%) and fatal PE (0.51%; CI, 0.33% to 0.76%) after a negative CTPA proximate to the test, neonatal thyroid function should be checked
study.53 These results compare very favorably with both a negative during the first week after the procedure.62 Given the high sensitivity

7. CHAPTER 41 Thromboembolic Disease in Pregnancy 861
and specificity of CTPA and MRA, as well as the relatively high mater-
nal morbidity and concerns with both fetal irradiation and iodinated Assess risk score
contrast exposure attendant on contrast pulmonary arteriography, the
latter has fallen into disuse as a tool for diagnosing PE in pregnancy.
Low 2 Not low 2
EVALUATION OF LOWER EXTREMITIES FOR
VENOUS THROMBOSIS
( )
Approximately 75% of patients with PE have imaging evidence of VUS and CXR
DVT, and two thirds of those lesions are present in the proximal vein. D-dimer
However, only a quarter of patients with symptomatic PE have symp- ( ) ( )
tomatic DVT.63 Therefore, in stable patients before definitive diagnos- ( )
tic imaging, and in high-risk pregnant patients in whom CTPA, V/Q ( )
scanning, or MRA is not diagnostic, detection of leg vein DVT by VUS ( )
D/C Tx CTPA V/Q
can establish the need for anticoagulation.64
( ) ( ) ( )
D-DIMER ASSAYS AS A SCREEN FOR ( ) ( )
PULMONARY EMBOLISM MRA, contrast Low or Tx D/C
A negative D-dimer concentration (<500 ng/mL) has been advo- angiography, or interm.
cated as a “rule-out” test in patients with low probability of PE because serial VUS prob.
of its high (95%) negative predictive value.31 Kearon and colleagues
observed that, among patients at low clinical risk for PE, none of those FIGURE 41-4 Testing algorithm for pulmonary emboli with initial
with a negative D-dimer result and no additional diagnostic testing triage based on clinical probability. CTPA, computed tomographic
had a subsequent VTE, compared with 1 patient with VTE among 182 pulmonary angiography; CXR, chest radiography; D/C, discharge;
with negative D-dimer result who had additional testing.65 They con- interm. prob., intermediate probability; MRA, magnetic resonance
cluded that, for patients with a low probability of PE whose D-dimer angiography; Tx, treatment; V/Q, ventilation-perfusion studies; VUS,
result is negative, additional diagnostic testing can be withheld without venous ultrasonography.
increasing the frequency of VTE.
Meta-analysis of studies examining the accuracy of D-dimer deter-
minations in the diagnosis of PE demonstrate a mean sensitivity of
95% (CI, 88.0% to 100%), a specificity of 45% (CI, 38% to 53%), and Assess D-dimer and CTPA
positive and negative likelihood ratios of 1.74 (CI, 1.55 to 1.91) and
0.11 (CI, 0.03 to 0.39), respectively.66 The quantitative rapid ELISA had
a sensitivity of 98% (CI, 88.0% to 100%), a specificity of 40% (CI, 29%
D-dimer ( ) D-dimer ( ) CTPA ( )
to 50%), and positive and negative likelihood ratios of 1.62 (CI, 1.38 CTPA ( ) CTPA ( )
to 1.91) and 0.05 (CI, 0.00 to 4.15), respectively. The whole blood D-
dimer assay kit yielded a sensitivity of 82% (CI, 74 to 91), a specificity
of 63% (CI, 54% to 71%), and positive and negative likelihood ratios
( ) ( )
of 2.21 (CI, 1.81 to 2.70) and 0.28 (CI, 0.18 to 0.43), respectively. The ( ) D/C Consider serial VUS, Treat
authors concluded that a negative result on quantitative rapid ELISA patient MRA, or contrast
was as diagnostically useful as a normal V/Q scan for excluding PE. As angiography
was discussed for the use of D-dimer assays in the diagnosis of DVT,
the specificity and positive predictive value for D-dimer assays in the FIGURE 41-5 Testing algorithm for pulmonary emboli with
workup of patients at risk for PE are likely to be far lower in pregnant, triage based on results from D-dimer testing and computed
puerperal, and postoperative patients, whereas the sensitivity and tomographic pulmonary angiography (CTPA). D/C, discharge;
negative predictive value should be higher in these settings. MRA, magnetic resonance angiography; VUS, venous
ultrasonography.
