Thromboembolism in the pregnant patient may be difficult to diagnose since many symptoms such as lower extremity edema, dyspnea, and tachycardia are common during normal pregnancy. Signs and symptoms of PE include tachypnea, dyspnea, pleuritic chest pain, apprehension, cough, tachycardia, hemoptysis, and fever. The most common presenting sign is tachypnea, which was present in 89% of patients with proven PE (7) in one study. Dyspnea was the second most common finding, followed by pleuritic pain. Ten percent of symptomatic PE cases are fatal within the first hour following the onset of symptoms. Five to ten percent of patients will present with cardiovascular shock (7). Approximately 50% of patients
with PE will have echocardiographic findings suggestive of cor pulmonale or intracardiac emboli that are associated with an increased risk of short-term mortality (7,8). A high level of suspicion must be maintained and rapid evaluation performed in pregnant patients presenting with signs or symptoms of PE.

Any pregnant patient who presents with signs or symptoms of PE should be fully evaluated. Initial evaluation should include auscultation and arterial blood gas analysis. A normal PaO₂ in room air is reassuring; however, a pulmonary embolus may still be present. Up to 14% of patients with a pulmonary embolus have a PaO₂ of >85 mm Hg. Chest radiography and electrocardiography may also be helpful. A chest radiograph may reveal an infiltrate suggestive of pneumonia or atelectasis. These findings, however, do not rule out the possibility of PE, and the diagnosis should be pursued whenever one has a high suspicion of embolism (8,9). The most common ECG abnormality during a pulmonary embolus is tachycardia; however, findings suggestive of acute right-heart failure may be seen including S1, Q3, T3 patterns, right bundle-branch block, P-wave pulmonale, or right axis deviation. These are more common with massive embolism than with smaller emboli, but these findings are also nonspecific (10,11).

D-dimer test measures plasma levels of cross-linked fibrin formed after fibrin lysis by plasmin. This test is a nonspecific indicator of venous thrombosis, and PE is a possible diagnosis. It may be positive in patients with pregnancy, surgery, infection, cancer, trauma, and other inflammatory states and cannot guide decisions about treatment (11,12). Highly sensitive enzyme-linked immunosorbent assay (ELISA)-based D-dimer tests have sensitivity for the diagnosis of PE and DVT of 96% to 98% and a negative likelihood ratio of 0.12 that yield a high certainty for excluding DVT or PE. The sensitivity and positive likelihood values that are between 1.5 and 2.5 do not greatly increase the certainty of diagnosis because of the high frequency of false-positive results. These highly sensitive D-dimer tests can be used to rule out pulmonary embolus. The negative predictive value for these tests when used alone is not high enough to rule out PE, but they may be useful when used in conjunction with another test for PE (13,14). Troponin and brain natriuretic peptide have also been used as indirect markers of PE secondary to the development of myocardial ischemia or right ventricular overload (7).

Evidence of DVT can be used as a surrogate method for diagnosis of PE. In patients who present with acute PE, bilateral venography and compression ultrasonography detect DVT in approximately 75% and 50% of patients, respectively. Additional methods include CT venography and magnetic resonance imaging (MRI) of the lower extremities (7). When there is a high clinical suspicion of PE, and a DVT has been detected, anticoagulation therapy should be started. A negative imaging study for DVT reduces the likelihood of PE; however, the diagnosis cannot be excluded (14).

Ventilation-perfusion (V/Q) lung scanning can be used to evaluate for PE. A normal scan rules out PE but is obtained in only 25% of patients in whom the diagnosis is suspected (15). A high-probability V/Q scan is associated with a prevalence of PE of >80%, but only 45% of patients with suspected pulmonary embolus will have a high-probability scan. Patients with intermediate- or low-probability scans will require further evaluation (14).

