NATIONAL ASTHMA EDUCATION AND PREVENTION PROGRAM
Quick Reference from the Working Group Report on Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment Update 2004*
* This Quick Reference summarizes the findings of the NAEPP Working Group Report on Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment—Update 2004 (NIH Publication No. 05-3279), which is available at http://www.nhlbi.nih.gov/health/prof/lung/asthma/astpreg.htm.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Heart, Lung, and Blood Institute NATIONAL ASTHMA EDUCATION AND collective expertise of an expert panel The experimental animal studies on asthma and pregnancy (Working confirm the association of high-dose PREVENTION PROGRAM Group). The NAEPP Science Base theophylline and adverse pregnancy Committee and NAEPP Coordinating outcomes in animals. The eight human Quick Reference from the Committee members provided review studies, consisting of two case reports23, 24 Working Group Report on and comment. The recommendations and six clinical studies11, 13, 25–28 (of made in Asthma and Pregnancy—Update which two were randomized controlled Managing Asthma 2004 are intended to assist clinical deci- trials), included a total of 57,163 preg- sionmaking; the clinician and patient still nant women, of whom 3,616 had asth- During Pregnancy: need to develop individual treatment ma and 660 had taken theophylline. plans that are tailored to the specific Studies and clinical experience confirm Recommendations needs and circumstances of the patient. the safety of theophylline at recommend- ed doses (to serum concentration of for Pharmacologic The scope of the current systematic 5–12 mcg/mL) during pregnancy. In a review is pharmacologic treatment randomized controlled trial, there were Treatment of asthma in women during their no differences in asthma exacerbations Update 2004 pregnancy; however, highlights from or maternal or perinatal outcomes in the EPR-2 1997 and EPR—Update 2002 theophylline versus the beclomethasone relative to other aspects of asthma care dipropionate treatment groups. are also presented because they should Maintaining adequate control of asthma enhance the overall success and safety However, in the theophylline treatment during pregnancy is important for the of managing asthma in pregnancy. group, there were higher levels of report- health and well-being of both the moth- ed side effects and discontinuation of the er and her baby. Asthma has been Systematic Review of the Evidence medication and an increase in the pro- reported to affect 3.7 to 8.4 percent of portion of women with forced expirato- 1 pregnant women, making it potentially A systematic review of the evidence on ry volume in 1 second (FEV1) at less the most common serious medical the safety of asthma medications during than 80 percent of that predicted.25 problem to complicate pregnancy. The pregnancy was conducted by drug class. largest and most recent studies suggest Of 226 articles retrieved in the search Anticholinergics that maternal asthma increases the risk of literature published in peer-reviewed of perinatal mortality, preeclampsia, journals from January 1990 through No data on anticholinergics were avail- preterm birth, and low birth weight May 2003, 42 met criteria for inclusion able for the current evidence review. infants. More severe asthma is associat- in the evidence review; 2 additional ed with increased risks,2, 3 while better- articles published after May 2003 were Inhaled corticosteroids controlled asthma is associated with included, for a total of 44 articles. decreased risks.4 A summary of the findings from the Three experimental animal studies29–31 evidence, arranged by medication and 10 human studies were included. In 1993, the National Asthma Education category, follows. The human studies included eight and Prevention Program (NAEPP) pub- studies of pregnant women. Of the eight 11, 13, 32–34 lished the Report of the Working Group Beta2-Agonists studies, five were cohort studies; on Asthma and Pregnancy (Asthma one was a controlled trial;35 and two and Pregnancy Report 1993),5 which One experimental animal study9 and six were randomized controlled trials.25, 28 presented recommendations for the man- human studies were included. The six These eight studies included a total of agement of asthma during pregnancy. human studies consisted of one case 21,072 pregnant women, of whom Since then, there have been revisions to report10 and five clinical studies11–15 16,900 had asthma and 6,113 had taken the general asthma treatment guidelines, that included a total of 6,667 pregnant inhaled corticosteroids. Also included Guidelines for the Diagnosis and women, of whom 1,929 had asthma and were two studies of newborns from the
Management of Asthma—Expert Panel 1,599 had taken beta2-agonists. The Swedish Birth Registry—one compared Report 2 (EPR-2 1997),6 and Expert data were reassuring regarding the safety the rate of abnormalities among 2,014
Panel Report: Guidelines for the of beta2-agonists during pregnancy. newborns whose mothers had taken Diagnosis and Management of Asthma More data were available for albuterol. budesonide to the rate of abnormalities
—Update on Selected Topics 2002 Two long-acting inhaled beta2-agonists in the total newborn population, (EPR—Update 2002);7 release of new have become available since 1993— although the number in that population asthma medications; and publication salmeterol and formoterol. Limited was not reported;36 the other study com- of new gestational safety data. data are available on their use during pared 2,900 newborns whose mothers pregnancy. The pharmacologic and had taken budesonide to the total new- Managing Asthma During Pregnancy: toxicologic profiles of these two drugs born population of 293,948;37 there may Recommendations for Pharmacologic are similar to the short-acting inhaled be some overlap in the populations of
Treatment—Update 2004 (Asthma and beta2-agonists, with the exception of these two studies. There are three major Pregnancy—Update 2004)8 reflects the their prolonged retention in the lungs. conclusions from the evidence review: NAEPP’s commitment to keep recom- (1) the risk of asthma exacerbations mendations for clinical practice up to Theophylline associated with pregnancy can be date and based on systematic reviews of reduced and lung function (FEV1) the evidence. Asthma and Pregnancy— Seven experimental animal studies16–22 improved with the use of inhaled corti- Update 2004 was developed through the and eight human studies were included. costeroid therapy;25, 28, 34 (2) no studies
