Asthma and Pregnancy
1. What every clinician should know
Asthma is one of the most common potentially serious medical problems that can occur during pregnancy. It is characterized by chronic airway inflammation, with increased airway hyperresponsiveness to a variety of stimuli, and obstruction that is partially or completely reversible. Approximately 8% of pregnant women reported current asthma in recent national surveys. The prevalence of and morbidity from asthma are increasing, although asthma mortality rates have decreased in recent years.
Women with asthma have been reported to have higher risks of adverse perinatal outcomes, including low birth weight, small for gestational age, preterm labor and delivery and preeclampsia. Recent data show a strong association between these risks and asthma control during pregnancy. A woman with mild and well controlled moderate asthma will likely have better pregnancy outcomes than a woman with severe and poorly controlled asthma.
2. Diagnosis and differential diagnosis
A. Establishing the diagnosis
If the patient has no known history of asthma prior to pregnancy, asthma is suspected based on the presence of typical symptoms such as: wheezing, chest tightness, cough and associated shortness of breath. The diagnosis is confirmed by the demonstration of reversible airways obstruction, which most commonly is an increase in forced expiratory volume in 1 second (FEV1)or forced expiratory volume in 1 second of 12% or more and at least 200 mL after an inhaled short-acting bronchodilator.
B. Other possible diagnoses
The most common alternative diagnosis is dyspnea of pregnancy, which may occur in early pregnancy in approximately 70% of women. This dyspnea is usually differentiated from asthma by its lack of association with cough, wheezing or airway obstruction.
Other differential diagnoses include:
Gastroesophageal reflux disease
Cough due to postnasal drainage
Methacholine testing, which is used to confirm bronchial hyperreactivity in non-pregnant patients with normal pulmonary function, is contraindicated during pregnancy because of the lack of data on the safety of such testing in pregnant patients.
Therapeutic trials, such as 2-4 weeks of regular inhaled corticosteroid therapy, may be used in those patients with possible but unconfirmed asthma.
Management of asthma during pregnancy involves the following:
Education regarding the relationship between asthma and pregnancy.
Management of coexisting conditions such as: rhinitis, sinusitis and gastroesophageal reflux disease, all of which may complicate asthma during pregnancy.
Control measures to reduce exposure to potential environmental triggers such as: animal dander, dust mites and cockroaches.
Demonstration of proper inhaler technique.
Self-treatment action plan that includes: schedule of controller medication and instructions on rescue therapy, when to increase medications, how to recognize symptoms of exacerbation, and when to seek emergency treatment.
Adherence to controller medications.
Asthma medicines are generally divided into long-term control medications and rescue therapy. Long-term control medications are used for maintenance therapy to prevent asthma manifestations and include inhaled corticosteroids, cromolyn, long-acting beta-agonists, leukotriene receptor antagonists and theophylline. Rescue therapy, most commonly inhaled short-acting beta-agonists, provides immediate relief of symptoms. Oral corticosteroids can either be used as a form of rescue therapy or as chronic therapy for severe persistent asthma.
Table I. Steps of asthma therapy during pregnancy
|Step||Preferred controller medication||Alternative controller medication|
|2||Low dose ICS||LTRA, theophylline|
|3||Medium dose ICS||Low dose ICS+ either LABA, LTRA or theophylline|
|4||Medium dose ICS + LABA||Medium dose ICS + theophylline|
|5||High dose ICS + LABA||–|
|6||High dose ICS + LABA + oral prednisone||–|
Inhaled corticosteroids are the mainstay of controller therapy during pregnancy. Many studies have shown no increased perinatal risks (including preeclampsia, preterm birth, low birthweight and congenital malformations) associated with inhaled corticosteroids. Because it has the most published reassuring human gestational safety data, budesonide is the only inhaled corticosteroid with an FDA Category B designation, and for this reason is considered to be the inhaled corticosteroid of choice for asthma during pregnancy.
There are no data at this point to suggest that the other inhaled corticosteroid preparations are unsafe. Therefore, inhaled corticosteroids other than budesonide may be continued in patients who were well-controlled by these agents prior to pregnancy, especially if it is thought that changing formulations may jeopardize asthma control.
Inhaled short-acting beta-agonists are the rescue therapy of choice for asthma during pregnancy. Inhaled albuterol is the first-choice short-acting beta-agonist for pregnant women because it has been studied the most extensively, although other agents may be used if uniquely helpful or well tolerated. The use of long-acting beta-agonists are the preferred add-on controller therapy for asthma during pregnancy. This therapy should be added when patients’ symptoms are not controlled with the use of medium-dose inhaled corticosteroids. Because long-acting and short-acting inhaled beta-agonists have similar pharmacology and toxicology, long-acting beta-agonists are expected to have a safety profile similar to that of albuterol.
