US Pharm. 2011;36(7):30-34.

Asthma, an obstructive disorder characterized by airway inflammation, airway hyperresponsiveness, and bronchoconstriction, affects 3.7% to 8.4% of pregnant women in the United States.^1,2 The National Asthma Education and Prevention Program (NAEPP) emphasizes the importance of asthma control during pregnancy for the health and well-being of both the mother and the fetus.^1,3

PREGNANCY’S EFFECTS ON ASTHMA

Asthma tends to follow the “rule of thirds.” Among pregnant women, one-third experience an improvement of symptoms, one-third experience a deterioration of symptoms, and one-third experience no change in symptoms.⁴ Factors that may improve the course of asthma during pregnancy include estrogen- or progesterone-mediated bronchodilation and descent of the fetus.⁵ Factors that may worsen the course of asthma include increased stress, gastroesophageal reflux, and increased occurrence of viral or bacterial respiratory tract infection.⁵

Multiple studies have demonstrated increased exacerbation and hospitalization rates in pregnant women with asthma.^6-8 It is important to note that this increased incidence depends upon the severity of the asthma prior to pregnancy asthma.⁶ A classification of asthma severity and control appears in TABLE 1. Compared with pregnant women with mild asthma, those with severe asthma were more likely to experience a worsening of disease progression during their pregnancy.⁶ In a prospective, observational cohort study, pregnant patients classified as having mild asthma had an exacerbation rate of 12.6% and a hospitalization rate of 2.3%; however, among pregnant patients with severe asthma, the exacerbation rate was 51.9% and the hospitalization rate was 26.9%.⁶

The first trimester of pregnancy is generally free of exacerbations, with the increase in asthma symptoms usually peaking around the sixth month of gestation.⁸ The occurrence of asthma symptoms and exacerbations tends to decrease during the final month of pregnancy and during delivery, with only 10% to 20% of women experiencing symptoms.⁶ Finally, the occurrence of increased symptoms and exacerbations during subsequent pregnancies mirrors that seen during the first pregnancy.⁶

ASTHMA’S EFFECTS ON PREGNANCY

A pregnant woman with asthma is at increased risk for complications in herself and her fetus.^9,10 In a large prospective study, a moderate association was found between asthma and preterm delivery. Furthermore, a significant relationship was found between an increase in asthma symptoms or severity and decreased fetal growth.¹¹ A different study found that, compared with their nonasthmatic counterparts, pregnant patients with asthma were more likely to experience the following adverse complications: preterm delivery, infant being small for gestational age, congenital malformations, increased infant hospital stay, preeclampsia, placenta previa, cesarean delivery, and increased maternal hospital stay.¹⁰ Finally, a retrospective study found that pregnant women with asthma were more likely to have hypertensive disorders, antepartum hemorrhage, postpartum hemorrhage, membrane-related disorders, gestational diabetes, preterm delivery, cesarean section, and low birthweight.¹² Given these increased risks among pregnant women with asthma, emphasis should be placed on improving asthma control in these patients.

MANAGEMENT: NONPHARMACOLOGIC APPROACH

To optimize the management of an asthmatic patient, it is extremely important to identify and avoid factors that may worsen the disease. Reducing exposure to animal dander, dust mites, cockroaches, and other environmental triggers can improve asthma control. Optimally, patients sensitive to animal dander should remove the animal from the home, but if this is not acceptable to the patient, the animal should be kept out of the bedroom and away from upholstered furniture and carpets. Patients sensitive to dust mites should encase their mattress and pillow in an allergen-impermeable cover and wash the bed linens weekly in hot water. Cockroaches can be controlled by removing exposed food and garbage and using poison baits and traps in lieu of other chemical agents.¹

Another condition that may exacerbate asthma is gastroesophageal reflux disease (GERD). Patients with GERD should avoid food and drink within 3 hours of bedtime, elevate the head of the bed, and eat smaller meals.¹

MANAGEMENT: PHARMACOLOGIC THERAPY

Asthma treatment can be divided into two categories: controller medications and rescue medications. Controller medications are used to prevent asthma symptoms, while rescue medications are used to relieve asthma symptoms.

Controller Medications

Inhaled Corticosteroids: Inhaled corticosteroids (ICSs), which help prevent and control inflammation, are the preferred controller therapy for asthmatic patients, including those who are pregnant. These medications have been shown to improve asthma symptoms and increase pulmonary function.³ Currently available ICSs include beclomethasone, budesonide, ciclesonide, flunisolide, and fluticasone. Budesonide is preferred during pregnancy because of its proven efficacy and safety in numerous studies. A study of teratogenic effects of budesonide use during early pregnancy on 2,014 infants concluded that clinically significant teratogenic risk is unlikely when budesonide is used in early pregnancy.¹³ Other ICSs have not been proven unsafe. Side effects of ICSs include cough, dysphonia, and oral candidiasis. To reduce the risk of thrush and dysphonia, patients should be counseled to rinse the mouth with warm water and then spit.¹ The ICS dosage depends upon the patient classification of severity and level of control. Preferred and alternative therapies for asthma control during pregnancy are discussed in TABLE 2.