2 NAEPP Working Group Report on Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment to date, including studies of large birth Cromolyn - Minimal or no chronic symptoms registries, have related inhaled cortico- day or night steroid use to any increases in congeni- No experimental animal studies and - Minimal or no exacerbations tal malformations or other adverse two human studies were included in - No limitations on activities perinatal outcomes; and (3) the the current review. The two human - Maintenance of (near) normal preponderance of data on inhaled studies consisted of prospective cohort pulmonary function corticosteroids during pregnancy is studies11, 13 that included 4,110 preg- - Minimal use of short-acting with budesonide. Few or no studies are nant women, of whom 1,917 had inhaled beta2-agonist available on the other inhaled cortico- asthma and 318 had taken cromolyn. - Minimal or no adverse effects steroid formulations during pregnancy. The safety of using cromolyn during from medications pregnancy is supported by the current Oral (systemic) corticosteroids review of evidence. • It is safer for pregnant women with asthma to be treated with asthma Nine experimental animal studies38–46 Leukotriene modifiers medications than for them to have and eight human studies were includ- asthma symptoms and exacerbations. ed. The animal studies do not change Leukotriene modifiers include two Monitoring and making appropriate the previous understanding (Asthma compounds available as oral tablets adjustments in therapy may be required and Pregnancy Report 1993)5 of the (the receptor antagonists montelukast to maintain lung function and, hence, steroid-mediated clefting or decreases and zafirlukast) and 5-lipoxygenase blood oxygenation that ensures oxy- in fetal growth in animals. The eight pathway inhibitors (e.g., zileuton). No gen supply to the fetus. Inadequate human studies in the current evidence animal studies and one human study control of asthma is a greater risk to review included one report of two were available for review. The human the fetus than asthma medications meta-analyses:47 one meta-analysis study was an observational study of are. Proper control of asthma should used six cohort studies that included 2,205 pregnant women, 873 with enable a woman with asthma to 51,380 pregnant women, of whom asthma, of whom 9 took leukotriene maintain a normal pregnancy with lit- 535 had taken oral corticosteroids; the modifiers, but the specific agent was tle or no risk to her or her fetus. other meta-analysis used four case- not identified.11 The conclusion is that control studies,48–51 each of which was minimal data are currently available • The obstetrical care provider should also eligible to be included in the evi- on the use of leukotriene modifiers be involved in asthma care, includ- dence review. These four case-control during pregnancy. Reassuring animal ing monitoring of asthma status dur- studies included 52,038 pregnant studies have been submitted to the ing prenatal visits. A team approach women, of whom 25 had taken oral Food and Drug Administration (FDA) is helpful if more than one clinician corticosteroids. The remaining three for leukotriene receptor antagonists is managing a pregnant woman with human studies included one case- but not for the leukotriene lipoxy- asthma. control study52 and two prospective genase inhibitor. cohort studies11, 13 that included a total • Asthma treatment is organized around of 4,321 pregnant women, of whom Recommendations for Managing Asthma four components of management: 1,998 had asthma and 213 had taken During Pregnancy oral corticosteroids. The findings - Assessment and monitoring of from the current evidence review are The Working Group recommends asthma, including objective meas- conflicting. Oral corticosteroid use, the following principles and stepwise ures of pulmonary function. especially during the first trimester approach to pharmacologic therapy Because the course of asthma of pregnancy, is associated with an for managing asthma during pregnan- changes for about two-thirds of increased risk for isolated cleft lip with cy. (See figures 1–6.) The principles women during pregnancy,53 or without cleft palate (the risk in the and approach are based on the monthly evaluations of asthma general population is 0.1 percent; the Working Group’s interpretation of history and pulmonary function risk in women on oral corticosteroids the current scientific review of the are recommended. Spirometry is 0.3 percent).47 However, very few evidence on the safety of asthma tests are recommended at the time pregnant women who had oral medications during pregnancy and of initial assessment. For routine steroid-dependent asthma were includ- consideration of previous NAEPP monitoring at most subsequent ed in the studies, and the length, reports: the Asthma and Pregnancy followup outpatient visits, timing, and dose of exposure to the Report 1993, the EPR-2 1997, and spirometry is preferable, but drug were not well described. Oral the EPR—Update 2002. measurement of peak expiratory corticosteroid use during pregnancy flow (PEF) with a peak flow meter in patients who have asthma is associ- General principles is generally sufficient. Patients ated with an increased incidence of should be instructed to be preeclampsia and the delivery of • The treatment goal for the pregnant attentive to fetal activity. Serial both preterm and low birth weight asthma patient is to provide optimal ultrasound examinations starting infants.13, 47, 52 However, the available therapy to maintain control of asth- at 32 weeks gestation may be data make it difficult to separate the ma for maternal health and quality considered for patients who have effects of the oral corticosteroids on of life as well as for normal fetal suboptimally controlled asthma these outcomes from the effects of maturation. Asthma control is and for women with moderate- severe or uncontrolled asthma, which defined as: to-severe asthma. Ultrasound has been associated with maternal examinations are also helpful after and/or fetal mortality. recovery from a severe exacerbation.
Quick Reference 3 - Control of factors contributing to • Step 1: Mild Intermittent Asthma. not preferred treatment for pregnant asthma severity. Identifying and Short-acting bronchodilators, women whose asthma was successfully
controlling or avoiding such particularly short-acting inhaled beta2- controlled with this medication prior factors as allergens and irritants, agonists, are recommended as quick- to their pregnancy. Theophylline has particularly tobacco smoke, that relief medication for treating symptoms demonstrated clinical effectiveness in contribute to asthma severity as needed in patients with intermittent some studies and has been used for can lead to improved maternal asthma. Albuterol is the preferred years in pregnant women with asthma.
well-being with less need for short-acting inhaled beta2-agonist It also, however, has the potential for medications. (See figure 7.) because it has an excellent safety profile serious toxicity resulting from exces- and the greatest amount of data related sive dosing and/or select drug-drug - Patient education. Asthma control to safety during pregnancy of any cur- interactions (e.g., with erythromycin).