Two long-acting beta-agonists are available: salmeterol and formoterol. Limited observational data exist on their use during pregnancy. A possible association between long-acting beta-agonists and an increased risk of severe and even fatal asthma exacerbations has been observed in non-pregnant patients. As a result, long-acting beta-agonists are no longer recommended as monotherapy for the treatment of asthma and are available and recommended for use as fixed combination preparations with inhaled corticosteroids.
Both zafirlukast and montelukast are selective leukotriene receptor antagonists indicated for the maintenance treatment of asthma. Both are pregnancy category B based on animal studies; however, human data on the use of these medications during pregnancy are limited. The evidence available does not indicate an increased risk of adverse perinatal outcomes with their use.
Cromolyn and theophylline
Based on the superiority of inhaled corticosteroids, cromolyn and theophylline are considered alternative treatments for mild persistent asthma. Theophylline is also an alternative, but not preferred, add-on treatment for moderate to persistent asthma. Reassuring data on the use of cromolyn and theophylline in pregnant women have been published. Theophylline serum levels should be monitored during pregnancy and maintained between 5 and 12 microg/mL. Cromolyn is now only available in the U.S. as a nebulized preparation.
Some patients with severe asthma may require regular oral corticosteroids to achieve adequate asthma control. Oral corticosteroids are also part of the discharge regimen for an acute asthma episode. Doses are typically 40-60 mg in a single or divided dose for 3-10 days. Their use has been associated with an increased risk of complications which include: preterm birth, low birth weight and possibly orofacial clefts. However, these risks would be less than the potential risk of maternal or fetal mortality from a severe asthma exacerbation. Currently oral corticosteroids are recommended when indicated for the management of severe asthma during pregnancy. If a patient requires chronic oral corticosteroids, she will need stress doses of steroids during labor and delivery.
Asthma course may worsen, improve, or remain unchanged during pregnancy and these outcomes occur with approximately equal frequency. The first trimester is generally well-tolerated in asthmatic women with infrequent acute episodes. Increased symptoms and more frequent exacerbations have been reported to occur between weeks 17 and 36 of gestation. In contrast, women tend to experience fewer symptoms and less frequent asthma exacerbation during weeks 37-40 than during any earlier gestational periods.
The mechanisms for the altered asthma course during pregnancy are unclear. Certainly, the myriad of pregnancy-related hormones may play a role. Other factors include: emotional stress, adherence to asthma medications and infections. Some degree of decrease in cell-mediated immunity may make the pregnancy patient more susceptible to viral infection, and upperrespiratory tract infections have been reported to be the most common precipitants of asthma exacerbations during pregnancy. Sinusitis, a known asthma trigger, has been shown to be six times more common in pregnant compared with non-pregnant women. In addition, pneumonia has been reported to be more than five times more ocmmon in asthmatic than non-asthmatic women during pregnancy.
5. Prognosis and outcome
Several large studies have shown that the pregnant patient with mild to moderate asthma can have excellent maternal and infant outcomes. However, suboptimal control of asthma during pregnancy may be associated with increased maternal or fetal risk. Classification of asthma severity and therapy tailored according to asthma severity has been shown to result in excellent infant and maternal outcomes.
Table II.Classification of asthma severity in pregnant patients
|Asthma severity||Symptom frequency||Nighttime awakening||Interference with normal activity||FEV1 or peak flow (percentage of predicted or personal best)|
|Intermittent||2 days per week or less||Twice per month or less||None||More than 80%|
|Mild persistent||More than 2 days per week, but not daily||More than twice per month||Minor limitation||More than 80%|
|Moderate persistent||Daily symptoms||More than once per week||Some limitation||60-80%|
|Severe persistent||Throughout the day||Four times per week or more||Extremely limited||Less than 60%|
Abbreviation: FEV1, forced expiratory volume in the first second of expiration
* Data from Schatz M, Dombroski M. Obstet Gynecol 2008;111:457-464.
Monthly visits to assess asthma control are recommended for women who require therapy during pregnancy.
