ASTHMA IN PREGNANCY

How to treat pregnant patients with asthma

By Ellen Sakornbut, MD

A proactive, stepwise approach to the management of asthma in pregnancy can help ensure a good perinatal outcome. Focus on preventing acute asthma attacks because they can leave both mother and fetus vulnerable to progressive hypoxia and potentially disastrous consequences.

Five percent of pregnancies are complicated by asthma, which is the most common chronic medical problem in young women and of growing concern in the general population of the United States and other industrialized countries. Early studies of pregnant women with asthma revealed high rates of perinatal complications, including perinatal loss, prematurity, preeclampsia, and low birthweight. Prospective studies performed in the last decade demonstrate essentially normal perinatal outcomes with modern management of asthma.¹ Nonetheless, large, population-based retrospective studies done during the same period still show increased rates of poor outcomes, with some evidence that outcomes were poorer if the intensity of asthma therapy was decreased.^2,3

Your treatment plan for the pregnant patient with asthma should be designed to minimize the risk to mother and fetus of short- and long-term consequences—such as medication toxicity and/or side effects—avoid teratogenicity, and preserve an intact uteroplacentofetal circulation. At the same time, you should make every effort to prevent acute exacerbations of your patient's asthma and reduce her symptoms to a bare minimum. Acute asthma attacks render both the mother and fetus vulnerable to progressive hypoxia and potentially disastrous results. Patient education is key in controlling asthma, since self-monitoring is the cornerstone of ambulatory management.

Pathophysiology of asthma

Asthma combines reversible airway constriction, inflammation, airway edema, and mucous plugging. Multiple aspects of the inflammatory pathway are triggered with release of leukotrienes and histamines; recruitment of eosinophils, neutrophils, TH2 lymphocytes, and antigen-presenting cells; and mast cell degranulation. This inflammatory process is mediated by numerous humoral factors, especially leukotrienes and cytokines.⁴ Chronic inflammation may lead to bronchial hyperreactivity and smooth-muscle hyperplasia.

Clinical signs and symptoms

A patient who has uncontrolled asthma may present to you with a cough (especially one that is spasmodic), a sensation of chest tightness or discomfort, dyspnea, or audible wheezing. In monitoring the disease, pay particular attention to night and early morning symptoms. When taking the patient's history, remember to ask how frequently she uses rescue medication, whether she has limitations on activity or fatigues easily, what her exercise tolerance is, whether there are factors that exacerbate the asthma, and how compliant she is with medication. Acute exacerbations should also prompt you to ask about viral and respiratory infections.

Physical examination of the pregnant asthmatic during an acute exacerbation should include assessment of respiratory effort and rate, perfusion status, a qualitative assessment of airflow (both volume of exchange and any prolongation of the expiratory phase), and signs of infection. You should also determine the fetal heart rate. In the patient with a severe exacerbation, an abnormal pulsus paradoxus may reflect impedance of blood return to the heart with overinflation of the lungs. You may note both inspiratory and expiratory wheezes as well as rales. However, rales often do not reflect an infiltrative or pneumonic process and will resolve after inhalation therapy. The presence of a "silent chest" with poor air movement is ominous and requires immediate intervention

Reversible bronchoconstriction manifests itself with restriction of airflow in the large to medium bronchi, resulting in a decrease in peak expiratory flow rate (PEFR), measured with a hand-held peak flow meter, or decreased forced expiratory volume (FEV₁) as measured by spirometry. The risk of hypocapnia increases with PEFR values less than 25% of predicted or less than 120 L/min. You can assess the reversibility of the defect by having the patient use a bronchodilator during spirometry and taking readings before and after administration of a short-acting beta-agonist inhalant.

How asthma differs in pregnant women

The severity of asthma worsens in 20% to 35% of pregnant women, remains stable in 40% to 50%, and improves in 20% to 30%. Prospective studies have demonstrated that during pregnancy, as many as 42% of women require more medication to control their asthma.⁵ Disease exacerbation is more common at the end of the second trimester and the early third trimester.

