NAEPP Expert Panel Report: Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment—2004 Update

Abstract

View Large Image Figure ViewerDownload Hi-res image Download (PPT) Maintaining adequate control of asthma during pregnancy is important for the health and well-being of both the mother and her baby. Asthma has been reported to affect 3.7 to 8.4 percent of pregnant women,1Kwon H.L. Belanger K. Bracken M.B. Asthma prevalence among pregnant and childbearing-aged women in the United States: estimates from national health surveys.Ann Epidemiol. 2003; 13: 317-324Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar making it potentially the most common serious medical problem to complicate pregnancy. The largest and most recent studies suggest that maternal asthma increases the risk of perinatal mortality, preeclampsia, preterm birth, and low birth weight infants. More severe asthma is associated with increased risks,2Demissie K. Breckenridge M.B. Rhoads G.G. Infant and maternal outcomes in the pregnancies of asthmatic women.Am J Respir Crit Care Med. 1998; 158: 1091-1095Crossref PubMed Scopus (243) Google Scholar, 3Källén B. Rydhstroem H. Åberg A. Asthma during pregnancy—a population based study.Eur J Epidemiol. 2000; 16: 167-171Crossref PubMed Scopus (144) Google Scholar while better-controlled asthma is associated with decreased risks.4Schatz M. Zeiger R.S. Hoffman C.P. Harden K. Forsythe A. Chilingar L. et al.Perinatal outcomes in the pregnancies of asthmatic women: a prospective controlled analysis.Am J Respir Crit Care Med. 1995; 151: 1170-1174PubMed Google Scholar In 1993, the National Asthma Education and Prevention Program (NAEPP) published the Report of the Working Group on Asthma and Pregnancy (Asthma and Pregnancy Report 1993),5Asthma and pregnancy report. NAEPP report of the Working Group on Asthma and Pregnancy: management of asthma during pregnancy. NIH publication no. 93-3279. Bethesda (MD): US Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute, 1993. Available from URL: http://www.nhlbi.nih.gov/health/prof/lung/asthma/astpreg.txt. Accessed July 8, 2004.Google Scholar which presented recommendations for the management of asthma during pregnancy. Since then, there have been revisions to the general asthma treatment guidelines, Guidelines for the Diagnosis and Management of Asthma—Expert Panel Report 2 (EPR-2 1997),6EPR-2. NAEPP expert panel report 2: guidelines for the diagnosis and treatment of asthma. NIH publication no. 97-4051. Bethesda (MD): US Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute, 1997. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed July 8, 2004.Google Scholar and Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma—Update on Selected Topics 2002 (EPR—Update 2002)7EPR—Update 2002. NAEPP expert panel report: guidelines for the diagnosis and treatment of asthma—update on selected topics 2002. NIH publication no. 02–5074. Bethesda (MD): US Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute, 2003. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthupdt.htm. Accessed July 8, 2004.Google Scholar; release of new asthma medications; and publication of new gestational safety data. Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment—Update 2004 (EPR—Update 2004)8EPR—Update 2004. NAEPP expert panel report: managing asthma during pregnancy: recommendations for pharmacologic treatment—update 2004. NIH publication no. 04-3279. Bethesda (MD): US Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute, 2004.Google Scholar reflects the NAEPP's commitment to keep recommendations for clinical practice up to date and based on systematic reviews of the evidence. EPR—Update 2004 was developed through the collective expertise of an expert panel on asthma and pregnancy (Working Group), the NAEPP Science Base Committee, and NAEPP Coordinating Committee members. The recommendations made in EPR—Update 2004 are intended to assist clinical decision-making; the clinician and patient still need to develop individual treatment plans that are tailored to the specific needs and circumstances of the patient. The scope of the current systematic review is pharmacologic treatment of asthma in women during their pregnancy; however, highlights from EPR-2 1997 and EPR—Update 2002 relative to other aspects of asthma care are also presented because they should enhance the overall success and safety of managing asthma in pregnancy. A systematic review of the evidence on the safety of asthma medications during pregnancy was conducted by drug class. Of 226 articles retrieved in the search of literature published in peer-reviewed journals from January 1990 through May 2003, 42 met criteria for inclusion in the evidence review; 2 additional articles published after May 2003 were included, for a total of 44 articles. A summary of the findings from the evidence, arranged by medication category, follows. One experimental animal study9Alexander D.J. Mather A. Dines G.D. A snout-only inhalation exposure system for use in rabbit teratology studies.Inhal Toxicol. 1997; 9: 477-490Crossref Scopus (2) Google Scholar and six human studies were included. The six human studies consisted of one case report10Baker E.R. Flanagan M.F. Fetal atrial flutter associated with maternal beta-sympathomimetic drug exposure.Obstet Gynecol. 