[Postgraduate Medicine]
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[SYMPOSIUM]

Managing asthma during pregnancy

The whys and hows of aggressive control

Michael S. Blaiss, MD

VOL 115 / NO 5 / MAY 2004 / POSTGRADUATE MEDICINE

CME learning objectives

  • To understand how the physiologic changes during pregnancy affect asthma control
  • To be familiar with the three cornerstones of asthma care: environment control, pharmacotherapy, and allergen immunotherapy
  • To become knowledgeable about the risks, benefits, and US Food and Drug Administration pregnancy category of various asthma medications

Dr Blaiss has received honoraria from GlaxoSmithKline, AstraZeneca, Merck, Aventis, Novartis, and Genentech and is a consultant for GlaxoSmithKline, Aventis, and Merck. He discloses no unlabeled uses of any product mentioned in this article.

Preview: Asthma occurs in about 4% of pregnancies and can worsen during pregnancy. Aggressive treatment is needed because failure to control asthma during pregnancy can lead to poor outcomes for both mother and child. At the same time, the risk-benefit profile of various asthma medications should be considered to avoid any adverse effects. In this article, Dr Blaiss discusses the foundations for management of asthma during pregnancy: environmental control, pharmacotherapy, and allergen immunotherapy. Blaiss MS. Managing asthma during pregnancy: the whys and hows of aggressive control. Postgrad Med 2004;115(5):55-64

Asthma is one of the most common respiratory tract conditions that occurs during pregnancy and is estimated to affect up to 4% of pregnant women (1). In fact, asthma may present for the first time during pregnancy. Among women with asthma who become pregnant, symptoms improve in about one third, stay the same in a third, and worsen in a third (2). Most asthmatic patients have the same degree of asthma severity in future pregnancies as in their first pregnancy (1). The level of asthma symptoms during pregnancy tends to parallel that of rhinitis symptoms (3). Asthma exacerbations most commonly occur during the 24th to 36th week of gestation, whereas flare-ups are rare during the last 4 weeks of pregnancy and during labor and delivery. Within 3 months after delivery, almost 75% of women return to their prepregnancy status (4).

Importance of aggressive asthma control

Both mother and child are at risk if asthma is not well managed during pregnancy. Severe persistent asthma has been related to the development of maternal hypertension, preeclampsia, placenta previa, uterine hemorrhage, and oligohydramnios (4). Patients whose asthma is poorly controlled during pregnancy are at increased risk of cesarean delivery (5). In addition, inadequate asthma control is associated with premature birth, low birth weight, and stillbirth (6).

Asthma monitoring during pregnancy

Because asthma is a chronic inflammatory disease of the airways with acute exacerbations that lead to distress for mother and child, continued monitoring with frequent office visits is important throughout the pregnancy. Regular follow-up should include monitoring with both subjective and objective clinical measures. The goal of asthma management during pregnancy is twofold: to keep the mother symptom-free and to prevent complications to the fetus.

It is important to question the patient about the amount of wheezing, cough, shortness of breath, and nocturnal symptoms she is experiencing and her need for albuterol (AccuNeb, Ventolin) therapy. In addition to an appropriate physical examination that includes auscultation of the lungs, spirometry to assess the airways should be performed. Pregnancy does not change the forced expiratory volume in 1 second, forced vital capacity, or forced expiratory flow, midexpiratory phase; therefore, obstructive patterns during pregnancy should be thought of as abnormal rather than the result of pregnancy (7). As in patients who are not pregnant, an asthma flare-up can result in a decrease in arterial PO2. This can be devastating to the fetus, because even small decreases in maternal PO2 can lead to a significant drop in fetal oxygenation.

Cornerstones of asthma management

Environmental control, proper pharmacologic treatment, and specific allergen immunotherapy are the foundation of care for all patients with asthma. Of these, institution of environmental control measures is even more vital during pregnancy to lessen exposures to triggers.