Testing Algorithms for Pulmonary Embolism
There is considerable controversy regarding the optimal paradigm for
diagnosing PE in pregnancy. Clinical risk assessment tools have not are deemed to be at low risk then undergo both VUS and D-dimer
been validated for pregnant patients. D-dimer testing is likely to be testing; those at high risk and those with a positive D-dimer test receive
associated with a very high false-positive rate. Moreover, as noted chest radiography followed by either CTPA or V/Q scanning. This
earlier, concern has been expressed regarding the relatively high radia- approach would be favored in nonacute settings with equivocal signs
tion exposure to maternal breasts after CTPA. Conversely, V/Q scans and symptoms. The second approach (Fig. 41-5) seeks to maximize the
deliver higher radiation doses to the fetus, have limited application in speed and sensitivity of the diagnosis and should be used for patients
the setting of cardiorespiratory comorbidities, and are frequently no who are more symptomatic or where there is a high index of suspicion.
longer available in contemporary radiology practices. MRA may prove In this paradigm, triage is done with D-dimer testing and CTPA.
to be the ideal alternative, but there are currently too few studies to rec- In Figure 41-4, patients should be minimally symptomatic and
ommend its widespread use, even where the technology is available. preferably should have reassuring oxygen saturation values (>80%).
Two general strategies emerge. The first (Fig. 41-4) seeks to mini- The workup commences with a risk assessment (see Table 41-3).
mize radiation exposure to both the fetus and maternal breasts by Patients who are considered to be at low clinical risk (i.e., risk score
performing an initial triage based on clinical probability. Patients who <2) should have a VUS and D-dimer test. Obviously, if the VUS result

8. 862 CHAPTER 41 Thromboembolic Disease in Pregnancy
is positive, treatment should be initiated. If both the D-dimer and the TABLE 41-4 ADMINISTRATION OF
VUS studies are negative, the patient can be discharged to routine INTRAVENOUS HEPARIN USING A
follow-up. If the VUS is negative but the D-dimer test is positive, the
WEIGHT-BASED NOMOGRAM*
patient is regarded as if she had a clinical risk assessment that was not
low (i.e., ≥2). In these latter patients, the workup commences with a aPTT Value Adjustment
chest radiograph. If the results are positive, the patient proceeds to a
<35 sec (<1.2 × control) Repeat 80 U/kg bolus, then increase
CTPA. If this is positive for PE, treatment is immediately commenced.
infusion rate by 4 U/kg/hr
If the CTPA is negative, consideration can be given to a serial VUS if
35-45 sec (1.2-1.5 × control) Repeat 40 U/kg bolus, then increase
not already done. If other ancillary tests are not reassuring (e.g., low infusion rate by 2 U/kg/hr
oxygen saturation, abnormal ECG), then consideration should be given 46-70 sec (1.6-2.3 × control) No change in dosing
to an MRA or contrast angiogram. Alternatively, if the chest radio- 71-90 sec (2.4-3.0 × control) Decrease infusion rate by 2 U/kg/hr
graph is negative, a V/Q scan is performed. If this is negative or normal, >90 sec (>3.0 × control) Stop infusion for 1 hr, then restart
the patient can be discharged to routine follow-up. If the V/Q scan original dose decreased by
indicates a high probability of PE, treatment should begin. If the V/Q 3 U/kg/hr
scan returns an intermediate or low probability of PE, then considera-
*Give bolus of 80 U/kg of body weight, followed by a maintenance
tion can be given to a serial VUS if not already done, or, if other ancil- dose of 18 U/kg/hr. Assess aPTT values every 4-6 hr and make
lary tests are not reassuring, an MRA or contrast angiogram can be done. adjustments made based on the aPTT values obtained.