Spiral computed tomography (CT) is becoming more widely used for detection of PE. Intraluminal filling defects in lobar or main pulmonary arteries have a positive predictive value for PE of 85%. The sensitivity for subsegmental emboli is only 30%; therefore, intraluminal defects in segmental or subsegmental pulmonary vessels require further evaluation. The combination of CT venography with CT of the pulmonary arteries increases the sensitivity for the diagnosis of PE from 85% to 90% (7). A normal spiral CT significantly reduces the likelihood
of PE but does not exclude the diagnosis. Contrast-enhanced CT arteriography has advantages over V/Q scanning, including speed, characterization of nonvascular structures, and detection of venous thrombosis (7).

Pulmonary angiography is the gold standard for diagnosis of PE. Maternal morbidity is associated with catheterization and injection of the contrast solution at a rate of 4% to 5%. The procedure-related maternal mortality rate is 0.2% to 0.3%. Pulmonary angiography is used only when a high suspicion of PE is present, but the other less invasive diagnostic tests are inconclusive (9,10).

The fetal radiation dose with chest radiography (<100 mrad), V/Q scan (<64 mrad), spiral CT (<200 mrad), or pulmonary angiography (<2,000 mrad) is low. Even when chest radiography, V/Q scan, and pulmonary angiography are used in combination, the total radiation dose to the fetus is significantly below the generally accepted dose associated with adverse fetal and neonatal outcomes (5 rad) (10,16). The radiation dose may also be decreased by using abdominal shielding.

MRI has not been used as extensively for detection of PE but seems to have an accuracy similar to that of spiral CT. MRI has the added benefit of avoiding radiation exposure to the fetus (14). The limitations of MRI include availability at the health care facility, time, and cost.

Bed rest is not recommended for DVT unless there is substantial pain and swelling. The data for PE are not conclusive. When PE is diagnosed, inpatient therapy with initial bed rest for 24 to 48 hours is often recommended (7,17,18). Inpatient parenteral anticoagulation with low molecular weight heparin (LMWH) or unfractionated heparin should be initiated unless contraindicated (18). Anticoagulation improves survival among patients with symptomatic PE, but the risk of recurrent, nonfatal venous thromboembolism is estimated at 5% to 10% during the 1st year after diagnosis (18). If the suspicion of PE is high, parenteral anticoagulation should be considered even before imaging, as long as the risk of bleeding does not appear to be excessive. Among pregnant patients, parenteral anticoagulation with subcutaneous unfractionated heparin or LMWH should be maintained throughout pregnancy. Heparin is the drug of choice for acute PE in pregnancy. It has a high molecular weight, is negatively charged, and does not cross the placenta. A heparin bolus of 5,000 units (80 IU/kg) should be given, followed by an hourly infusion of 1,000 units. The dose should be adjusted to keep the activated partial thromboplastin time (aPTT) at 1.5 to 2.5 times normal levels. After 5 to 10 days of intravenous anticoagulation, subcutaneous heparin injections may be started at doses of 7,500 to 10,000 units every 8 to 12 hours to keep the aPTT at 1.5 to 2.5 times normal. Monitoring LMWH by measuring the level of activity against activated factor × (anti-factor Xa) is common practice in patients who are morbidly obese (weighing >150 kg) or very small (<40 kg), in patients with either very severe renal insufficiency or rapidly changing renal function or in patients who are pregnant (19). Full anticoagulation should be continued for 3 to 6 months or longer depending on the presence of risk factors (20). After that time, there is controversy regarding whether to continue full-dose or low-dose prophylactic heparin for the remainder of the pregnancy and for 6 to 12 weeks postpartum (21). Among postpartum patients diagnosed with PE, coumadin can be initiated simultaneously on the 1st day of therapy with subcutaneous LMWH, fondaparinux, or weight-based intravenous unfractionated heparin administered for at least 5 days, preferably until the international normalized ratio (INR) is in the therapeutic range (2.0 to 3.0) for 2 consecutive days (18).