As pregnancy progresses, typical changes in respiratory physiology include an increased respiratory rate and a decrease in diaphragmatic excursion with a decrease in functional residual capacity. In the second half of pregnancy, normal pCO₂ readings for pregnant women fall to 32 torr. Early blood gas changes with acute asthma exacerbation include worsening hypocapnia, while more severe and sustained asthma attacks are associated with normalization of pCO₂. During the second and third trimester, a "normal" pCO₂ during an attack indicates very serious CO₂ retention as a result of inadequate ventilation.

Clinical classification of asthma

Treatment protocols for asthma differ depending upon the severity of the condition. The National Asthma Education and Prevention Program defines mild intermittent asthma as symptoms that occur less than two times per week, night symptoms less than two times per month, and pulmonary function (either PEFR or FEV₁) greater than 80% of predicted. Mild persistent asthma constitutes symptoms that occur twice a week or more but not daily, night symptoms three to four times per month, and pulmonary function greater than 80% of predicted. Moderate asthma is classified as daily symptoms, night symptoms five or more times per month, and pulmonary function 60% to 80% of predicted. A patient's asthma is considered severe if she experiences continuous symptoms of asthma, frequent night symptoms, and pulmonary function less than 60% of predicted.⁶

These classifications should be of value to you in quantifying control of a patient's asthma as well as the severity of her illness. Consider some flexibility in clinical use of the definitions, however, since a patient who has been hospitalized for asthma or placed in intensive care should probably be considered to have more severe disease even if her symptoms are currently mild and intermittent.

Supportive measures

Patients with asthma should be vaccinated for influenza to lessen the risk that severe respiratory illness will complicate their disease. Many individuals who have asthma are aware of what triggers their attacks and will already have implemented environmental controls, such as use of HEPA filters, special mattress and pillow covers, and avoidance of pet dander. Tobacco smoke—from both primary and secondary exposure—also should be absolutely avoided. Because antibody to cockroach allergen has now been strongly associated with asthma severity in inner-city women, regular control measures should be instituted in susceptible housing. Immunotherapy can be continued in pregnancy without risk to the fetus.^7,8

Pharmacotherapy

A spacer device vastly improves the delivery of almost all medication to the bronchi via metered dose inhalation (MDI). Some manufacturers have chosen to package inhaled medications in unique delivery systems to improve efficacy, but most MDIs can be prescribed with a universal spacer device that will fit both bronchodilators and anti-inflammatory medications. Occasionally a patient with severe asthma will need home nebulizer equipment, but in most cases, MDIs used with spacers are as effective as delivery of medication through a nebulizer.

You should judge the efficacy of a patient's therapy based on her report of symptom frequency and severity. Women with mild persistent or more severe asthma also should be monitored with a hand-held peak expiratory meter. Peak flow meters are easy to use and do not require lengthy instruction, and patients can easily be taught to use one by your nursing staff. Once you've established the expected normal peak flow and the patient's best, have her repeat the measurement daily as a way of identifying when therapy for exacerbation may be necessary, when she needs to call the physician, and when to go to the emergency room.

Table 1 summarizes classes of anti-asthmatic medications, including application for chronic or acute treatment of asthma. Table 2 summarizes dosages of commonly used medications, along with FDA Category. Figure 1 provides an algorithm for management of chronic asthma in pregnancy.

TABLE 1
Classes of medications for treating asthma

TABLE 2
Dosages of commonly used asthma medications

Anti-inflammatory medication. Inhaled steroids are indicated to treat most patients with persistent asthma as a way of decreasing symptoms and preventing acute attacks. Multiple published studies are available documenting the safety of inhaled steroids like beclomethasone, triamcinolone acetonide, and budesonide in pregnancy.^1,9,10 Efficacy studies have demonstrated a significant decrease in the rate of asthma exacerbations during pregnancy and significant decreases in readmission for asthma in women started on inhaled steroids following an admission for asthma during pregnancy.¹¹ Recent studies also demonstrate 25% lower infant birthweights in asthmatic women who were not treated with inhaled steroids in pregnancy compared to those who did receive the therapy.¹² A large, randomized controlled trial is under way comparing inhaled steroids and oral theophylline in the treatment of women with moderate asthma.¹³ Consensus statements from the American College of Obstetricians and Gynecologists and the American College of Allergy, Asthma, and Immunology recommend inhaled steroids to improve outcome in all pregnant women who have at least mild persistent asthma.¹⁴