Environmental control
Decreasing the patient's exposure to allergens and irritants may lessen the amount of medication required to control asthma and prevent exacerbations. Steps should be taken to decrease levels of indoor allergens, such as dust mites and animal danders. Procedures to remove dust mites from the home include removal of carpeting in the bedroom; use of mite-proof encasing on the mattress, box spring, and pillow; washing bedding and draperies in hot water; and removal of dust collectors. If the patient is allergic to animal danders, pets should be removed from the home. If this is not possible, then animals should never be allowed in the bedroom, bedroom carpeting should be removed, and a high-efficiency particulate air-filtering system should be used in the bedroom. Such irritants as active or passive cigarette smoke can also be a factor in worsening asthma symptoms, and avoidance is critical for good asthma control (8).

Even when the best environmental control measures for asthma are undertaken, almost all patients need some degree of medication management. Because few safety studies on medication use during pregnancy are available, the US Food and Drug Administration (FDA) has published pregnancy risk categories for drugs (table 1). All commonly used asthma medications fall under safety categories B and C (table 2). This system was developed from animal exposure data and epidemiologic data from population studies. Unfortunately the categories do not necessarily guarantee the safety of the agent. Because of their shortcomings, these categories are currently being reviewed by the FDA. Healthcare practitioners and patients alike need better information in determining the risk-benefit ratio of a particular agent when used during pregnancy. Fear of adverse fetal effects may lead to restrictive use of asthma drugs that are needed for control of asthma during pregnancy.

Table 1. FDA pregnancy risk categories (1998)
A Adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters.
B Animal studies have not demonstrated a risk to the fetus, but there are no adequate studies in pregnant women.
     or
Animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters.
C Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.
     or
There are no animal reproduction studies and no adequate studies in humans.
D There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.
X Studies in animals or humans demonstrate fetal abnormalities, or adverse reaction reports indicate evidence of fetal risk. The risk of use in a pregnant woman clearly outweighs any possible benefit.

FDA, US Food and Drug Administration.

Table 2. FDA pregnancy risk categories for asthma medications
Agent Risk category
Bronchodilators
Albuterol (AccuNeb, Ventolin) C
Pirbuterol acetate (Maxair) C
Levalbuterol HCl (Xopenex) C
Salmeterol (Serevent) C
Formoterol fumarate (Foradil Aerolizer) C
Ipratropium bromide (Atrovent) B
Respiratory inhalants
Cromolyn sodium (Intal) B
Nedocromil sodium (Tilade) B
Leukotriene agents
Zafirlukast (Accolate) B
Montelukast sodium (Singulair) B
Inhaled corticosteroids
Budesonide (Pulmicort) B
Beclomethasone dipropionate (QVAR) C
Fluticasone propionate (Flovent) C
Triamcinolone acetate (Azmacort) C
Flunisolide (AeroBid, Nasarel) C
Fluticasone propionate/salmeterol (Advair Diskus) C
Oral corticosteroids C
Theophylline C
Omalizumab (Xolair) B

FDA, US Food and Drug Administration.

Medical management
To address the need for guidelines to help physicians manage asthma during pregnancy, the National Institutes of Health (NIH) developed a Working Group on Asthma and Pregnancy and published its information in 1993 (9). The report was revised in 1997 to make recommendations on medical treatment in relationship to the NIH classifications of asthma severity (10). The most recent position paper on medical management of asthma during pregnancy was published in 2000 by a committee of the American College of Obstetricians and Gynecologists and the American College of Allergy, Asthma, and Immunology (11). These updated guidelines take into consideration new medications approved for use in asthma since the 1997 report. Further revisions to the asthma management guidelines should be forthcoming as knowledge of the disease increases and more data on the safety of current treatments become available.

On review of the medical literature, it appears sensible to use the NIH definitions of asthma severity (table 3) and follow the 2002 NIH asthma treatment guidelines as proposed for patients who are not pregnant (12) (table 4).

Table 3. NHLBI preferred treatment for persistent asthma in adults and children aged 5 years or older
Disease severity Preferred treatment
Mild persistent Low-dose inhaled corticosteroids
Moderate persistent Low- to medium-dose inhaled corticosteroids and long-acting inhaled beta2-agonists
Severe persistent High-dose inhaled corticosteroids and long-acting inhaled beta2-agonists

NHLBI, National Heart, Lung, and Blood Institute.

Adapted from Guidelines for the diagnosis and management of asthma: update in selected topics, 2002. Bethesda: National Institutes of Health, National Heart, Lung, and Blood Institute, 2002; NIH publication 02-5075.