The paradigm in Figure 41-5 should be used for women with more aPTT, activated partial thromboplastin time.
pronounced symptoms or unfavorable signs (e.g., oxygen saturation Adapted from Raschke RA, Reilly BM, Guidry JR, et al: The weight-
based heparin dosing nomogram compared with a “standard care”
values <80%, abnormal ECG). The workup begins with D-dimer
nomogram: A randomized controlled trial. Ann Intern Med 119:874-
determination and CTPA. In patients with a high pretest probability 881, 1993.
of PE or who are very symptomatic, anticoagulation should be com-
menced as soon as the blood sample is sent to the laboratory for D-
dimer determination. If both the D-dimer and CTPA studies are
negative, the patient is at very low risk and can be discharged to routine The overall goal is to obtain and maintain an aPTT of 1.5 to 2.5 ×
follow-up, though the cause of her symptoms must be identified (e.g., control values. The aPTT should not be used to guide unfractionated
pneumonia, pulmonary edema, cardiomyopathy, esophagitis). If the heparin therapy in patients with prolonged aPTT values due to the
CTPA is positive, then anticoagulant treatment is begun or continued. presence of lupus anticoagulants. In these patients, plasma heparin
If the CTPA is negative and the D-dimer value is positive or the index activity can be measured by either a protamine sulfate or an anti-factor
of suspicion remains high because of low oxygen saturation or an Xa chromogenic assay. Target plasma heparin concentrations of 0.2 to
abnormal ECG, consideration should be given to a serial VUS, MRA, 0.4 U/mL are equivalent to anti-factor Xa concentrations of 0.4 to
or contrast angiography. 0.7 U/mL. The usual duration of intravenous heparin therapy is 5 days,
although patients with large iliofemoral thromboses or massive PEs
should receive heparin for 7 to 10 days or until clinical improvement
is noted.31 After hospital discharge, therapeutic doses of unfractionated
Treatment of Venous heparin are administered subcutaneously every 8 to 12 hours to main-
tain the aPTT at 1.5 to 2 × control values 6 hours after the injection.
Thromboembolism This therapy should be continued for 20 weeks and then followed by
in Pregnancy prophylactic dosing until delivery.
The standard prophylactic regimen of unfractionated heparin used
Patients with new-onset VTE during pregnancy should receive thera- in pregnancy consists of 5000 units administered subcutaneously every
peutic anticoagulation for at least 4 months during the pregnancy, 12 hours, increased by 2500 U in the second and third trimesters.
followed by prophylactic therapy continuing for at least 6 weeks after However, Barbour and associates observed that this standard heparin
delivery. During pregnancy, either unfractionated heparin or low- regimen was inadequate to achieve the desired anti-factor Xa thera-
molecular-weight heparin (LMWH) is the anticoagulant of choice, peutic range in 5 of 9 second-trimester pregnancies and in 6 of 13
given its efficacy and safety profile. Neither formulation crosses the third-trimester pregnancies.68 Therefore, careful assessment of anti-
placenta, and neither poses teratogenic risks. After delivery, oral anti- factor Xa levels 4 to 6 hours after injection is required to properly
coagulation with warfarin may be started and is considered safe in adjust the dosage.