is enhanced by ensuring access to rently available inhaled beta2-agonist. Using theophylline during pregnancy education about asthma and about Women’s experience with these drugs is requires careful titration of the dose the skills necessary to manage it— extensive, and no evidence has been and regular monitoring to maintain such as self-monitoring, correct found either of fetal injury from the use the recommended serum theophylline
use of inhalers, and following a of short-acting inhaled beta2-agonists or concentration range of 5–12 mcg/mL. plan for managing asthma long of contraindication during lactation. term and for promptly handling • Step 3: Moderate Persistent Asthma. signs of worsening asthma. • Step 2: Mild Persistent Asthma. Two preferred treatment options are The preferred treatment for long- noted: either a combination of low- - A stepwise approach to pharmaco- term-control medication in Step 2 dose inhaled corticosteroid and a
logic therapy. In this approach to is daily low-dose inhaled cortico- long-acting inhaled beta2-agonist, or achieving and maintaining asthma steroid. This preference is based increasing the dose of inhaled cortico- control, the dose and number of on the strong effectiveness data in steroid to the medium dose range. No medications and the frequency of nonpregnant women6, 7 as well as data from studies during pregnancy administration are increased as effectiveness and safety data in preg- clearly delineate that one option is necessary, based on the severity nant women that show no increased recommended over the other. of the patient’s asthma, and are risk of adverse perinatal outcomes. decreased when possible. Budesonide is the preferred inhaled Limited data describe the effectiveness corticosteroid because more data are and/or safety of using combination Recommendations for Pharmacologic available on using budesonide in preg- therapy during pregnancy, but strong Treatment of Asthma During Pregnancy nant women than are available on evidence from randomized controlled other inhaled corticosteroids, and the trials in nonpregnant adults shows
Stepwise approach for managing data are reassuring. It is important to that adding long-acting inhaled beta2- asthma. To develop recommendations note that there are no data indicating agonist to a low dose of inhaled for the stepwise approach to the phar- that the other inhaled corticosteroid corticosteroid provides greater asthma macologic treatment of asthma in preg- preparations are unsafe during preg- control than only increasing the dose nant women, the Working Group first nancy. Therefore, inhaled cortico- of corticosteroid.7 The pharmacologic considered the stepwise approach in the steroids other than budesonide may and toxicologic profiles of long-acting
EPR—Update 2002, which was based be continued in patients who were and short-acting inhaled beta2-agonists on systematic review of the evidence well controlled by these agents prior are similar; there is justification for from medication effectiveness studies in to pregnancy, especially if it is thought expecting long-acting inhaled beta2- nonpregnant adults and children. The that changing formulations may agonists to have a safety profile simi- Working Group also considered EPR-2 jeopardize asthma control. lar to that of albuterol, for which 1997 and the Asthma and Pregnancy there are data related to safety during Report 1993. Cromolyn, leukotriene receptor antag- pregnancy. Two long-acting inhaled
onists, and theophylline are listed as beta2-agonists are available—salme- The effectiveness of medications is alternative but not preferred therapies. terol and formoterol. Limited observa- assumed to be the same in pregnant Cromolyn has an excellent safety tional data exist on their use during women as in nonpregnant women, profile, but it has limited effectiveness pregnancy; salmeterol might be chosen although there are no studies that compared with inhaled corticosteroids. because it has been available longer in directly test this assumption. Based Leukotriene receptor antagonists have the United States. on their current systematic review of been demonstrated to provide statisti- evidence from safety studies of asthma cally significant but modest improve- Increasing the dose of inhaled cortico- medications during pregnancy, the ments in children and nonpregnant steroid to medium dose will benefit Working Group then tailored existing adults with asthma, although in stud- many patients, and, as noted previous- recommendations for stepwise therapy. ies comparing overall efficacy of the ly, the data on using inhaled cortico- Refer to figures 1, 2, and 3 for a com- two drugs, most outcomes clearly steroids during pregnancy—including plete list of recommended therapies and favor inhaled corticosteroids. studies of large birth registries—are medication dosages in the stepwise Published data are minimal on using reassuring. approach to managing asthma. The leukotriene receptor antagonists dur- following information highlights the ing pregnancy; however, animal safety • Step 4: Severe Persistent Asthma. rationale for the preferred data submitted to the FDA are reas- If additional medication is required medications. suring. Thus, leukotriene receptor after carefully assessing patient tech- antagonists are an alternative but nique and adherence with using Step 3
4 NAEPP Working Group Report on Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment medication, then the inhaled cortico- Pharmacologic management of allergic be used for the treatment of allergic steroid dose should be increased within rhinitis. Rhinitis, sinusitis, and gastro- rhinitis—but minimal data are avail- the high-dose range, and the use of esophageal reflux are conditions that able on the use of this medication budesonide is preferred. If this is insuf- are often associated with asthma, are during pregnancy. ficient to manage asthma symptoms, frequently more troublesome during then the addition of systemic corticos- pregnancy, and may exacerbate coexist- • The current second-generation antihis- teroid is warranted; although the data ing asthma. If these conditions are tamines of choice are loratadine or are uncertain about some risks of oral present, appropriate treatment is an cetirizine. corticosteroids during pregnancy, integral part of asthma management. severe uncontrolled asthma poses a These topics were outside the scope of • There may be a relationship between definite risk to the mother and fetus. the current evidence-based review, but use of oral decongestants in early relevant studies on the safety of rhinitis pregnancy and a rare birth defect, Management of acute exacerbations. medications during pregnancy were gastroschisis; however, the absolute Asthma exacerbations have the potential reviewed in order to present the follow- risk of gastroschisis in exposed fetuses to lead to severe problems for the fetus. ing recommendations. is still extremely small. If nasal decon- Therefore, asthma exacerbations during gestion is indicated in early pregnancy, pregnancy should be managed aggres- • Intranasal corticosteroids are the most an external nasal dilator, short-term sively. Refer to figure 4 for home treat- effective medications for the manage- topical oxymetazoline, or intranasal ment of asthma exacerbation, figure 5 ment of allergic rhinitis and have a corticosteroid can be considered for emergency department and hospital low risk of systemic effect when used before use of oral decongestants. management, and figure 6 for medica- at recommended doses. Montelukast, tions and dosages. a leukotriene receptor antagonist, can
National Asthma Education and Prevention Program Asthma and Pregnancy Working Group
William W. Busse, M.D., Chair, University Harold S. Nelson, M.D., National Jewish Anthony R. Scialli, M.D., Georgetown of Wisconsin Medical School, Madison, WI Medical and Research Center, Denver, CO University Hospital, Washington, DC
Michelle Cloutier, M.D., Connecticut Michael Reed, Pharm.D., Rainbow Babies Stuart Stoloff, M.D., University of Nevada Children’s Medical Center, Hartford, CT and Children’s Hospital, Cleveland, OH School of Medicine, Reno, NV
Mitchell Dombrowski, M.D., St. John Michael Schatz, M.D., M.S., Kaiser- Stanley Szefler, M.D., National Jewish Hospital, Detroit, MI Permanente Medical Center, San Diego, CA Medical and Research Center, Denver, CO
Financial Disclosures
Dr. Busse has served on the Speakers’ Bureaus Altana, AstraZeneca, Aventis, Dey Dr. Schatz has served on the Speakers’ Bureaus of Aventis, GlaxoSmithKline, and Merck; Laboratories, Dynavax Technologies, of AstraZeneca and Merck; he has received he has served on the Advisory Boards of Genentech, GlaxoSmithKline, Integrated funding/grant support for research projects AstraZeneca, Aventis, Pfizer, and Schering; Therapeutics Group, Protein Design from Aventis and GlaxoSmithKline. he has received funding/grant support for Laboratories, Rigel Pharmaceuticals, UCB, research projects from Aventis, Fujisawa, and Wyeth. Dr. Scialli has none. GlaxoSmithKline, Hoffmann LaRoche, Pfizer, and Wyeth; he has served as a consultant for Dr. Reed has served on the Speakers’ Bureaus Dr. Stoloff has served on the Speakers’ Bristol-Myers Squibb, Dynavax, Fujisawa, of Abbott Laboratories, Bristol-Myers Squibb, Bureaus of Alcon, AstraZeneca, Aventis, Hoffmann LaRoche, and Wyeth. Enzon, GlaxoSmithKline, Pfizer, Roche, Genentech, GlaxoSmithKline, Pfizer, and and Somerset; he has received funding/grant Schering; he has served as a consultant for Dr. Cloutier has received funding/grant support for research projects from Health Alcon, AstraZeneca, Aventis, Genentech, support for research projects from Resources and Services Administration, GlaxoSmithKline, Pfizer, and Schering. GlaxoSmithKline. National Institutes of Health, Abbott Laboratories, AstraZeneca, Aventis, Dr. Szefler has received funding/grant support Dr. Dombrowski has none. Bristol-Myers Squibb, Eli Lilly, Forrest for research projects from the National Laboratories, GlaxoSmithKline, Janssen, Institutes of Health, AstraZeneca, and Russ Dr. Nelson has served on the Speakers’ Johnson & Johnson, Merck, Novartis, Pharmaceuticals; he has served as a consultant Bureaus of AstraZeneca and GlaxoSmithKline; Organon, Pfizer, Roche, Schering, Somerset, for AstraZeneca, Aventis, GlaxoSmithKline, he has received funding/grant support for and Wyeth-Averst; he has served as a consult- and Merck. research projects from Altana, AstraZeneca, ant for Abbott Laboratories, Bristol-Myers Dey Laboratories, Eli Lilly, Epigenesis, and Squibb, Enzon, GlaxoSmithKline, Pfizer, and IVAX; he has served as a consultant for Somerset.