The main complication associated with heparin therapy is hemorrhage. The incidence is 4% in nonsurgical patients receiving intravenous heparin (21). Heparin is associated with two types of heparin-induced thrombocytopenia. The more common form of thrombocytopenia is benign and self-limiting. The more
severe form is due to heparin-dependent IgG antiplatelet antibodies and occurs 5 to 14 days after starting full-dose heparin in 3% of patients. Platelet levels should be checked for the first 2 to 3 weeks after instituting heparin therapy, and the medication should be discontinued if severe thrombocytopenia is detected (21). If a patient develops heparin-induced thrombocytopenia, the heparin therapy should be discontinued. Subsequent management options should include consultation with a maternal-fetal medicine specialist and/or hematologist/oncologist or an internist with an expanded knowledge in hematology. Options for treatment with a direct thrombin inhibitor (e.g., argatroban or lepirudin) may be considered. Similarly, newer alternatives include oral direct thrombin inhibitors (dabigatran), oral anti-factor Xa inhibitors (rivaroxaban and apixaban that are in phase 3 trials), and reversible parenteral anti-factor Xa inhibitor requiring dosing only once a week (biotinylated idraparinux) (22). Heparin can lead to significant bone loss, especially in pregnant women. This effect can be decreased, and we recommend supplementing vitamin D and calcium (21).

LMWH may be superior to unfractionated heparin for the treatment of DVT, and it is at least as effective as unfractionated heparin in reducing the risk of death and the risk of major bleeding during initial therapy for PE (23). Initial dosing should be according to maternal weight, and anti-Xa levels should be checked 4 hours after the morning dose every week. The dose should be adjusted to keep the anti-Xa level between 0.7 and 1.2 U/mL. LMWHs present less risk for the severe form of heparin-induced thrombocytopenia and for osteoporosis than unfractionated heparin; however, they are much more costly (21,24).

Coumarin derivatives cross the placenta and can lead to embryopathy in the first trimester, which consists of nasal and limb hypoplasia. Midtrimester exposure can lead to optic atrophy, microcephaly, and mental retardation. Bleeding within the fetoplacental unit may result in a high fetal loss rate. Coumarin derivatives are relatively contraindicated in pregnancy and should be used with extreme caution. There is an exception of the mechanical heart valve patient whose extreme risk for thrombosis even with anticoagulation with heparin may exceed the risk for embryopathy with coumarin, and she may be an appropriate candidate for coumarin during pregnancy. These medications may be used after delivery if full anticoagulation is still required (21,24).

The primary indications for placement of an inferior vena cava filter include contraindications to anticoagulation, major bleeding complications during anticoagulation, and recurrent embolism while the patient is receiving adequate therapy (18).

The treatment goal for the pregnant asthmatic is to obtain optimal therapy by maintaining control of her asthma thus ensuring improved maternal health and normal fetal maturation (36). The components of caring for a patient with asthma include assessment and monitoring of asthma, including objective measures of pulmonary function; control of factors contributing to asthma severity; patient education; and pharmacologic therapy using a stepwise approach (36).

Most asthma medications are safe and better than the alternative of asthma symptoms and exacerbations that may impair fetal oxygenation during pregnancy (36). Prevention of inflammation, airway hyperresponsiveness, and symptoms is the cornerstone of therapy. Stepwise therapy requires additional medications and dosages adjusted to the symptom severity. A patient not responding to any given treatment should be stepped up to the next level of therapy. Medications are categorized in two general classes: (a) long-term control medications to achieve and maintain control of persistent asthma—especially important is daily medication to suppress the inflammation that is considered an early and persistent component in the pathogenesis of asthma—and (b) quick-relief medications that are taken as needed to treat symptoms and exacerbations (36).

Inhaled β₂-agonists are recommended for the acute asthma exacerbation by relieving acute bronchospasm of any severity. They are also the first-line medication for mild intermittent and exercise-induced asthma. They are not very effective in preventing airway hyperresponsiveness among patients with persistent asthma (37). To date, no congenital anomalies have been associated with these medications in animals or humans (38). Subcutaneous injection of selective β₂-agonists, such as terbutaline, may be used in patients with severe exacerbation who are unconscious, cannot use an inhaler, or is moving air very poorly (39). Exclusive use of short-acting β₂-agonists for management of persistent asthma is associated with an increased mortality (40). Long-acting β₂-agonists have been shown to significantly decrease the number and severity of exacerbations when used in combination with inhaled corticosteroids; however, their safety in pregnancy has not been proven (30,38).