breastfeeding mothers. The primary risks of long-term heparin therapy If vaginal or cesarean delivery occurs more than 4 hours after a
in pregnancy are hemorrhage and osteoporosis. prophylactic dose of unfractionated heparin, the patient is not at sig-
nificant risk for hemorrhagic complications. Patients receiving unfrac-
tionated heparin who experience bleeding or require rapid reversal of
Heparin Therapy the anticoagulant to effect delivery can be administered protamine
sulfate by slow intravenous infusion of less than 20 mg/min, with no
Therapeutic Unfractionated Heparin more than 50 mg given over 10 minutes. The amount of protamine
The initial intravenous unfractionated heparin dosage for pregnant needed to neutralize heparin is derived by determining the amount of
patients with acute VTE should be determined with the use of a weight- residual heparin in the circulation, assuming a half-life for intrave-
based nomogram, and subsequent dosage modifications should be nously administered heparin of 45 minutes. Full neutralization of
predicated on the activated partial thromboplastin time (aPTT) (Table heparin activity would require 1 mg protamine sulfate per 100 units
41-4). This regimen has been shown in nonpregnant patients to reduce of residual circulating heparin. If the heparin was administered sub-
recurrence rates.67 cutaneously, repeated small infusions of protamine are required.

9. CHAPTER 41 Thromboembolic Disease in Pregnancy 863
Finally, antithrombin concentrates may be used in antithrombin- without a personal or strong family history of VTE should receive
deficient patients in the peripartum period. subtherapeutic doses of LMWH, with the goal of maintaining anti-
One of the most serious potential complications of heparin therapy factor Xa levels of 0.3 to 0.7 U/mL 4 hours after injection.
is heparin-induced thrombocytopenia (HIT). This condition arises in Regional anesthesia is contraindicated within 24 hours after thera-
3% of nonpregnant patients given initial heparin therapy. Type 1 HIT peutic LMWH administration because of the risk of epidural hema-
(HIT-1) occurs within days after initial heparin exposure, results from toma; therefore, we recommend switching to unfractionated heparin
benign platelet clumping in vitro, is self-limited, is not associated with at 36 weeks, or earlier if preterm delivery is expected. However, vaginal
a significant risk of hemorrhage or thrombosis, and does not require or cesarean delivery occurring more than 12 hours after a prophylactic
cessation of therapy. In contrast, type 2 HIT is a rare, immunoglobu- dose or 24 hours after a therapeutic dose of LMWH should not be
lin-mediated syndrome paradoxically associated with venous and arte- associated with treatment-induced hemorrhage. If shorter intervals are
rial thrombosis that occurs 5 to 14 days after initiation of therapy. encountered, protamine may partially reverse the anticoagulant effects
Monitoring for HIT should include every-other-day platelet counts for of LMWH. The dosage is 1 mg of protamine for every 100 anti-Xa
2 weeks.69 Because it can be difficult to distinguish the two entities, a units of LMWH, but anti-factor Xa activity can be only partially (80%)
50% decline in platelet count from its pretreatment high should reversed.73
prompt cessation of therapy. The diagnosis of HIT-2 is confirmed by The risk of HIT-2 appears to be far lower in patients receiving
serotonin release assays, heparin-induced platelet aggregation assays, LMWH compared to unfractionated heparin, and it is lower still for
flow cytometry, or solid phase immunoassays.70 If it is confirmed, all obstetric patients receiving prophylactic LMWH therapy.74,75 However,
forms of heparin, including intravenous flushes, must be avoided. platelet counts should still be obtained every 2 or 3 days from day 4 to
day 14.69
Low-Molecular-Weight Heparin
In nonpregnant patients, the mainstay of acute treatment of VTE is Postpartum Anticoagulation
now LMWH. Meta-analyses of 22 studies including 8867 nonpregnant Unfractionated heparin or LMWH can be restarted 4 to 6 hours after
patients suggest that LMWH has fewer thrombotic complications than vaginal delivery or 6 to 12 hours after cesarean delivery. Postpartum
unfractionated heparin (3.6% versus 5.4%; OR, 0.68; CI, 0.55 to 0.84; patients should be started immediately on warfarin. The initial doses
18 trials), produces a greater reduction in thrombus size (53% versus of warfarin should be 5 mg daily for 2 days. Subsequent doses are
45%; OR, 0.69; CI, 0.59 to 0.81; 12 trials), and results in fewer major determined by monitoring the international normalized ratio (INR).