Quick Reference 5 Figure Stepwise Approach for Managing Asthma During Pregnancy and Lactation: Treatment 1
Classify Severity: Clinical Features Before Medications Required To Maintain Treatment or Adequate Control Long-Term Control
Symptoms/ PEF Day or FEV 1 Daily Medications Symptoms/ PEF Variability Night Step 4 Continual ≤60% • Preferred treatment: - High-dose inhaled corticosteroid Severe Frequent >30% AND Persistent - Long-acting inhaled beta2-agonist AND, if needed, - Corticosteroid tablets or syrup long term (2 mg/kg per day, generally not to exceed 60 mg per day). (Make repeat attempts to reduce systemic corticosteroid and maintain control with high-dose inhaled corticosteroid.*)
• Alternative treatment: - High-dose inhaled corticosteroid* AND - Sustained release theophylline to serum concentration of 5–12 mcg/mL.
Step 3 Daily >60%–<80% • Preferred treatment: EITHER Moderate >1 night/week >30% - Low-dose inhaled corticosteroid* and long-acting inhaled beta2-agonist Persistent OR - Medium-dose inhaled corticosteroid.* If needed (particularly in patients with recurring severe exacerbations): - Medium-dose inhaled corticosteroid* and long-acting inhaled beta2-agonist.
• Alternative treatment: - Low-dose inhaled corticosteroid* and either theophylline or leukotriene receptor antagonist.† If needed: - Medium-dose inhaled corticosteroid* and either theophylline or leukotriene receptor antagonist.†
Step 2 >2 days/week but •Preferred treatment: ≥ Mild
Step 1 ≤2 days/week ≥80% • No daily medication needed. Mild ≤2 nights/month <20% • Severe exacerbations may occur, separated by long periods of normal lung function and no Intermittent symptoms. A course of systemic corticosteroid is recommended.
Quick • Short-acting bronchodilator: 2–4 puffs short-acting inhaled beta2-agonist‡ as needed for symptoms. Relief • Intensity of treatment will depend on severity of exacerbation; up to 3 treatments at 20-minute intervals or a single nebulizer treatment as needed. Course of systemic corticosteroid may be needed. All Patients • Use of short-acting inhaled beta2-agonist‡ >2 times a week in intermittent asthma (daily, or increasing use in persistent asthma) may indicate the need to initiate (increase) long-term-control therapy.
Step down Notes Review treatment every 1–6 months; a gradual stepwise reduction in treatment may be possible. • The stepwise approach is meant to assist, not replace, the clinical decisionmaking required to meet individual patient needs. Step up If control is not maintained, consider step up. First, • Classify severity: assign patient to most severe step in which any feature occurs (PEF review patient medication technique, adherence, and is percent of personal best; FEV1 is percent predicted). environmental control. • Gain control as quickly as possible (consider a short course of systemic corticosteroid), then step down to the least medication necessary to maintain control. Goals of Therapy: Asthma Control • Minimize use of short-acting inhaled beta2-agonist‡ (e.g., use of approximately one • Minimal or no chronic • Maintain (near) normal canister a month even if not using it every day indicates inadequate control of asthma symptoms day or night pulmonary function and the need to initiate or intensify long-term-control therapy). • Minimal or no exacerbations • Minimal use of short- • Provide education on self-management and controlling environmental factors that • No limitations on activities; acting inhaled beta2- no school/work missed agonist‡ make asthma worse (e.g., allergens, irritants). • Minimal or no adverse • Refer to an asthma specialist if there are difficulties controlling asthma or if Step 4 effects from medications care is required. Referral may be considered if Step 3 care is required.
* There are more data on using budesonide during pregnancy than on using other inhaled corticosteroids. † There are minimal data on using leukotriene receptor antagonists in humans during pregnancy, although there are reassuring animal data submitted to FDA. ‡ There are more data on using albuterol during pregnancy than on using other short-acting inhaled beta2-agonists.
6 NAEPP Working Group Report on Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment Figure Usual Dosages for Long-Term-Control Medications During Pregnancy 2 and Lactation*
Medication Dosage Form Adult Dose Inhaled Corticosteroids (See Estimated Comparative Daily Dosages for Inhaled Corticosteroids [Figure 3].)
Systemic Corticosteroids (Applies to all three corticosteroids.)
Methylprednisolone 2, 4, 8, 16, 32 mg tablets • 7.5–60 mg daily in a single dose in a.m. or qod as needed Prednisolone 5 mg tablets, for control 5 mg/5 cc, • Short-course “burst” to achieve control: 40–60 mg per 15 mg/5 cc day as single dose or 2 divided doses for 3–10 days Prednisone 1, 2.5, 5, 10, 20, 50 mg tablets 5 mg/cc, 5 mg/5 cc
Long-Acting Inhaled Beta2-Agonists (Should not be used for symptom relief or for exacerbations. Use with inhaled corticosteroids.) Salmeterol MDI 21 mcg/puff 2 puffs q 12 hours DPI 50 mcg/blister 1 blister q 12 hours Formoterol DPI 12 mcg/single-use capsule 1 capsule q 12 hours Combined Medication
Fluticasone/Salmeterol DPI 100, 250, or 1 inhalation bid; dose depends on severity of asthma 500 mcg/50 mcg Cromolyn
Cromolyn MDI 1 mg/puff 2–4 puffs tid-qid Nebulizer 20 mg/ampule 1 ampule tid-qid Leukotriene Receptor Antagonists Montelukast 10 mg tablet 10 mg qhs Zafirlukast 10 or 20 mg tablet 40 mg daily (20 mg tablet bid) Methylxanthines (Serum monitoring is important [serum concentration of 5–12 mcg/mL at steady state].) Theophylline Liquids, sustained-release Starting dose 10 mg/kg/day up to 300 mg max; usual max tablets, and capsules 800 mg/day
DPI, dry powder inhaler; MDI, metered-dose inhaler. *Adapted from EPR—Update 2002. Notes: • The most important determinant of appropriate dosing is the clinician’s judgment of the patient’s response to therapy. • Some doses may be outside package labeling, especially in the high-dose range.
