Clinical Presentation

The signs and symptoms of DVT are nonspecific and often mimic normal symptoms of pregnancy, specifically lower leg edema and pain. A systematic review of the anatomic distribution of DVT in symptomatic pregnant patients (six studies, pooled n = 124) identified left leg thrombus in 88% of pregnant women in whom the side of the DVT was reported. Most thrombi were proximally located in the iliac or femoral veins, or both. This distribution is different from the anatomic distribution in nonpregnant patients, who are more likely to have thrombi in the distal calf vessels. A prospective observational study of serial ultrasonographic examinations in pregnant women ( n = 24) found an increase in vessel diameter and a decrease in flow velocity in the proximal deep leg veins with increasing gestation; this finding was most notable in the common femoral vein. The flow velocity was slower in the left leg than in the right leg, presumably caused by uterine compression of the left iliac vein where it crosses the right iliac artery.

Diagnosis

For patients with new-onset signs or symptoms suggestive of DVT, the ACOG recommends compression ultrasonography of proximal veins as the initial diagnostic test. If the test is negative, and involvement of the iliac vessels is not suspected, no further action other than routine surveillance is necessary. A positive result warrants treatment (see later discussion). If the results are negative or equivocal, and iliac vein thrombosis is suspected, clinicians may opt for Doppler ultrasonography of the iliac vein, venography, or magnetic resonance imaging or presumptive anticoagulation.

The d -dimer test is useful in nonpregnant patients because it has a high sensitivity and a high negative predictive value. Unfortunately, d -dimer levels are increased in pregnancy, making interpretation of elevated levels difficult in pregnant women. In one prospective, longitudinal study, serial d -dimer levels were evaluated in 89 healthy pregnant women; values exceeded the normal nonpregnant reference range in all but one woman in the third trimester. Therefore, the d -dimer test is not currently recommended for diagnosis of DVT in pregnancy, although future work may delineate pregnancy-specific thresholds.

Clinical Presentation

Clinical suspicion for PTE is critical to ensure timely diagnosis and treatment. Physical signs and symptoms may be subtle and limited to symptoms (e.g., shortness of breath) that mimic normal pregnancy ( Table 38.1 ). Palpitations, anxiety, pleuritic chest pain, cyanosis, diaphoresis, and cough with or without hemoptysis may all indicate PTE. Physical examination of the patient commonly reveals tachypnea, crackles, decreased breath sounds, and tachycardia. Signs of right ventricular failure, including an accentuated or split-second heart sound, jugular venous distention, a parasternal heave, and hepatic enlargement, may be apparent. Although the Pa o ₂ is generally low (less than 80 mm Hg), as many as 30% of all patients with a pulmonary embolus have an arterial Pa o ₂ greater than 80 mm Hg; thus, the diagnosis of PTE cannot be excluded on the basis of an apparently normal Pa o ₂ . Left ventricular failure may occur secondary to poor left ventricular filling and arterial hypoxemia. One or more signs of DVT (calf or thigh edema, erythema, tenderness, palpable cord) generally accompanies the pulmonary or cardiovascular findings. The electrocardiogram may show signs of right ventricular strain, including a right-axis shift, P pulmonale, ST-segment abnormalities, and T-wave inversion, as well as supraventricular arrhythmias. Transthoracic echocardiography may reveal signs of right ventricular dysfunction or other findings consistent with acute pulmonary embolism, such as hypokinesis of the right ventricular free wall with normal contraction of the apical segment (McConnell’s sign).