hemorrhages (1.2% versus 2.0%; OR, 0.57; CI, 0.39 to 0.83; 19 trials) To avoid paradoxical thrombosis and skin necrosis from warfarin’s
and fewer deaths (4.5% versus 6.0%; OR, 0.76; CI, 0.62 to 0.92; 18 initial anti-protein C effect, it is critical to maintain these women on
trials).71 However, comparable data have not been assembled for preg- therapeutic doses of unfractionated heparin for a minimum of 5 days
nant patients. Nevertheless, LMWH is now commonly employed to and until the INR has been at therapeutic levels (2.0 to 3.0) for 2 con-
treat acute VTE in pregnancy and also as prophylaxis. secutive days. After an uncomplicated initial VTE during pregnancy,
The initial therapeutic dose of LMWH varies with the specific without other high-risk conditions such as APA syndrome or anti-
agent. Two agents have been approved by the U.S. Food and Drug thrombin deficiency, therapy should be continued in the postpartum
Administration (FDA) for the treatment of acute VTE: enoxaparin and period for 3 to 6 months. Because warfarin does not significantly
tinzaparin. Enoxaparin is given at a dose of 1 mg/kg administered accumulate in breast milk and does not induce an anticoagulant effect
subcutaneously twice daily (i.e., every 12 hours). For tinzaparin, the in the infant, it is not contraindicated in breastfeeding mothers.
dose is 175 IU/kg administered subcutaneously once daily. A third Management of warfarin overdoses or hemorrhagic complications
LMWH, dalteparin, has also been used off-label at doses of 100 U/kg is guided by the severity of the problem. For example, if patients are
every 12 hours. Barbour and colleagues evaluated whether the stan- found to have elevated INRs (>3.0) without bleeding, vitamin K can
dard therapeutic doses of dalteparin maintained peak therapeutic be given orally. However, if mild bleeding is present, vitamin K can be
levels of anticoagulation during pregnancy; in 85% of patients, dosage administered subcutaneously.76 Normalization of the INR can occur
adjustments were required to maintain peak anti-Xa activity between within 6 hours after a 5-mg oral or subcutaneous dose of vitamin K.
0.5 and 1.0 IU/mL.72 Given these data and the fact that pregnancy Larger doses have a more rapid onset but render patients resistant to
presents a period of rapidly changing volumes of distribution and re-anticoagulation with warfarin. In the setting of significant hemor-
fluctuating concentrations of heparin-binding proteins, it appears rhage, fresh-frozen plasma will replenish clotting factors and can be
prudent to monitor anti-Xa activity during therapeutic treatment with used with subcutaneous vitamin K to reverse the effects of warfarin.
LMWH in pregnant patients and to adjust the doses to maintain a
therapeutic level (i.e., anti-factor Xa levels of 0.6 to 1.2 U/mL) 4 hours
after an injection. Complex Presentations
As with unfractionated heparin, treatment should continue for 20
weeks, and then prophylactic dosages should be given (e.g., enoxapa- Type 2 Heparin-Induced Thrombocytopenia
rin, 40 mg SQ every 12 hr; dalteparin, 5000 U SQ once daily). There is In patients with a history or new presentation of HIT-2, heparin and
controversy as to whether prophylactic LMWH warrants surveillance LMWH are contraindicated. Fondaparinux presents an excellent alter-
with anti-factor Xa levels. If surveillance is undertaken, the goal should native. It is a synthetic heparin pentasaccharide that complexes with
be an anti-factor Xa level between 0.1 to 0.2 U/mL 4 hours after an the antithrombin binding site for heparin to permit the selective inac-
injection. tivation of factor Xa but not thrombin. Excretion is renal, and the
Patients with antithrombin deficiency, and patients who are homo- drug has a 15-hour half-life after a once-daily subcutaneous injection.