Figure Estimated Comparative Daily Dosages for Inhaled Corticosteroids* 3
Drug Adult Low Daily Dose Adult Medium Daily Dose Adult High Daily Dose
Beclomethasone CFC 42 or 84 mcg/puff 168–504 mcg 504–840 mcg >840 mcg Beclomethasone HFA 40 or 80 mcg/puff 80–240 mcg 240–480 mcg >480 mcg Budesonide DPI 200 mcg/inhalation 200–600 mcg 600–1,200 mcg >1,200 mcg Flunisolide 250 mcg/puff 500–1,000 mcg 1,000–2,000 mcg >2,000 mcg Fluticasone MDI: 44, 110, or 220 mcg/puff 88–264 mcg 264–660 mcg >660 mcg DPI: 50, 100, or 250 100–300 mcg 300–750 mcg >750 mcg mcg/inhalation Triamcinolone acetonide 100 mcg/puff 400–1,000 mcg 1,000–2,000 mcg >2,000 mcg
DPI, dry powder inhaler; MDI, metered-dose inhaler. *Adapted from EPR—Update 2002.
Quick Reference 7 Figure Management of Asthma Exacerbations During Pregnancy and Lactation: 4 Home Treatment
Assess Severity
Measure PEF: Value <50% personal best or predicted suggests severe exacerbation
Note signs and symptoms: Degrees of cough, breathlessness, wheeze, and chest tightness correlate imperfectly with severity of exacerbation
Accessory muscle use and suprasternal retractions suggest severe exacerbation
Note presence of fetal activity*
Initial Treatment
Short-acting inhaled beta2-agonist: up to 3 treatments of 2–4 puffs by MDI at 20-minute intervals or single nebulizer treatment
Good Response Incomplete Response Poor Response
Mild Exacerbation Moderate Exacerbation Severe Exacerbation PEF >80% predicted or personal best. PEF 50%–80% predicted or personal PEF <50% predicted or personal best. No wheezing or shortness of breath. best. Marked wheezing and shortness Response to short-acting inhaled of breath. beta -agonist sustained for 4 hours. Persistent wheezing and shortness of Decreased fetal activity.* 2 breath. Appropriate fetal activity.* Treatment: Decreased fetal activity.* Treatment: • Add oral corticosteroid. Treatment: • May continue short-acting inhaled • Repeat short-acting inhaled beta2-agonist every 3–4 hours for • Add oral corticosteroid. beta2-agonist immediately. 24–48 hours. • Continue short-acting inhaled • If distress is severe and nonrespon- • For patients on inhaled cortico- beta -agonist. sive, call your clinician immediate- steroid, double dose for 7–10 days. 2 ly and proceed to emergency department; consider calling ambulance or 911.
Contact clinician for followup Contact clinician urgently (this day) Proceed to emergency department. instructions. for instructions.
MDI, metered-dose inhaler; PEF, peak expiratory flow. *Fetal activity is monitored by observing whether fetal kick counts decrease over time.
8 NAEPP Working Group Report on Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment Figure Management of Asthma Exacerbations During Pregnancy and Lactation: 5 Emergency Department and Hospital-Based Care*
Initial Assessment History, physical examination (auscultation, use of accessory muscles, heart rate, respiratory rate), PEF or FEV1, oxygen saturation, and other tests as indicated Initiate fetal assessment (consider continuous electronic fetal monitoring and/or biophysical profile if pregnancy has reached fetal viability)
FEV1 or PEF >50% FEV1 or PEF <50% (Severe Exacerbation) Impending or Actual Respiratory Arrest • Short-acting inhaled beta2-agonist by • High-dose short-acting inhaled beta2- • Intubation and mechanical ventilation MDI or nebulizer, up to three doses in agonist by nebulization every 20 minutes with 100% O2 first hour or continuously for 1 hour plus inhaled • Nebulized short-acting inhaled beta2- ≥ • Oxygen to achieve O2 saturation 95% ipratropium bromide agonist plus inhaled ipratropium bromide • Oral systemic corticosteroid if no imme- • Oxygen to achieve O2 saturation >95% • Intravenous corticosteroid diate response or if patient recently took • Oral systemic corticosteroid oral systemic corticosteroid
Repeat Assessment Admit to Hospital Symptoms, physical examination, PEF, O2 saturation, other tests as needed Intensive Care Continue fetal assessment (see box below)
Moderate Exacerbation Severe Exacerbation FEV1 or PEF 50%–80% predicted/personal best FEV1 or PEF <50% predicted/personal best Physical exam: moderate symptoms Physical exam: severe symptoms at rest, • Short-acting inhaled beta2-agonist every accessory muscle use, chest retraction 60 minutes History: high-risk patient • Systemic corticosteroid No improvement after initial treatment • Oxygen to maintain O2 saturation >95% • Short-acting inhaled beta2-agonist hourly or • Continue treatment 1–3 hours, provided continuously plus inhaled ipratropium bromide there is improvement • Oxygen • Systemic corticosteroid
Good Response Incomplete Response Poor Response ≥ ≥ • FEV1 or PEF 70% • FEV1 or PEF 50% but <70% • FEV1 or PEF <50% • Response sustained 60 minutes after last • Mild or moderate symptoms • PCO2 >42 mmHg treatment • Continue fetal assessment • Physical exam: symptoms severe, • No distress drowsiness, confusion • Physical exam: normal • Continue fetal assessment • Reassuring fetal status
Individualized Decision re: Hospitalization
Discharge Home Admit to Hospital Ward Admit to Hospital Intensive Care • Continue treatment with short-acting • Short-acting inhaled beta2-agonist plus • Short-acting inhaled beta2-agonist hourly inhaled beta2-agonist inhaled ipratropium bromide or continuously plus inhaled ipratropium • Continue course of oral systemic • Systemic (oral or intravenous) bromide corticosteroid corticosteroid • Intravenous corticosteroid • Initiate or continue inhaled corticosteroid • Oxygen • Oxygen until review at medical followup • Monitor FEV1 or PEF, O2 saturation, • Possible intubation and mechanical • Patient education pulse ventilation - Review medicine use • Continue fetal assessment until patient • Continue fetal assessment until patient - Review/initiate action plan stabilized stabilized - Recommend close medical followup
Improve
Discharge Home • Continue treatment with short-acting inhaled beta2-agonist • Continue course of oral systemic corticosteroid • Initiate or continue inhaled corticosteroid until review at medical followup • Patient education - Review medicine use - Review/initiate action plan - Recommend close medical followup
FEV1, forced expiratory volume in 1 second; MDI, metered-dose inhaler; PCO2, carbon dioxide partial pressure; PEF, peak expiratory flow. *Adapted from EPR-2 1997.