Inhaled steroids available in the US include beclomethasone, triamcinolone, budesonide, flunisolide, and fluticasone. Differences between available medications include relative potency and frequency of dosing. Older medications such as beclomethasone and triamcinolone require a larger number of inhalations repeated at least three times daily to be effective, which has an impact on patient compliance. Safety data related to fetal defects are not currently available for newer inhaled steroids, but systemic absorption should be minimal with usual dosage ranges.

Nedocromil, used as an anti-inflammatory agent, is comparable to cromolyn in efficacy. Its mechanism of action is complex, including mast cell stabilization and inhibition of bronchoconstriction. No animal studies suggest teratogenicity, and no human data is available.¹⁵ Because nedocromil is inhaled and has minimal or no systemic absorption, it is likely to be safe and is categorized as FDA Category B. There is little to suggest that it is preferable to inhaled steroids in a woman with mild persistent asthma, since no outcome data are available during pregnancy comparable to what we have for inhaled steroids. Consider using nedocromil, however, in the woman whose asthma was well-controlled with it before pregnancy.

Cromolyn has been used extensively in the pediatric population, particularly in atopic individuals. It acts as a mast cell stabilizer, preventing release of histamines and slow-reacting substances that produce anaphylaxis. Cromolyn is not absorbed systemically and is delivered via aerosolized suspension in a metered dose inhaler or via nebulizer. Like nedocromil, it can be considered for continuation in the woman who had a good therapeutic response prior to pregnancy. There are no studies at this time that demonstrate improved outcomes comparable to those obtained with inhaled steroids.

Systemic corticosteroids. Clinicians often are concerned about the risks associated with use of systemic steroids. In addition to treatment of asthma, systemic steroids have been used during pregnancy for other medical illnesses, particularly lupus. Concerns about the fetal hypothalamic-pituitary-adrenal axis have proven to be relatively unfounded, since fetal/ neonatal adrenal suppression is extraordinarily rare. Actual risks include well-known metabolic effects, such as steroid-induced hyperglycemia, elevation of blood pressure, and the potential for immune suppression. There appears to be a small increase in the rate of cleft palate with first-trimester exposure, although a large population-based case–control study failed to establish any pattern of anomaly or increased risk of defect in pregnancies with first-trimester exposure to oral steroids.^16,17

In the vast majority of patients, asthma can be controlled with a combination of inhaled steroids and other medications. Overall, the use of systemic steroids to treat severe asthma during pregnancy has been associated with good outcomes, and lower birthweight or a small-for-gestational-age infant can result when a pregnancy is complicated by at least one episode of status asthmaticus.¹⁸ When comparing risks and benefits, then, systemic steroids appear justified in patients with serious exacerbations.

Current treatment standards for asthmatic exacerbations include initiating systemic steroid therapy in all patients whose condition cannot be readily stabilized with repeated bronchodilator treatments. Tapering need not be done slowly after stabilization of the acute respiratory event but all patients treated with systemic steroids should be tapered off the medication. Before discontinuing the oral therapy, give inhaled steroids for a minimum of 5 to 7 days so that the inhalation treatment will have established a therapeutic effect. Maintain steroid-dependent asthmatics on the lowest possible dose and consider a leukotriene receptor antagonist in patients who are not already on this medication.

Bronchodilators. Systemic beta agonists have been used extensively in obstetrics for premature labor. For respiratory disease, inhaled short-acting beta agonists are the primary therapy for acute relief of wheezing, dyspnea, and exercise intolerance. Included in this category are albuterol, metaproterenol, pirbuterol, fenoterol, and terbutaline. Of these, albuterol and pirbuterol are more selective for beta-2 receptors than terbutaline and metaproterenol. Fenoterol has been associated with cardiac arrhythmias and is not available in the US. Ipratroprium bromide (an antimuscarinic agent) can be used for acute exacerbation of asthma in the patient who has a suboptimal response to beta- agonist therapy.