zygotes or compound heterozygotes for the FVL or PGM mutation and Buller and associates conducted a randomized, double-blind trial of
have a prior VTE or affected first-degree relative, require therapeutic fondaparinux, administered subcutaneously once a day at a dose of
anticoagulation throughout pregnancy. In our practice, pregnant 5.0 mg for patients weighing less than 50 kg, 7.5 mg for those weighing
patients with these highly thrombogenic thrombophilias who are 50 to 100 kg, and 10.0 mg for those weighing more than 100 kg, versus

10. 864 CHAPTER 41 Thromboembolic Disease in Pregnancy
enoxaparin among 2205 patients with acute symptomatic DVT.77 No levels immediately before the next dose. Dose adjustments should be
differences in recurrent VTE were observed between the two groups. made to insure that trough levels remain between 0.5 and 1.2 U/mL.83
Fondaparinux is considered a pregnancy class B agent by the FDA. It In addition, the use of low-dose aspirin was recommended for such
has been used in a small number of pregnant patients without adverse patients.83 These patients should be extensively counseled about the
sequelae, although it has been found to be present in umbilical-cord risks and benefits of these different regimens to both their own health
plasma at concentrations approximately 10% of those in the maternal and that of their fetus.
plasma.78 These levels are well below those required for effective anti-
coagulation. However, fondaparinux use in pregnant women is best
limited to those patients with no obvious therapeutic alternatives, such Thrombolytic Therapy
as patients with HIT-2 or severe allergic reaction to heparin. Although the mortality rate for expeditiously diagnosed and treated
uncomplicated PE is less than 2% to 7%,84 rates higher than 50% have
Thromboprophylaxis in Pregnant Patients with been reported for patients who were hemodynamically unstable at the
Mechanical Heart Valves time of presentation.85 This has led to more aggressive use of throm-
There remains considerable controversy concerning optimal manage- bolytic therapy in patients with massive PE. However, meta-analysis
ment of VTE in pregnant women with mechanical heart valves. These of 9 randomized, controlled trials comparing thrombolytic agents
patients are given warfarin when in the nonpregnant state. However, versus intravenous heparin in patients with PE found thrombolytic
warfarin is loosely bound to albumin, readily crosses the placenta, and therapy offered no statistically significantly different effect on mortal-
is associated with an increased rate of birth defects (OR, 3.86; CI, 1.86 ity (RR, 0.63; CI, 0.32 to 1.23) or on recurrence of PE (RR, 0.59; CI,
to 8.00) with exposure between 8 and 12 weeks’ gestation.79 The classic 0.30 to 1.18) compared with heparin, but such therapy was associated
fetal warfarin syndrome includes nasal hypoplasia, stippled epiphysis, with a significantly increased risk of major hemorrhage (RR, 1.76; CI,
and characteristic central nervous system defects including agenesis 1.04 to 2.98).86
of the corpus callosum, Dandy-Walker malformation, midline cere- Pregnancy poses special concerns for thrombolytic therapy given
bellar atrophy, and ventral midline dysplasia with optic atrophy. the risk of abruption and puerperal hemorrhage. Turrentine and col-
Maternal warfarin therapy after 12 weeks’ gestation has been associ- leagues reviewed the outcomes of 172 pregnancies treated with throm-
ated with fetal and placental hemorrhage which can occur throughout bolytic therapy and reported a maternal mortality rate of 1.2%, a fetal
pregnancy. loss rate of 6%, and maternal hemorrhagic complications in 8%.87
For these reasons, the agent is usually avoided during pregnancy. Although the data are limited, the risk of hemorrhage in the postpar-
However, it may be appropriate to use warfarin in pregnant patients tum period appears to be limited to those treated within 8 hours of
who have a mechanical heart valve. Meta-analysis suggests that, when delivery.88 Therefore, given the lack of clear benefit and potentially
warfarin is used throughout pregnancy the cumulative risk of embry- unique risks in decompensated pregnant patients refractory to heparin
opathy in 6.4% (CI, 4.6% to 8.9%), but the risk of valvular thrombosis therapy, surgical thrombolectomy may be the preferred option.
is quite low (3.9%; CI, 2.9% to 5.9%).80 In contrast, a regimen consist-
ing of unfractionated heparin from 6 to 12 weeks, followed by warfarin
until 36 weeks and then by unfractionated heparin until delivery,
appears to reduce fetal risks but is associated with a substantially Prevention
increased risk of valve thrombosis (9.2%; CI, 5.9% to 13.9%).