Quick Reference 9 Figure Medications and Dosages for Asthma Exacerbations During Pregnancy and Lactation* 6 Dosages Medications Adult Dose Child Dose Comments
Short-Acting Inhaled Beta2-Agonists
Albuterol Nebulizer solution 2.5–5 mg every 20 minutes for 0.15 mg/kg (minimum dose 2.5 mg) Only selective beta2-agonists are recom- (5.0 mg/mL, 3 doses, then 2.5–10 mg every every 20 minutes for 3 doses, then mended. For optimal delivery, dilute 2.5 mg/3mL, 1–4 hours as needed, or 10–15 0.15–0.3 mg/kg up to 10 mg every aerosols to minimum of 3 mL at gas flow 1.25 mg/3mL, mg/hour continuously 1–4 hours as needed, or 0.5 mg/kg/ of 6–8 L/min. 0.63 mg/3 mL) hour by continuous nebulization MDI 4–8 puffs every 20 minutes up to 4 4–8 puffs every 20 minutes for 3 As effective as nebulized therapy if patient (90 mcg/puff) hours, then every 1–4 hours as needed doses, then every 1–4 hours inhalation is able to coordinate. maneuver; use spacer/holding chamber
Bitolterol Nebulizer solution See albuterol dose. See albuterol dose; thought to be half Has not been studied in severe asthma exac- (2 mg/mL) as potent as albuterol on a mg basis. erbations. Do not mix with other drugs. MDI See albuterol dose. See albuterol dose. Has not been studied in severe asthma (370 mcg/puff) exacerbations. Levalbuterol (R-albuterol) Nebulizer solution 1.25–2.5 mg every 20 minutes for 0.075 mg/kg (minimum dose 1.25 mg) 0.63 mg of levalbuterol is equivalent to (0.63 mg/3 mL, 3 doses, then 1.25–5 mg every 1–4 every 20 minutes for 3 doses, then 1.25 mg of racemic albuterol for both 1.25 mg/3 mL) hours as needed, or 5–7.5 mg/hour 0.075–0.15 mg/kg up to 5 mg every efficacy and side effects. continuously 1–4 hours as needed, or 0.25 mg/kg/ hour by continuous nebulization
Pirbuterol MDI See albuterol dose. See albuterol dose; thought to be half Has not been studied in severe asthma (200 mcg/puff) as potent as albuterol on a mg basis. exacerbations.
Systemic (Injected) Beta2-Agonists Epinephrine 1:1000 (1 mg/mL) 0.3–0.5 mg every 20 minutes for 0.01 mg/kg up to 0.3–0.5 mg every No proven advantage of systemic therapy 3 doses sq 20 minutes for 3 doses sq over aerosol.
Terbutaline (1 mg/mL) 0.25 mg every 20 minutes for 0.01 mg/kg every 20 minutes for 3 doses, No proven advantage of systemic therapy 3 doses sq then every 2–6 hours as needed sq over aerosol.
Anticholinergics Ipratropium bromide Nebulizer solution 0.5 mg every 30 minutes for 3 doses, 0.25 mg every 20 minutes for 3 doses, May mix in same nebulizer with albuterol. (0.25 mg/mL) then every 2–4 hours as needed then every 2 to 4 hours Should not be used as first-line therapy; should be added to beta2-agonist therapy. MDI 4–8 puffs as needed 4–8 puffs as needed (18 mcg/puff) Dose delivered from MDI is low and has not been studied in asthma exacerbations.
Ipratropium with albuterol Nebulizer solution 3 mL every 30 minutes for 3 doses, 1.5 mL every 20 minutes for 3 doses, Contains EDTA to prevent discoloration. (Each 3 mL vial con- then every 2–4 hours as needed then every 2–4 hours This additive does not induce tains 0.5 mg ipratrop- bronchospasm. ium bromide and 2.5 mg albuterol) MDI 4–8 puffs as needed 4–8 puffs as needed (Each puff contains 18 mcg ipratropium bromide and 90 mcg albuterol) Systemic Corticosteroids (Dosages and comments apply to all three corticosteroids)
Prednisone 120–180 mg/day in 3 or 4 divided 1 mg/kg every 6 hours for 48 hours, For outpatient “burst” use 40–60 mg Methylprednisolone doses for 48 hours, then 60–80 then 1–2 mg/kg/day (maximum = 60 in single or 2 divided doses for adults Prednisolone mg/day until PEF reaches 70% mg/day) in 2 divided doses until PEF (children: 1–2 mg/kg/day, maximum of predicted or personal best is 70% of predicted or personal best 60 mg/day) for 3–10 days.
* Adapted from EPR—Update 2002. Notes: • The most important determinant of appropriate dosing is the clinician’s judgment of the patient’s response to therapy. • No advantage has been found for higher dose corticosteroids in severe asthma exacerbations, nor is there any advantage for intravenous administration over oral therapy provided gastrointestinal transit time or absorption is not impaired. The usual regimen is to continue the frequent multiple daily dose until the patient achieves an FEV1 or PEF of 50 percent of predicted or personal best and then lower the dose to twice daily. This usually occurs within 48 hours. Therapy following a hospitalization or emergency department visit may last from 3 to 10 days. If patients are then started on inhaled corticosteroids, studies indicate there is no need to taper the systemic corticosteroid dose. If the followup systemic corticosteroid therapy is to be given once daily, one study indicates that it may be more clinically effective to give the dose in the afternoon at 3 p.m., with no increase in adrenal suppression.54
10 NAEPP Working Group Report on Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment Figure Summary of Control Measures for Environmental Factors 7 That Can Make Asthma Worse*
Allergens: Reduce or eliminate exposure to the allergen(s) the patient is sensitive to, including:
• Animal dander: Remove animal from house, or, at a minimum, keep animal out of patient’s bedroom and seal or cover with a filter the air ducts that lead to the bedroom.
• House-dust mites: - Essential: Encase mattress in an allergen-impermeable cover; encase pillow in an allergen–impermeable cover or wash it weekly; wash sheets and blankets on the patient’s bed in hot water weekly (water temperature of >130˚F is necessary for killing mites). - Desirable: Reduce indoor humidity to less than 50 percent; remove carpets from the bedroom; avoid sleeping or lying on upholstered furniture; remove carpets that are laid on concrete.
• Cockroaches: Use poison bait or traps to control. Do not leave food or garbage exposed.
• Pollens (from trees, grass, or weeds) and outdoor molds: To avoid exposure, adults should stay indoors—especially during the afternoon—with the windows closed during the season in which they have problems with outdoor allergens.
• Indoor mold: Fix all leaks and eliminate water sources associated with mold growth; clean moldy surfaces. Consider reducing indoor humidity to less than 50 percent.
Tobacco Smoke: Advise patients and others in the home who smoke to stop smoking or to smoke outside the home. Discuss ways to reduce exposure to other sources of tobacco smoke, such as from daycare providers and the workplace.