Long-Acting Beta Agonists (LABAs): LABAs, which are indicated in patients who are not controlled on ICSs alone, are the preferred add-on therapy. There is little evidence regarding the safety of LABAs in pregnancy; however, they are considered safe based on evidence available for short-acting beta agonists (SABAs). LABAs have a black box warning regarding increased risk of death. This risk was primarily associated with LABAs used as monotherapy, not in combination with an ICS. Side effects include tachycardia, tremor, and palpitations. Currently, formoterol and salmeterol are the two agents available; both are given twice daily.¹

Theophylline: While theophylline is not a preferred adjunctive therapy in asthma, it may be used as an alternative in patients who are not adequately controlled on ICSs alone. One study followed a cohort of 824 pregnant patients with and 678 pregnant patients without asthma. There was no significant relationship between theophylline use and major congenital malformation or preterm birth.¹⁴ If theophylline is used in pregnancy, a low dose is recommended, with maintenance serum concentrations of 5 mcg/mL to 12 mcg/mL.³ Side effects of theophylline include nausea, palpitations, and insomnia.¹⁰

Cromolyn: Although cromolyn has an excellent safety profile, this agent is not preferred in pregnant patients with asthma. Studies have shown that cromolyn is less effective than ICSs; therefore, it is an alternative therapy for asthma during pregnancy.³

Leukotriene Modifiers: Montelukast and zafirlukast, two available leukotriene receptor antagonists (LTRAs), are not preferred therapies in asthma, but they may be used as an adjunctive alternative in persistent asthma.¹ In a study comparing 96 pregnant patients taking LTRAs with nonpregnant patients taking SABAs and patients without asthma, LTRA use was not associated with an increased risk of pregnancy loss, gestational diabetes, preeclampsia, low maternal weight gain, preterm delivery, or neonatal head circumference.¹⁵

There is limited evidence on the safety of zileuton, a 5-lipoxygenase inhibitor, in pregnancy. For this reason, its use is not recommended in pregnant patients.³

Immunomodulator: There are no adequate, well-controlled studies regarding the use of omalizumab in pregnancy. Omalizumab is indicated for patients over age 12 years who have moderate-to-severe allergic asthma and are inadequately controlled with ICSs. Omalizumab is administered by subcutaneous injection every 2 or 4 weeks. Currently, the manufacturer recommends that the drug be used in pregnancy only if it is clearly needed.¹⁶

Rescue Medications

SABAs: SABAs, such as albuterol, are the drugs of choice for asthma during pregnancy. Studies evaluating exposure to SABAs during pregnancy resulted in no significant relationship between SABA use and congenital malformations, preterm delivery rate, or intrauterine growth restriction.^1,11,14 SABAs have a rapid onset of action of 3 to 5 minutes and a duration of action of 4 to 6 hours. Side effects of these medications include tachycardia, tremor, and palpitations. Use of rescue medications more than twice weekly may indicate the need for additional controller therapy.¹

Systemic Corticosteroids: Severe asthma and asthma exacerbations are associated with maternal and fetal mortality; therefore, the guidelines recommend the use of oral corticosteroids in pregnancy when indicated.³ The use of systemic corticosteroids during pregnancy is associated with preeclampsia and with preterm and low-birthweight infants. Use of oral corticosteroids in the first trimester may be associated with cleft lip with or without cleft palate.¹⁰ The recommended dosage of prednisone (or its equivalent) in poorly controlled patients is 40 mg to 60 mg daily in single or divided doses for 3 to 10 days.³

MONITORING

The effect of pregnancy on the course of asthma varies among patients, so careful monitoring is recommended for all pregnant patients with asthma.¹⁷ The patient should provide a history of symptom frequency, nocturnal asthma, interference with daily activities, exacerbations, and controller and rescue-medication use.³ Spirometry, including forced expiratory volume in 1 second (FEV₁), is recommended during the initial assessment and preferred for subsequent outpatient visits. Patients with an FEV₁ of 60% to 80% of the predicted value are at increased risk for subsequent asthma morbidity during pregnancy, and those with an FEV₁ of less than 60% of the predicted value are at even greater risk.⁶ Asthma also may be monitored with the use of a peak flow meter, a device that measures the rate of air flow out of the lungs. An asthma action plan should be developed to help the patient monitor symptoms.¹

Fetal evaluation is also extremely important. First-trimester sonography provides a benchmark for progressive fetal growth.^10,17 Subsequent sonographic evaluations of fetal growth are indicated in the second and third trimesters in moderate-to-severe asthma or if growth retardation is suspected. The patient should monitor fetal activity to determine fetal changes.¹⁰ Serial ultrasound examinations to monitor fetal activity and growth should be considered at 32 weeks’ gestation in patients with poorly controlled or moderate-to-severe asthma and in those recovering from a severe asthma exacerbation.