Safety data on albuterol show nonreassuring animal studies but reassuring human studies.¹⁵ Beta-agonist therapy has not been associated with an increased rate of fetal malformations or other adverse pregnancy outcomes in prospective or retrospective population-based studies involving large numbers of pregnant asthmatic women being treated with these medications.¹

Acute (rescue) use of albuterol is recommended for both mild symptoms and more severe attacks. It can be given as often as every 3 to 4 hours for acute exacerbations or as prolonged inhalation treatment during severe exacerbation, with close monitoring of patient condition and maternal heart rate. In women with exercise-induced asthma, two inhalations of albuterol 30 minutes prior to exertion is useful for prophylaxis.

Salmeterol is a long–acting beta-agonist that can be given twice daily. Little safety data is available on the inhaled form and animal studies with systemically administered salmeterol are not reassuring, although the pharmacologic structure and mechanism of action are similar to albuterol.¹⁹ Salmeterol should be considered in women who have moderate-to-severe asthma and responded well to therapy before pregnancy. It is also useful for preventing nocturnal symptoms in patients who are already on inhaled steroids at a medium dose and has been demonstrated to be more effective than doubling the dose of the steroids. ²⁰ Salmeterol appears to be more effective and has a better side-effect profile than theophylline.²¹

Oral beta-agonist therapy with oral albuterol or terbutaline is of little therapeutic benefit in the management of asthma, and side effect profiles make these medications unattractive as compared to the inhaled forms.

Methylxanthines. Theophylline and dyphylline increase cyclic AMP levels by inhibiting phosphodiesterase. They work by directly relaxing the bronchial smooth muscles, dilating the pulmonary arteries, and increasing pulmonary blood flow. Although theophylline has been used extensively in pregnancy without causing teratogenic effects, it is not an easy medication to use in this setting.^22,23 It has significant potential for toxicity with a low therapeutic index, and there are case reports of serious toxicity in mothers and newborns.^24,25 Blood levels in the therapeutic range are 8 to 12 µg/mL (some sources show 10 to 15), with toxicity occurring as low as 16 to 18 µg/mL and frequently above 20 µg/mL. Theophylline can interact with several drugs including phenytoin, erythromycin, and propranolol. Dosages must be adjusted in the presence of altered cardiac output or hepatic or renal disease. Its volume of distribution is increased in the third trimester of pregnancy due to reduced protein-plasma binding. Symptoms of toxicity include nausea and vomiting, tachycardia, insomnia, and irritability.

Aminophylline, the IV form of theophylline, has not been shown to reduce hospital stay or response time when compared to systemic steroids.²⁶ Therefore, it can be considered as an adjunct but not an alternative to systemic steroids in the severely ill patient. For prevention, consider theophylline in severe asthmatics who have had a good therapeutic response to it before pregnancy. Monitor a patient's blood levels at least every trimester and during acute exacerbations.

Leukotriene receptor antagonists. Montelukast and zafirlukast belong to a class of drugs that inhibit the actions of leukotrienes on airway smooth muscle and have other anti-inflammatory effects. They are highly effective and well-tolerated medications for preventing symptoms of asthma. Generally indicated in patients with moderate-to-severe disease, montelukast and zafirlukast often are preferred by patients because of ease of administration (oral form, daily or twice daily) and they may have a beneficial effect on allergic rhinitis. Montelukast and zafirlukast have no role in treatment of acute symptoms.

Although the manufacturers of montelukast and zafirlukast are maintaining ongoing databases of experience with the drugs in humans, this information has yet to be published in peer-reviewed literature. Animal studies do not reveal teratogenicity with either drug, but zafirlukast has some potential for tumorigenicity in high doses in animal studies and therefore it is not recommended for breastfeeding mothers.