Indoor/Outdoor Pollutants and Irritants: Discuss ways to reduce exposures to the following:
• Wood-burning stoves or fireplaces • Unvented stoves or heaters • Other irritants (e.g., perfumes, cleaning agents, sprays)
*Adapted from EPR-2 1997.
REFERENCES Bethesda, MD: U.S. Department of Health toms, severity, and drug therapy: a prospec- and Human Services; National Institutes of tive study of effects on 2205 pregnancies. Health; National Heart, Lung, and Blood Obstet Gynecol 2003;102(4):739–52. 1. Kwon HL, Belanger K, Bracken MB. Institute, 1997. Available from URL: 12. Rayburn WF, Atkinson BD, Gilbert K, Asthma prevalence among pregnant and http://www.nhlbi.nih.gov/guidelines/ Turnbull GL. Short-term effects of inhaled childbearing-aged women in the United asthma/asthgdln.htm. Accessed July 8, 2004. albuterol on maternal and fetal circulations. States: estimates from national health sur- 7. EPR—Update 2002. NAEPP Expert Panel Am J Obstet Gynecol 1994;171(3):770–3. veys. Ann Epidemiol 2003;13(5):317–24. Report: Guidelines for the Diagnosis and 13. Schatz M, Zeiger RS, Harden K, Hoffman 2. Demissie K, Breckenridge MB, Rhoads GG. Treatment of Asthma—Update on Selected CC, Chilingar L, Petitti D. The safety of Infant and maternal outcomes in the preg- Topics 2002. NIH Publication No. 02-5074. asthma and allergy medications during nancies of asthmatic women. Am J Respir Bethesda, MD: U.S. Department of Health pregnancy. J Allergy Clin Immunol Crit Care Med 1998;158(4):1091–5. and Human Services; National Institutes 1997;100(3):301–6. 3. Källén B, Rydhstroem H, Åberg A. Asthma of Health; National Heart, Lung, and Blood 14. Wilton LV, Pearce GL, Martin RM, Mackay during pregnancy—a population based study. Institute, 2003. Available from URL: FJ, Mann RD. The outcomes of pregnancy Eur J Epidemiol 2000;16(2):167–71. http://www.nhlbi.nih.gov/guidelines/asthma/ in women exposed to newly marketed drugs 4. Schatz M, Zeiger RS, Hoffman CP, Harden asthupdt.htm. Accessed July 8, 2004. in general practice in England. Br J Obstet K, Forsythe A, Chilingar L, Saunders B, 8. Asthma and Pregnancy—Update 2004. Gynaecol 1998;105(8):882–9. Porreco R, Sperling W, Kagnoff M, et al. NAEPP Working Group Report on Managing 15. Wilton LV, Shakir SA. A post-marketing Perinatal outcomes in the pregnancies of Asthma During Pregnancy: Recommendations surveillance study of formoterol (Foradil): asthmatic women: a prospective controlled for Pharmacologic Treatment—Update 2004. its use in general practice in England. analysis. Am J Respir Crit Care Med NIH Publication No. 05-3279. Bethesda, Drug Saf 2002;25(3):213–23. 1995;151(4):1170–4. MD: U.S. Department of Health and 16. Harris MW, Chapin RE, Lockhart AC, 5. Asthma and Pregnancy Report. NAEPP Human Services; National Institutes of Jokinen MP. Assessment of a short-term Report of the Working Group on Asthma and Health; National Heart, Lung, and Blood reproductive and developmental toxicity Pregnancy: Management of Asthma During Institute, 2004. screen. Fundam Appl Toxicol Pregnancy. NIH Publication No. 93-3279. 9. Alexander DJ, Mather A, Dines GD. A snout- 1992;19(2):186–96. Bethesda, MD: U.S. Department of Health only inhalation exposure system for use in 17. Hart AD, Grimble RF. Effect of meth- and Human Services; National Institutes of rabbit teratology studies. Inhal Toxicol ylxanthines on lactational performance of Health; National Heart, Lung, and Blood 1997;9(5):477–90. rats. Ann Nutr Metab 1990;34(5):297–302. Institute, 1993. Available from URL: http:// 10. Baker ER, Flanagan MF. Fetal atrial flutter 18. Hart AD, Grimble RF. The effect of www.nhlbi.nih.gov/health/prof/lung/asthma/ associated with maternal beta-sympath- methylxanthines on milk volume and compo- astpreg.txt. Accessed July 8, 2004. omimetic drug exposure. Obstet Gynecol sition, and growth of rat pups. Br J Nutr 6. EPR-2. NAEPP Expert Panel Report 2: 1997;89(5 Pt 2):861. 1990;64(2):339–50. Guidelines for the Diagnosis and Treatment 11. Bracken MB, Triche EW, Belanger K, Saftlas 19. Lamb J, Gulati D, Chambers R, Shaver S, of Asthma. NIH Publication No. 97-4051. A, Beckett WS, Leaderer BP. Asthma symp- Sabharwal P. Reproductive toxicology.