PHARMACOTHERAPY CONSIDERATIONS DURING LABOR AND DELIVERY

Asthma medications should be continued during labor and delivery. If the patient required chronic systemic corticosteroids in the previous 4 weeks, then IV corticosteroids (e.g., hydrocortisone 100 mg q8h) should be administered during labor and for the 24-hour period after delivery to prevent maternal adrenal crisis. During an asthma exacerbation, uterine contractions are common but rarely result in emergency cesarean delivery. Once asthma symptoms are controlled, contractions usually cease.^3,10,17,18

Terbutaline sulfate, a beta agonist that is approved for prevention and treatment of bronchospasm associated with asthma, bronchitis, and emphysema, is often used to treat preterm labor and uterine hyperstimulation. Terbutaline has also been used over longer periods of time to prevent recurrent preterm labor. On February 17, 2011, the FDA warned that terbutaline injection should not be used in pregnant women for prevention or prolonged treatment (beyond 48-72 hours) of preterm labor because of the potential for serious maternal heart problems and death. In addition, oral terbutaline should not be used for prevention or treatment of preterm labor because it has not been shown to be effective and has similar safety concerns. The FDA requires the addition of a boxed warning and a contraindication to the terbutaline injection and tablet labels to warn against this use.¹⁹

BREASTFEEDING

In general, only small amounts of asthma medications enter breast milk. The NAEPP reported that the use of prednisone, theophylline, antihistamines, ICSs, beta agonists, and cromolyn are safe for women who are breastfeeding. Patients should be counseled to use the least amount of medication effective for controlling their symptoms and to take the medication after breastfeeding to minimize infant exposure.³

CONCLUSION

It is important for patients to recognize that proper asthma control during pregnancy is essential to the health of the fetus. All patients should have a basic understanding of asthma, the differences between controller and rescue medications, trigger recognition, self-monitoring, and appropriate use of asthma medications. Pregnant patients with asthma should be regularly followed by a clinician to assess asthma control.^1,3

REFERENCES

1. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. NIH Publication No. 07-4051. Bethesda, MD: NHLBI; 2007.
2. Kwon HL, Belanger K, Bracken MB. Asthma prevalence among pregnant and childbearing-aged women in the United States: estimates from national health surveys. Ann Epidemiol. 2003;13:317-324.
3. National Asthma Education and Prevention Program. Working Group Report on Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment. NIH Publication No. 05-5236. Bethesda, MD: NHLBI; 2005.
4. Schatz M, Harden K, Forsythe A, et al. The course of asthma during pregnancy, post partum, and with successive pregnancies: a prospective analysis. J Allergy Clin Immunol. 1988;81:509-517.
5. Schatz M. Interrelationships between asthma and pregnancy: a literature review. J Allergy Clin Immunol. 1999;103:S330-S336.
6. Schatz M, Dombrowski MP, Wise R, et al. Asthma morbidity during pregnancy can be predicted by severity classification. J Allergy Clin Immunol. 2003;112:283-288.
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9. Dobrowski M, Schatz M. Asthma in pregnancy. Clin Obstet Gynecol. 2010;53:301-310.
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11. Bracken MB, Triche EW, Belanger K, et al. Asthma symptoms, severity, and drug therapy: a prospective study of effects on 2205 pregnancies. Obstet Gynecol. 2003;102:739-752.
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13. Källén B, Rydhstroem H, Aberg A. Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol. 1999;93:392-395.
14. Schatz M, Zeiger RS, Harden K, et al. The safety of asthma and allergy medications during pregnancy. J Allergy Clin Immunol. 1997;100:301-306.
15. Bakhireva LN, Jones KL, Schatz M, et al. Safety of leukotriene receptor antagonists in pregnancy. J Allergy Clin Immunol. 2007;119:618-625.
16. Xolair (omalizumab) package insert. South San Francisco, CA: Genentech; July 2010.
17. Whitty JE, Dombrowski MP. Respiratory diseases in pregnancy. In: Gabbe SG, Niebyl JR, Simpson JL, et al, eds. Obstetrics: Normal and Problem Pregnancies. 5th ed. Philadelphia, PA: Churchill Livingstone; 2007.
18. ACOG practice bulletin no. 90: asthma in pregnancy. Obstet Gynecol. 2008;111:457-464.
19. FDA. FDA drug safety communication: new warnings against use of terbutaline to treat preterm labor. www.fda.gov/Drugs/DrugSafety/ ucm243539.htm. Accessed February 20, 2011.

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