Diagnosis

Diagnosing PTE in pregnancy is challenging given the lack of validated criteria specific for the peripartum period. The American Thoracic Society developed an evidence-based guideline for the evaluation of suspected PTE in pregnancy, which has been endorsed by the ACOG. A diagnostic algorithm for suspected PTE is shown in Fig. 38.1 . If the pregnant patient has signs or symptoms suggestive of DVT, in addition to the signs or symptoms of PTE, compression ultrasonography should be done. If the results are positive, treatment should ensue. However, if the results are negative, further imaging is necessary. If there are no signs or symptoms of DVT, a chest radiograph should be performed, both to exclude alternative diagnoses, and to guide decision-making for the next most appropriate test. If the chest radiograph is normal, V/Q scanning should be performed. A retrospective study of 304 women who underwent computed tomographic angiography (CTA) or V/Q scanning at a single institution between 2001 and 2006 demonstrated that pregnant women with a normal chest radiograph have a fivefold higher rate of a nondiagnostic result from a CTA compared with a V/Q scan (relative risk [RR], 5.3; 95% CI, 2.1 to 13.8). The use of chest radiography as a screening procedure may also minimize the amount of radiation to which a pregnant woman and her fetus are exposed if the pregnant patient is a candidate for V/Q scanning. If the chest radiograph is abnormal, CTA is the next appropriate test because the proportion of nondiagnostic V/Q scans in the presence of an abnormal chest radiograph has been reported to be as high as 48%. If either the V/Q scan or CTA is positive, anticoagulation should ensue. The use of magnetic resonance pulmonary angiography has not been validated in the pregnant population.

Diagnostic algorithm for workup of suspected pulmonary thromboembolism during pregnancy. CTA, Computed tomography pulmonary angiography; CUS, compression ultrasonography; CXR, chest radiograph; DVT, deep vein thrombosis; V/Q scan, ventilation-perfusion scan.

Single-photon emission computed tomography (SPECT) is another diagnostic modality that has been evaluated in pregnant women. In a nonpregnant patient population, the V/Q SPECT demonstrated 100% sensitivity and 94% specificity compared with CTA as the “gold standard.” A retrospective analysis of 127 women who underwent evaluation for PTE with V/Q SPECT identified PTE in 11 women (9%). The negative predictive value was 100%, and the calculated fetal and breast absorbed radiation doses were low (less than 0.014 mGy and 0.25 mGy, respectively).

Perhaps the greatest concern with diagnostic imaging for PTE is maternal and fetal exposure to ionizing radiation. The teratogenic effects of ionizing radiation are discussed in Chapter 17 . Both V/Q scanning and CTA are associated with low doses of fetal radiation exposure (less than 1 mGy). V/Q scanning delivers a higher fetal dose of radiation than CTA; however, the maternal radiation exposure is higher with CTA, particularly radiation to the breast tissue. A patient’s lifetime breast cancer risk may increase as much as 14% after CTA. Maternal radiation exposure is lower with V/Q SPECT than with CTA.

Anticoagulation

All women with a new-onset thromboembolic event in pregnancy should be therapeutically anticoagulated. Patients with a previous history of thrombosis, certain high-risk populations (e.g., patients with acquired or inherited thrombophilias), or patients with a mechanical heart valve should be anticoagulated during pregnancy as well as the postpartum period. The ACOG practice bulletin on thromboembolism in pregnancy summarizes which patients should receive prophylactic versus therapeutic anticoagulation. Given the significant morbidity and mortality associated with VTE, the National Partnership for Maternal Safety, a multidisciplinary body that develops evidence-based safety bundles, published a consensus bundle on VTE in 2016. This bundle broadens the indications for antepartum and postpartum pharmacologic anticoagulation beyond the ACOG practice guidelines, including recommending daily thromboprophylaxis for antepartum patients hospitalized for greater than 72 hours. This expanded use of pharmacologic thromboprophylaxis has anesthetic implications (see later discussion).

Although the exact dose and regimen for anticoagulation remain controversial, two classes of drugs are typically used to initiate anticoagulation: unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH). Table 38.2 lists anticoagulation regimens commonly used in pregnancy. Both the ACOG and the American College of Chest Physicians recommend LMWH rather than UFH for prophylactic and therapeutic anticoagulation for pregnant women. No differences in symptomatic thrombotic events (RR 0.47; 95% CI, 0.09 to 2.49) were identified in a 2014 Cochrane review that compared antenatal prophylaxis with UFH or LMWH (four trials, pooled n = 404).