Short-acting beta2-agonists: For mild intermittent asthma and acute exacerbations in all asthmatic patients, inhalation of short-acting beta2-agonists is the preferred treatment. These agents have not been shown to have any adverse effects on pregnancy outcomes or teratogenic effects on the fetus (13). There appears to be no safety difference among various inhaled short-acting beta2-agonists (eg, albuterol, pirbuterol acetate [Maxair]). Use of oral and parenteral beta2-agonists should be avoided because of lack of safety data, the increased risk of side effects (eg, tremor), and the potential to inhibit delivery.

Inhaled corticosteroids: Inhaled corticosteroids are the "gold standard" for controlling all forms of persistent asthma. These agents have been shown to decrease asthma exacerbations and mortality and improve overall quality of life. Using data derived from the Swedish Medical Birth Register (which includes 99% of births in Sweden), Norjavaara and de Verdier (14) compared pregnancy outcomes for mothers reporting asthma medication usage with those for women who reported no usage. Among the 293,948 births identified from 1995 to 1998, the researchers found that 2,968 mothers who reported use of inhaled budesonide during early pregnancy gave birth to infants of normal gestational age, birth weight, and length; there was no increase in rate of stillbirths or multiple births.

How should an inhaled corticosteroid be chosen for use in pregnant patients with asthma? Because of the Swedish data, the FDA has assigned budesonide a safety category B rating. At present, all other inhaled corticosteroids are category C. Newer inhaled corticosteroids, such as fluticasone propionate (Flovent), are more potent per microgram than older agents but appear to have less bioavailability. As yet, no adequate, well-controlled studies on fluticasone have been performed. Because safety data are lacking on use of fluticasone and other newer inhaled corticosteroids during pregnancy, the 2000 position paper of the American College of Obstetricians and Gynecologists and the American College of Allergy, Asthma, and Immunology (11) states, "it would not be unreasonable to continue a different (from beclomethasone or budesonide) inhaled corticosteroid in a patient well-controlled by that drug (fluticasone or other newer agents) prior to pregnancy."

Other controller agents: Alternative controller therapies for mild persistent asthma are cromolyn sodium (Intal), nedocromil sodium (Tilade), leukotriene receptor antagonists, and theophylline. Long-term safety data are available for inhaled cromolyn, and it is a feasible option for use during pregnancy, especially if there is a concern about prescribing inhaled corticosteroids (15). The leukotriene receptor antagonists, zafirlukast (Accolate) and montelukast sodium (Singulair), are classified as FDA category B because no human or animal teratogenic effects have been seen with these agents (16). Therefore, it would not be unreasonable to continue therapy with leukotriene receptor antagonists during pregnancy if the mother has used these agents in the past with good success. These oral agents have been approved for use in the United States only since 1996, so there are no long-term data at this time.

Theophylline, which has been used for more than 50 years, has also been shown to lack teratogenic effects during pregnancy, although its use has radically decreased because of possible toxicity with elevated serum levels and because of the development of the newer, safer agents. When theophylline is used during pregnancy, clearance of the agent decreases later in the pregnancy. Therefore, dosing should be carefully watched and adjusted. Because theophylline crosses the placenta, the newborn may have jitteriness, increased heart rate, and even vomiting at birth.

Long-acting beta2-agonists: Long-acting beta2-agonists, salmeterol (Serevent) and formoterol fumarate (Foradil Aerolizer), are the preferred adjunctive therapy to inhaled corticosteroids for managing moderate to severe persistent asthma. According to the 2002 NIH guidelines (12), alternative choices for adjunctive therapy are leukotriene receptor antagonists, theophylline, cromolyn, and nedocromil. Although no adequate or well-controlled human data are available on salmeterol or formoterol use during pregnancy, there are also no reports of congenital defects (1). Use of an inhaled long-acting beta2-agonist with an inhaled corticosteroid appears to be acceptable during pregnancy, especially if the patient has taken such agents without problems before the pregnancy.