Table III. Assessing control in pregnant asthmatics
|Variable||Well-controlled asthma||Not well controlledasthma||Very poorly controlled asthma|
|Frequency of symptoms||2 days/wk||More than 2 days /wk||Throughout the day|
|Frequency of nighttime awakening||2 times/mo||1-3 times/wk||4 or more times/wk|
|Interference with normal activity||None||Some||Extreme|
|Use of short-acting beta-agonist for symptom control||2 days/wk||More than2 days/wk||Several times/day|
|FEV1 or peak flow (% of the predicted or personal best value)||>80||60-80||<60|
|Exacerbation requiring use of systemic corticosteroid||0-1 in the past 12 mos||greater than or equal to 2 in the past 12 mos||greater than or equal to 2 in the past 12 mos|
For women with Not Well Controlled Asthma, a step up in therapy (see Table I) is usually necessary if adherence, inhaler techniqe and non-pharmacologic therapy have bee optimized. For patients with Very Poorly Controlled Asthma, a two-step increase in therapy, a course of oral corticosteroids, or both should be considered.
6. What is the evidence for specific management and treatment recommendations
Dombrowski, MP, Schatz, M, Wise, R, Momirova, V, Landon, M. “Asthma during pregnancy”. Obstet Gynecol. vol. 103. 2004 Jan. pp. 5-12. (In a large, prospective observational cohort study, the authors report pregnancy outcomes in a group of asthmatic women stratified by asthma severity.)
Bracken, MB, Triche, EW, Belanger, K. “Asthma symptoms, severity, and drug therapy: a prospective study of effects on 2205 pregnancies”. Obstet Gynecol. vol. 102. 2003. pp. 739-52. (Data from this study suggest that use of certain asthma medications and increasing severity of asthma may both contribute to a higher risk of adverse perinatal outcomes in pregnant women.)
Schatz, M, Dombrowski, MP, Wise, R. “Asthma morbidity during pregnancy can be predicted by severity classification”. J Allergy Clin Immunol. vol. 112. 2003. pp. 283-8. (The authors report that asthma morbidity as reflected in hospitalizations, urgent care visits, oral corticosteroid use and asthma symptoms during labor and delivery correlate closely with asthma classification at entry. Surprisingly, one third of mild asthmatics had become moderate to severe asthmatics by the end of the study.)
Schatz, M, Dombrowski, MP, Wise, R. “The relationship of asthma medication use to perinatal outcomes”. J Allergy Clin Immunol. vol. 113. 2004. pp. 1040-5. (The study provides important information regarding the effects of specific asthma medications on perinatal outcomes.)
Busse, WW. “NAEPP expert panel report. Managing asthma during pregnancy: recommendations for pharmacologic treatment – 2004 update”. J Allergy Clin Immunol. vol. 115. 2005 Jan. pp. 34-46. (An overview of current guideline recommendations for management of acute and chronic asthma during pregnancy.)
Louik, C, Schatz, M, Hernandex-Diaz, S, Werler, MM, Mitchell, AA. “Asthma in pregnancy and its pharmacologic treatment”. Ann Allergy Asthma Immunol. vol. 105. 2010. pp. 110-7. (This study highlights the challenges of adherence to asthma medications during pregnancy.)
Murphy, V, Namazy, J, Powell, H, Schatz, M, Chambers, C. “A meta-analysis of adverse perinatal outcomes in women with asthma”. BJOG. vol. 118. 2011 Oct. pp. 1314-23. (A thorough review of the most recent data regarding pregnant asthmatics' increased risk of perinatal outcomes.)
Murphy, VE, Gibson, P, Talbot, PI, Clifton, VL. “Severe asthma exacerbations during pregnancy”. Obstet Gynecol. vol. 106. 2005 Nov. pp. 1046-54. (Pregnant women with severe asthma are at increased risk for exacerbations and poor outcomes for the fetus.)
Breton, MC, Beauchesne, MF, Lemiere, C, Rey, E, Forget, A. “Risk of perinatal mortality associated with inhaled corticosteroid use for the treatment of asthma during pregnancy”. J Allergy Clin Immunol. vol. 126. 2010 Oct. pp. 772-7. (A large retrospective cohort study that found the risk of perinatal mortality was not significantly associated with inhaled corticosteroid use during pregnancy.)
Triche, EW, Saftlas, AF, Belanger, K, Leaderer, BP, Bracken, MB. “Association of asthma diagnosis, severity, symptoms and treatment with risk of preeclampsia”. Obstet Gynecol. vol. 104. 2004 Sep. pp. 585-93. (Pregnant asthmatics with moderate to severe asthma are at an increased risk of preeclampsia.)
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