Inhaled corticosteroids are the mainstay of long-term control of persistent asthma of any severity. These medications decrease airway inflammation, thereby decreasing the number and severity of exacerbations as well as the need for additional inhaled β₂-agonist therapy. The majority of inhaled corticosteroids are pregnancy category C, with the exception of budesonide, which is now pregnancy
category B. Several large studies have shown no increased risk for congenital anomalies when budesonide was used during pregnancy (36,41,42). Oral corticosteroids have been associated with orofacial clefting and intrauterine growth restriction in some trials; however, poor asthma control may lead to worse maternal and fetal complications (28,38,42,43). The main indication for oral steroids is patients not responsive to short-acting bronchodilators and inhaled corticosteroids regardless of the severity of the disease. Quick-relief medication β₂-agonists should be available to all patients with persistent asthma being treated with inhaled corticosteroids or other long-term anti-inflammatory medications (36).

Theophylline is rarely used for asthma management during pregnancy because of its side effects. Drug levels may change dramatically during the course of pregnancy due to pregnancy-related changes in pharmacokinetics and interactions with other drugs. Serum levels must be checked regularly since theophylline has a narrow therapeutic window, and supratherapeutic drug levels can cause death (38,42). The recommended serum concentration is 5 to 12 µg/mL. It is used as an alternative treatment for mild persistent asthma or adjunctive treatment to be used with inhaled corticosteroids in moderate to severe persistent asthma (36).

Cromolyn and nedocromil are mast cell stabilizers dispensed as inhalers. They are used as an alternative to inhaled corticosteroids for therapy in mild persistent asthma. Leukotriene receptor antagonists, including zafirlukast and montelukast, may also be considered as an alternative for mild persistent asthma and as an adjunctive therapy for long-term control in moderate persistent asthma (36).

Ipratropium bromide is an inhaled anticholinergic agent and is pregnancy category B. A recent metaanalysis revealed significantly improved pulmonary function following administration of anticholinergic inhalers in combination with inhaled β₂-agonists for patients with a severe exacerbation (44).

Treatment of an acute asthma exacerbation during pregnancy is very similar to treatment for nonpregnant patients (Fig. 1.1). Treatment of an acute exacerbation begins at home. Patients should have individualized treatment plans. Treatment begins with inhaled albuterol 2 to 4 puffs every 20 minutes for up to 1 hour (36). This is followed by inhaled or oral corticosteroids for long-term management and suppression of inflammation and hyperreactivity. For the patient that has a severe exacerbation not responsive to home therapy, rapid evaluation upon presentation is critical. Initially, airway patency should be established. The physical examination should include auscultation, heart rate and respiratory rate evaluation, and, in addition, observing if the patient is using accessory muscles. Pulse oximetry should be obtained. In the pregnant patient, supplemental oxygen should be administered to maintain the pulse oximetry value at ≥95% to assure adequate fetal oxygenation. In patients at >24 weeks of gestation, external fetal heart rate (FHR) monitoring should be continued until significant maternal improvement. Pulmonary function should be determined using both spirometry and FEV₁ or a peak expiratory flow meter (45). Peak expiratory flow rate (PEFR) appears to be equivalent to FEV₁ for determining airway constriction. Arterial blood gas testing should be considered for any patient with pulse oximetry values <95%, severe distress, or a PEFR ≤30% of the predicted value after initial therapy (45).

If the initial PEFR is >50% of that predicted, an inhaled β₂-agonist should be administered every 20 minutes for 1 hour. Oral systemic corticosteroids should be added if there is no response or if the patient recently took inhaled corticosteroids. If the initial PEFR is <50% of the predicted value, it is considered a severe exacerbation, and inhaled ipratropium bromide should be given in conjunction with the β₂-agonist every 20 minutes for 1 hour (36). Metered dose inhalers used with inhaler spacer devices provide doses of medications equivalent to those
with nebulizer therapy (45). Subcutaneous terbutaline may be administered in patients who cannot comply with the administration of inhaled medications (39

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