LMWH has an enhanced ratio of antithrombotic (anti–factor Xa) to anticoagulant (anti–factor IIa) activity compared with UFH and does not affect activated partial thromboplastin time (aPTT) measurement. A 2005 systematic review (64 studies, pooled n = 2777) evaluated the efficacy and safety of LMWH in pregnancy. The rate of VTE in women receiving LMWH for thromboprophylaxis, prevention of adverse pregnancy outcome, or for unspecified indications was 0.9% (95% CI, 0.6% to 1.3%), and the rate of significant maternal bleeding was 2.0% (95% CI, 1.5% to 2.6%). There were no reported cases of heparin-induced thrombocytopenia when LMWH was used for any indication in pregnancy. An older systematic review (1999) did not identify any increase in osteoporosis in pregnant women treated with LMWH compared with nonpregnant controls.

The pharmacokinetics of LMWH are altered during pregnancy. When LMWH is used for therapeutic anticoagulation, dosing can be adjusted based on anti–factor Xa activity. The desired peak level is 0.6 to 1.0 U/mL measured 4 hours after injection ; however, because of the cost of the assays, routine monitoring of anti–factor Xa activity is not recommended during therapy in pregnancy. Viscoelastic monitoring provides an alternative method to assess LMWH activity. Carroll et  al. demonstrated that the delta reaction time (ΔR) measured by thromboelastography correlates with anti–factor Xa levels in the pregnant woman and allows LMWH doses to be adjusted to ensure anticoagulation or, conversely, confirms the absence of anticoagulation. LMWH is cleared by the kidney; therefore, dose reduction may be required in patients with renal failure.

UFH therapy may be used to initiate anticoagulation or to maintain therapy as the patient nears delivery (see later discussion). UFH exerts its anticoagulant activity by binding to antithrombin III and potentiates inactivation of other coagulation factors, including thrombin (factor IIa); factors IXa, Xa, XIa, and XIIa; and kallikrein. Typically, UFH is administered as a subcutaneous injection for both prophylactic and therapeutic therapy. The aPTT measured 6 hours after an injection or dose adjustment should be maintained at 1.5 to 2.5 times the normal range. In pregnancy, the bioavailability of UFH decreases as a result of an increase in heparin-binding proteins, increased plasma volume, increased renal clearance, and increased degradation by plasma heparinases. Based on pharmacodynamic studies, even a twice-daily dose of subcutaneous UFH is often inadequate to achieve prophylactic plasma heparin concentrations in the second half of pregnancy, possibly because of the presence of a heparin-neutralizing protein or the presence of increased factor VIII and fibrinogen levels in pregnancy. For therapeuti c anticoagulation, the ACOG currently recommends a subcutaneous, twice-daily UFH dose of 10,000 units or greater, with aPTT monitoring and dose adjustment. In the event of an antepartum massive PTE resulting in hemodynamic instability, thrombolytic therapy should be considered as it is associated with high maternal and fetal survival. However, in the postpartum period, other options, including thrombectomy, should be considered because thrombolysis is associated with a significant risk for hemorrhage.

In patients who develop heparin-induced thrombocytopenia, or severe cutaneous reactions to heparin, fondaparinux is the preferred anticoagulant because it has minimal cross-reactivity with UFH. Anticoagulation with other classes of drugs such as vitamin K antagonists, thienopyridines, direct factor Xa inhibitors, and direct thrombin inhibitors is possible in pregnancy, but the use of these medications is less common. Animal studies with rivaroxaban, a direct factor Xa inhibitor, and dabigatran, a direct thrombin inhibitor, have found teratogenic effects, reduced fetal viability, hemorrhagic changes, and placental abnormalities; thus, their use in pregnancy is not recommended.

Antithrombotic Therapy and Anesthetic Implications

In 2018, the American Society of Regional Anesthesia and Pain Medicine (ASRA) published updated guidelines for regional anesthesia in patients receiving antithrombotic or thrombolytic therapy. Owing to the relative paucity of outcome data in pregnant women, the ASRA suggests following the guidelines for surgical patients when developing clinical policy for obstetric patients with regard to initiation of neuraxial procedures and postpartum thromboprophylaxis. The ASRA-recommended time intervals between anticoagulant administration and the initiation of neuraxial anesthesia are summarized in Table 38.3 .

TABLE 38.3

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