Oral corticosteroids: Oral corticosteroids are administered (1) in short bursts for acute asthma episodes when the patient's condition has not responded to short-acting beta2-agonists and (2) for the long term in severe persistent asthma. Use of oral corticosteroids during pregnancy poses some risks. For example, the risk of cleft palate is increased threefold to sixfold when oral corticosteroids are used in the first trimester (15). Also, some studies have suggested decreased fetal weight gain and a higher risk of preeclampsia with oral corticosteroid use, especially with prednisone in doses greater than 10 mg per day (17). Long-term use of oral corticosteroids carries the risk of significant hyperglycemia and worsening gestational diabetes or preexisting diabetes. As with all medications during pregnancy, it is important to weigh the risks versus the benefits.

Other agents for asthma: Ipratropium bromide (Atrovent) is an inhaled anticholinergic agent that is used as adjunctive therapy to short-acting beta2-agonists for acute asthma exacerbations. Animal data have not demonstrated any birth defects, but human data are lacking (18).

Omalizumab (Xolair), an IgG monoclonal antibody directed against IgE, was recently approved in the United States for use in moderate to severe allergic asthma that has not responded to moderate to high doses of inhaled corticosteroids (19). The FDA gave this agent a pregnancy category B rating because no teratogenic effects were seen in animal studies. In clinical studies with omalizumab before FDA approval, several women became pregnant and delivered normal infants. Because of the newness of this agent, it should be prescribed cautiously during pregnancy.

Allergen immunotherapy
Allergen immunotherapy is a significant disease-modifying treatment that has been shown to improve atopic conditions, such as asthma. Its use can be continued safely during pregnancy (20). However, starting allergen immunotherapy during pregnancy is not recommended (21). Because of the slight but possible risk of an anaphylactic reaction, the strength of the allergen extract should not be increased during pregnancy.

Acute asthma

When the mother is in respiratory difficulty, the oxygenation of the fetus is compromised. Therefore, it is even more important to aggressively treat acute asthma during pregnancy than outside of pregnancy. If the mother has an acute asthma exacerbation, oxygen saturation should be monitored and supplemental oxygen administered.

Use of inhaled short-acting beta2-agonists is the treatment of choice for acute flare-ups. Alternatively, epinephrine may be given subcutaneously or intramuscularly. However, caution should be used in administering epinephrine during pregnancy, because it is linked to congenital defects in animals. It is recommended only when the patient has not responded to short-acting beta2-agonists. For patients in moderate distress, oral corticosteroids (eg, prednisone, 40 to 60 mg) should be given.

If significant improvement is not seen after treatment with short-acting beta2-agonists and oral corticosteroids, the patient is in status asthmaticus and needs to be hospitalized. During hospitalization, the patient should be given inhaled short-acting beta2-agonists, corticosteroids, and fluids for volume depletion. Excessive fluid replacement should be prevented because it poses the risk of acute pulmonary edema in patients who already have volume expansion due to pregnancy. Careful monitoring of the fetus should be part of the care during status asthmaticus. If respiratory failure occurs, mechanical ventilation and an emergency cesarean delivery may be necessary.

Conclusion

Management of asthma during pregnancy does not differ greatly from treatment outside of pregnancy. The medical literature points out that the most commonly used controller therapies have a high benefit-to-risk ratio in pregnant patients. It is important for the patient to understand the need for proper treatment, because failure to control asthma during pregnancy can lead to poor outcomes for both mother and child. During this special time, frequent monitoring of the mother should help ensure a symptom-free pregnancy and a healthy, happy baby.