Warfarin is best employed in pregnant patients with mechanical Nonpharmacologic Prevention
heart valves when the dosage can be kept lower than 5 mg/day, because A Cochrane review of randomized, controlled trials indicated that use
cohort studies suggest that this dose is associated with a lower rate of of graduated compression stockings in hospitalized patients with pro-
fetal complications.81 If warfarin is used in this setting, the target INR longed medical immobilization, or application of such stockings from
should be 2.5 to 3.5. Low-dose aspirin should be used as an adjunct to before surgery until discharge or restoration of full mobility, reduced
warfarin, based on a study of antithrombotic therapy in high-risk the occurrence of DVT from 27% to 13% (OR, 0.34; CI, 0.25 to 0.46).89
patients with mechanical valves.82 Warfarin therapy should be stopped A cohort study suggested that use of graduated elastic compression
by 36 weeks, and unfractionated heparin should then be administered stockings also reduced the prevalence of VTE in puerperal patients,
subcutaneously every 8 to 12 hours, with doses adjusted to keep the from 4.3% to 0.9%.90 In addition, graduated elastic compression stock-
aPTT value at 2 × control or the anti-Xa heparin level at 0.35 to ings have been shown to increase femoral vein flow velocity in late
0.70 U/mL. pregnancy.91
No large clinical studies exist to guide use of LMWH in pregnant Meta-analysis in nonpregnant patients with high or moderate risk
patients with mechanical heart valves. However, the manufacturer suggests that intermittent pneumatic compression devices decrease the
of enoxaparin (Lovenox, Aventis, Bridgewater, NJ) specifically relative risk of DVT by 62% compared with placebo, by 47% compared
recommends against its use in this setting, based on a small number with graduated compression stockings, and by 48% compared with
of reports to the FDA of valvular thrombosis in pregnant women so low-dose unfractionated heparin.92 Because graduated elastic com-
treated. The Anticoagulation in Prosthetic Valves and Pregnancy Con- pression stockings and pneumatic compression stockings have no
sensus Report Panel and Scientific Roundtable analyzed these reported hemorrhagic risk and have been shown to be an effective means of
cases of valvular thrombosis in pregnant patients receiving LMWH for DVT prophylaxis in surgical patients and possibly in pregnant patients,
mechanical heart valve prostheses in 2002 and concluded that virtually they should be strongly considered for prophylaxis in high-risk preg-
all such cases were associated with underdosing or inadequate moni- nant patients (e.g., obesity, thrombophilia, strong family history) who
toring.83 Further, the panel recommended enoxaparin therapy in such are admitted for labor and/or delivery or who require prolonged bed
patients in lieu of warfarin, beginning at a dose of 1 mg/kg SQ every rest, and also in all pregnant patients undergoing an elective or repeat
12 hours. They also recommended weekly monitoring of peak anti- cesarean delivery without prior labor. Caution must be exercised
factor Xa levels 4 hours after injection, as well as monitoring trough in their immediate preoperative use after labor, because DVT may

11. CHAPTER 41 Thromboembolic Disease in Pregnancy 865
have already formed and could be theoretically dislodged by either followed by initiation of the proper diagnostic algorithm. Treatment
device. requires prompt initiation of unfractionated heparin or LMWH.
Finally, in pregnancy, left-lateral decubitus positioning during the Prevention includes identification of high-risk patients and both
third trimester may also reduce the risk of VTE. nonpharmacologic and pharmacologic interventions.
Pharmacologic Prevention
As noted, among pregnant patients who have had a previous VTE,
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