Pregnancy classification is Category B for montelukast and zafirlukast; in addition, montelukast has not been shown to be tumorigenic. Both montelukast and zafirlukast are generally considered to be safe and may be used in pregnancy if clearly indicated.²⁷ Consider using them in the woman with moderate asthma, and especially one who has severe asthma that was well-controlled on montelukast or zafirlukast prior to her pregnancy. In the pregnant patient who was not previously on these agents, consider using them to reduce the dosage of chronic systemic steroid therapy. Zafirlukast has been reported to interfere with theophylline metabolism, and levels must be monitored carefully if the two medications are used in combination.²⁸

Zileuton belongs to a related class of leukotriene synthesis inhibitors. It has multiple drug interactions and may also cause liver toxicity. Zileuton should be used with extreme caution in patients on theophylline since it reduces metabolism via inhibition of the cytochrome P-450 system. It is classified as Category C and should be used in pregnancy only in women with severe refractory asthma with good response prior to pregnancy.

Treating acute symptoms

A recommended "rescue" approach for symptoms of asthma in the pregnant patient includes a short-acting beta-agonist inhaler with two to four puffs every 20 minutes for up to 1 hour (Figure 2). If the patient's symptoms resolve and her peak expiratory flow is 70% or greater of her personal best, she can resume her usual routine. Otherwise, she should be instructed to seek immediate medical care.

A complete approach to the treatment of acute asthma attacks is beyond the scope of this article, but clinicians should keep in mind certain general principles:

• Oxygenation of the mother (and, therefore, fetus) should be liberal. Repeated bronchodilator inhalation treatments are usually helpful and well-tolerated but have the potential to produce significant side effects, such as tachycardia, jitteriness, and potentially, metabolic effects (demargination of WBCs, hypokalemia).

• A patient with an initial FEV₁ of less than 1.0 L or a PEFR of less than 100 L or a transcutaneous pulse oximetry of less than 90% is probably having a serious attack. Start her on IV steroids, continuous nebulizer treatment, and cardiac monitoring; she will probably also need intensive care admission.

• In the patient with severe respiratory distress, pulse oximetry should be supplemented by arterial blood gas measurement. A woman who presents with normal or elevated pCO₂ is suffering from severe ventilatory deficiency and intubation is warranted if she does not rapidly improve. Case reports indicate some possible benefits for inhalation anesthesia with halothane or ventilation with a helium-oxygen mixture in status asthmaticus.^29,30

• Acute asthma attacks in labor should be managed as above with an attempt to improve the fetal environment with maternal treatment.

Adjunctive medication

Although acute asthma attacks are rarely caused by bacterial bronchial infection, allergic rhinitis and secondary bacterial sinusitis can trigger them. In these circumstances, appropriate antibiotic therapy, nasal steroids, and antihistamines may be indicated. Of the antihistamines, reassuring human safety data are available for chlorpheniramine, hydroxyzine, and cetirizine in pregnancy.^31,32 Expectorant medications are not of particular value, since the best expectorant is adequate hydration. Because cough generally is a harbinger of uncontrolled bronchospasm, cough suppressants are not indicated in the typical patient who has acute symptoms.

In the final analysis

Pregnant patients with asthma should be managed proactively to achieve a good perinatal outcome. Initial and ongoing assessment of the severity of an asthmatic woman's condition facilitates the stepwise addition of medication to optimize control of symptoms and prevent acute attacks. Educating patients is key to their ability to use medication appropriately and initiate treatment before an acute disease process becomes critical. Most asthma medications are as safe to use in pregnancy as in the non-pregnant state. The benefits of good control clearly outweigh the risks of treatment with any commonly used asthma medication.

Key points

REFERENCES

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21. Pollard SJ, Spector SL, Yancey SW, et al. Salmeterol versus theophylline in the treatment of asthma. Ann Allergy Asthma Immunol. 1997;78:457-464.

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31. Einarson A, Bailey B, Jung G, et al. Prospective controlled study of hydroxyzine and cetirizine in pregnancy. Ann Allergy Asthma Immunol. 1997;78:183-186.

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Dr. Sakornbut is Executive Director and Program Director, Northeast Iowa Medical Education Foundation, Waterloo, Iowa.

Judy Orvos, ed. Ellen Sakornbut. How to treat pregnant patients with asthma.

Contemporary Ob/Gyn

Apr. 1, 2003;48:26-43.