Quick Reference 11 QUICK REFERENCE
Theophylline. Environ Health Perspect 32. Alexander S, Dodds L, Armson BA. 44. Tangalakis K, Lumbers ER, Moritz KM, 1997;105(Suppl):1355–6. Perinatal outcomes in women with asthma Towstoless MK, Wintour EM. Effect of 20. León D, Albasanz JL, Ruiz MA, Fernandez during pregnancy. Obstet Gynecol cort-isol on blood pressure and vascular M, Martin M. Adenosine A1 receptor down- 1998;92(3):435–40. reactivity in the ovine fetus. Exp Physiol regulation in mothers and fetal brain after 33. Dombrowski MP, Brown CL, Berry SM. 1992;77(5):709–17. caffeine and theophylline treatments to preg- Preliminary experience with triamcinolone 45. Uno H, Eisele S, Sakai A, Shelton S, Baker E, nant rats. J Neurochem 2002;82(3):625–34. acetonide during pregnancy. J Matern Fetal DeJesus O, Holden J. Neurotoxicity of 21. Lindström P, Morrissey RE, George JD, Price Med 1996;5(6):310–3. glucocorticoids in the primate brain. CJ, Marr MC, Kimmel CA, Schwetz BA. The 34. Stenius-Aarniala BS, Hedman J, Teramo KA. Horm Behav 1994;28(4):336–48. developmental toxicity of orally administered Acute asthma during pregnancy. Thorax 46. Watanabe C, Ishizuka Y, Nagao T. Palatal theophylline in rats and mice. Fundam Appl 1996;51(4):411–4. slit and cleft palate in rats treated with glu- Toxicol 1990;14(1):167–78. 35. Murphy VE, Zakar T, Smith R, Giles WB, cocorticoids—II. Comparative teratogenicity 22. Shibata M, Wachi M, Kawaguchi M, Kojima Gibson PG, Clifton VL. Reduced 11beta- of prednisolone, triamcinolone acetonide and J, Onodera K. Teratogenic and fetal toxicity hydroxysteroid dehydrogenase type 2 activity hydrocortisone. Congenital Anomalies following intravenous theophylline adminis- is associated with decreased birth weight cen- 1995;35(1):133–40. tration in pregnant rabbits is related to tile in pregnancies complicated by asthma. 47. Park-Wyllie L, Mazzotta P, Pastuszak A, maternal drug plasma levels. Methods Find J Clin Endocrinol Metab 2002;87(4):1660–8. Moretti ME, Beique L, Hunnisett L, Friesen Exp Clin Pharmacol 2000;22(2):101–7. 36. Källén B, Rydhstroem H, Åberg A. Congenital MH, Jacobson S, Kasapinovic S, Chang D, 23. Agarwal HS, Nanavati RN, Bhagwat MS, malformations after the use of inhaled budes- et al. Birth defects after maternal exposure Kabra NS, Udani RH. Transplancental onide in early pregnancy. Obstet Gynecol to corticosteroids: prospective cohort study aminophylline toxicity. Indian Pediatr 1999;93(3):392–5. and meta-analysis of epidemiological studies. 1998;35(5):467–70. 37. Norjavaara E, de Verdier MG. Normal preg- Teratology 2000;62(6):385–92. 24. Park JM, Schmer V, Myers TL. Cardio- nancy outcomes in a population-based study 48. Carmichael SL, Shaw GM. Maternal corti- vascular anomalies associated with prenatal including 2,968 pregnant women exposed to costeroid use and risk of selected congenital exposure to theophylline. South Med J budesonide. J Allergy Clin Immunol anomalies. Am J Med Genet 1990;83(12):1487–8. 2003;111(4):736–42. 1999;86(3):242–4. 25. Dombrowski MP, Schatz M, Wise R, Thom 38. Abbott BD, Diliberto JJ, Birnbaum LS. 49. Czeizel AE, Rockenbauer M. Population- EA, Landon M, Mabie W, Newman RB, Mechanisms of TCDD-induction of cleft based case-control study of teratogenic McNellis D, Hauth JC, Lindheimer M, et al. palate: insights from in vivo and in vitro potential of corticosteroids. Teratology Randomized trial of inhaled beclomethasone approaches. Chemosphere 1997;56(5):335–40. dipropionate versus theophylline for moder- 1992;25(1–2):75–8. 50. Robert E, Vollset SE, Botto L, Lancaster ate asthma during pregnancy. Am J Obstet 39. Abbott BD, Harris MW, Birnbaum LS. PAL, Merlob P, Mastroiacovo P, Cocchi G, Gynecol 2004;190(3):737–44. Comparisons of the effects of TCDD and Ashizawa M, Sakamoto S, Orioli I. 26. Neff RK, Leviton A. Maternal theophylline hydrocortisone on growth factor expression Malformation surveillance and maternal consumption and the risk of stillbirth. Chest provide insight into their interaction in the drug exposure: the MADRE project. 1995. 1990;97(5):1266–7. embryonic mouse palate. Teratology Int J Risk Safe Med 1994;6:75–118. 27. Stenius-Aarniala B, Riikonen S, Teramo K. 1992;45(1):35–53. 51. Rodríguez-Pinilla E, Martinez-Frias ML. Slow-release theophylline in pregnant 40. Abbott BD, Perdew GH, Buckalew AR, Corticosteroids during pregnancy and oral asthmatics. Chest 1995;107(3):642–7. Birnbaum LS. Interactive regulation of Ah clefts: a case-control study. Teratology 28. Wendel PJ, Ramin SM, Barnett-Hamm C, and glucocorticoid receptors in the synergis- 1998;58(1):2–5. Rowe TF, Cunningham FG. Asthma treat- tic induction of cleft palate by 2,3,7,8-tetra- 52. Perlow JH, Montgomery D, Morgan MA, ment in pregnancy: a randomized controlled chlorodibenzo-p-dioxin and hydrocortisone. Towers CV, Porto M. Severity of asthma and study. Am J Obstet Gynecol Toxicol Appl Pharmacol 1994;128(1): perinatal outcome. Am J Obstet Gynecol 1996;175(1):150–4. 138–50. 1992;167(4 Pt 1):963–7. 29. Rotschild A, Solimano A, Sekhon HS, 41. Abbott BD, Schmid JE, Brown JG, Wood 53. Schatz M, Dombrowski MP, Wise R, Thom Massoud EA, Thurlbeck WM. Effect of CR, White RD, Buckalew AR, Held GA. EA, Landon M, Mabie W, Newman RB, triamcinolone acetonide on the development RT-PCR quantification of AHR, ARNT, GR, Hauth JC, Lindheimer M, Caritis SN, et al. of the pulmonary airways in the fetal rat. and CYP1A1 mRNA in craniofacial tissues Asthma morbidity during pregnancy can be Pediatr Pulmonol 1997;23(2):76–86. of embryonic mice exposed to 2,3,7,8-tetra- predicted by severity classification. J Allergy 30. Sakamoto MK, Nakamura K, Handa J, chlorodibenzo-p-dioxin and hydrocortisone. Clin Immunol 2003;112(2):283–8. Kihara T, Tanimura T. Studies of variant Toxicol Sci 1999;47(1):76–85. 54. Beam WR, Weiner DE, Martin RJ. Timing palatal rugae in normal and cortico-steroid- 42. Dodic M, May CN, Wintour EM, Coghlan of prednisone and alterations of airways treated mouse embryos. Anat Rec JP. An early prenatal exposure to excess glu- inflammation in nocturnal asthma. Am Rev 1991;230(1):121–30. cocorticoid leads to hypertensive offspring in Respir Dis 1992;146(6):1524–30. 31. Wise LD, Vetter CM, Anderson CA, sheep. Clin Sci (Lond) 1998;94(2):149–55. Antonello JM, Clark RL. Reversible effects 43. Jobe AH, Wada N, Berry LM, Ikegami M, of triamcinolone and lack of effects with Ervin MG. Single and repetitive maternal aspirin or L-656,224 on external genitalia of glucocorticoid exposures reduce fetal growth male Sprague-Dawley rats exposed in utero. in sheep. Am J Obstet Gynecol Teratology 1991;44(5):507–20. 1998;178(5):880–5.
U.S. DEPARTMENT OF HEALTH AND For more information, contact: HUMAN SERVICES NHLBI Health Information Center National Institutes of Health P.O. Box 30105 National Heart, Lung, and Blood Institute Bethesda, MD 20824-0105 NIH Publication No. 05-5246 Phone: 301-592-8573; fax: 301-592-8563; TTY: 240-629-3255 Originally Printed March 2004 Revised January 2005 Web: http://www.nhlbi.nih.gov