References

  1. Blaiss MS. Management of rhinitis and asthma in pregnancy. Ann Allergy Asthma Immunol 2003;90(6 Suppl 3):16-22
  2. Stenius-Aarniala B, Piirila P, Teramo K. Asthma and pregnancy: a prospective study of 198 pregnancies. Thorax 1988;43(1):12-8
  3. Kircher S, Schatz M, Long L. Variables affecting asthma course during pregnancy. Ann Allergy Asthma Immunol 2002;89(5):463-6
  4. Tan KS, Thomson NC. Asthma in pregnancy. Am J Med 2000;109(9):727-33
  5. Beckmann CA. The effects of asthma on pregnancy and perinatal outcomes. J Asthma 2003;40(2):171-80
  6. Wendel PJ. Asthma in pregnancy. Obstet Gynecol Clin North Am 2001;28(3):537-51
  7. Wise R, Polito A. Respiratory physiologic changes in pregnancy. Immunol Allergy Clin North Am 2000;20(4):663-72
  8. Kurinczuk JJ, Parsons DE, Dawes V, et al. The relationship between asthma and smoking during pregnancy. Women Health 1999;29(3):31-47
  9. Clark SL. Asthma in pregnancy. National Asthma Education Program Working Group on Asthma and Pregnancy. National Institutes of Health, National Heart, Lung, and Blood Institute. Obstet Gynecol 1993;82(6):1036-40
  10. Expert panel report II: guidelines for the diagnosis and management of asthma. National Asthma Education and Prevention Program. Bethesda: National Institutes of Health, National Heart, Lung, and Blood Institute, 1997; NIH publication 97-4051
  11. The use of newer asthma and allergy medications during pregnancy. The American College of Obstetricians and Gynecologists (ACOG) and the American College of Allergy, Asthma, and Immunology (ACAAI). Ann Allergy Asthma Immunol 2000;84(5):475-80
  12. National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma update on selected topics--2002. J Allergy Clin Immunol 2002;110(5 Suppl):S141-219 [Erratum, J Allergy Clin Immunol 2003;111(3):466]
  13. Schatz M, Zeiger RS, Harden K, et al. The safety of asthma and allergy medications during pregnancy. J Allergy Clin Immunol 1997;100(3):301-6
  14. Norjavaara E, de Verdier MG. Normal pregnancy outcomes in a population-based study including 2,968 pregnant women exposed to budesonide. J Allergy Clin Immunol 2003;111(4):736-42
  15. Schatz M. The efficacy and safety of asthma medications during pregnancy. Semin Perinatol 2001;25(3):145-52
  16. Spector SL; Antileukotriene Working Group. Safety of antileukotriene agents in asthma management. Ann Allergy Asthma Immunol 2001;86(6 Suppl 1):18-23
  17. Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology 2000;62(6):385-92
  18. Liccardi G, Cazzola M, Canonica GW, et al. General strategy for the management of bronchial asthma in pregnancy. Respir Med 2003;97(7):778-89
  19. Busse W, Corren J, Lanier BQ, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 2001;108(2):184-90
  20. Schatz M, Zeiger RS. Asthma and allergy in pregnancy. Clin Perinatol 1997;24(2):407-32
  21. Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper. J Allergy Clin Immunol 1998;102(4 Pt 1):558-62

Informed consent for use of asthma medications during pregnancy

Because of the high degree of concern about possible adverse effects from medication use during pregnancy, it is very important to obtain informed consent from the patient and her partner. Schatz (1) has pointed out several principles for educating the patient and other family members about medications during pregnancy. The physician should state what is known and not known about any medication being used. It should be emphasized that no medication can be considered truly safe during pregnancy, but the patient must clearly understand the consequences of poorly controlled asthma for mother and child. If applicable, pharmacologic options should be discussed. Any questions the patient may have about medications should be addressed. Schatz also suggests that the following statement be placed in the chart record: "The benefits, risks, and alternatives of (the specific pharmacological approach) have been discussed with the patient, and her informed consent to that approach has been obtained." Written formal consent is not necessary.

Reference

  1. Schatz M. H1-antihistamines in pregnancy and lactation. In: Simons FE, ed. Histamine and H1-antihistamines in allergic diseases. New York: Marcel Dekker, 2002:421-36

Dr Blaiss is clinical professor of pediatrics and medicine, University of Tennessee Health Science Center, College of Medicine, Memphis. Correspondence: Michael S. Blaiss, MD, 7205 Wolf River Blvd, Germantown, TN 38138. E-mail: mblaiss@allergymemphis.com.

Symposium Index

  • MILD PERSISTENT ASTHMA: Traits, treatment set it apart from mild intermittent asthma. By Kaiser G. Lim, MD
  • MANAGING ASTHMA DURING PREGNANCY: The whys and hows of aggressive control. By Michael S. Blaiss, MD
  • Clinical Commentary. DOES RHINITIS LEAD TO ASTHMA?: Evidence for the one-airway hypothesis. By Gerald W. Volcheck, MD

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