1997; 89: 861Crossref PubMed Scopus (8) Google Scholar and five clinical studies11Bracken M.B. Triche E.W. Belanger K. Saftlas A. Beckett W.S. Leaderer B.P. Asthma symptoms, severity, and drug therapy: a prospective study of effects on 2205 pregnancies.Obstet Gynecol. 2003; 102: 739-752Crossref PubMed Scopus (199) Google Scholar, 12Rayburn W.F. Atkinson B.D. Gilbert K. Turnbull G.L. Short-term effects of inhaled albuterol on maternal and fetal circulations.Am J Obstet Gynecol. 1994; 171: 770-773Abstract Full Text PDF PubMed Google Scholar, 13Schatz M. Zeiger R.S. Harden K. Hoffman C.C. Chilingar L. Petitti D. The safety of asthma and allergy medications during pregnancy.J Allergy Clin Immunol. 1997; 100: 301-306Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 14Wilton L.V. Pearce G.L. Martin R.M. Mackay F.J. Mann R.D. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England.Br J Obstet Gynaecol. 1998; 105: 882-889Crossref PubMed Scopus (123) Google Scholar, 15Wilton L.V. Shakir S.A. A post-marketing surveillance study of formoterol (Foradil): its use in general practice in England.Drug Saf. 2002; 25: 213-223Crossref PubMed Scopus (23) Google Scholar that included a total of 6,667 pregnant women, of whom 1,929 had asthma and 1,599 had taken beta2-agonists. The data were reassuring regarding the safety of beta2-agonists during pregnancy. More data were available for albuterol. Two long-acting inhaled beta2-agonists have become available since 1993—salmeterol and formoterol. Limited data are available on their use during pregnancy. The pharmacologic and toxicologic profiles of these two drugs are similar to the short-acting inhaled beta2-agonists, with the exception of their prolonged retention in the lungs. Seven experimental animal studies16Harris M.W. Chapin R.E. Lockhart A.C. Jokinen M.P. Assessment of a short-term reproductive and developmental toxicity screen.Fundam Appl Toxicol. 1992; 19: 186-196Crossref PubMed Scopus (28) Google Scholar, 17Hart A.D. Grimble R.F. Effect of methylxanthines on lactational performance of rats.Ann Nutr Metab. 1990; 34: 297-302Crossref PubMed Scopus (10) Google Scholar, 18Hart A.D. Grimble R.F. The effect of methylxanthines on milk volume and composition, and growth of rat pups.Br J Nutr. 1990; 64: 339-350Crossref PubMed Scopus (13) Google Scholar, 19Lamb J. Gulati D. Chambers R. Shaver S. Sabharwal P. Reproductive toxicology. Theophylline.Environ Health Perspect. 1997; 105: 1355-1356Google Scholar, 20León D. Albasanz J.L. Ruiz M.A. Fernandez M. Martin M. Adenosine A1 receptor down-regulation in mothers and fetal brain after caffeine and theophylline treatments to pregnant rats.J Neurochem. 2002; 82: 625-634Crossref PubMed Scopus (60) Google Scholar, 21Lindström P. Morrissey R.E. George J.D. Price C.J. Marr M.C. Kimmel C.A. et al.The developmental toxicity of orally administered theophylline in rats and mice.Fundam Appl Toxicol. 1990; 14: 167-178Crossref PubMed Scopus (12) Google Scholar, 22Shibata M. Wachi M. Kawaguchi M. Kojima J. Onodera K. Teratogenic and fetal toxicity following intravenous theophylline administration in pregnant rabbits is related to maternal drug plasma levels.Methods Find Exp Clin Pharmacol. 2000; 22: 101-107Crossref PubMed Scopus (9) Google Scholar and eight human studies were included. The experimental animal studies confirm the association of high-dose theophylline and adverse pregnancy outcomes in animals. The eight human studies, consisting of two case reports23Agarwal H.S. Nanavati R.N. Bhagwat M.S. Kabra N.S. Udani R.H. Transplancental aminophylline toxicity.Indian Pediatr. 1998; 35: 467-470PubMed Google Scholar, 24Park J.M. Schmer V. Myers T.L. Cardiovascular anomalies associated with prenatal exposure to theophylline.South Med J. 1990; 83: 1487-1488Crossref PubMed Scopus (29) Google Scholar and six clinical studies11Bracken M.B. Triche E.W. Belanger K. Saftlas A. Beckett W.S. Leaderer B.P. Asthma symptoms, severity, and drug therapy: a prospective study of effects on 2205 pregnancies.Obstet Gynecol. 2003; 102: 739-752Crossref PubMed Scopus (199) Google Scholar, 13Schatz M. Zeiger R.S. Harden K. Hoffman C.C. Chilingar L. Petitti D. The safety of asthma and allergy medications during pregnancy.J Allergy Clin Immunol. 1997; 100: 301-306Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 25Dombrowski M.P. Schatz M. Wise R. Thom E.A. Landon M. Mabie W. et al.Randomized trial of inhaled beclomethasone dipropionate versus theophylline for moderate asthma during pregnancy.Am J Obstet Gynecol. 2004; 190: 737-744Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 26Neff R.K. Leviton A. Maternal theophylline consumption and the risk of stillbirth.Chest. 1990; 97: 1266-1267Crossref PubMed Scopus (20) Google Scholar, 27Stenius-Aarniala B. Riikonen S. Teramo K. Slow-release theophylline in pregnant asthmatics.Chest. 1995; 107: 642-647Crossref PubMed Scopus (80) Google Scholar, 28Wendel P.J. Ramin S.M. Barnett-Hamm C. Rowe T.F. Cunningham F.G. Asthma treatment in pregnancy: a randomized controlled study.Am J Obstet Gynecol. 1996; 175: 150-154Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar (of which two were randomized controlled trials), included a total of 57,163 pregnant women, of whom 3,616 had asthma and 660 had taken theophylline. Studies and clinical experience confirm the safety of theophylline at recommended doses (to serum concentration of 5–12 mcg/mL) during pregnancy. In a randomized controlled trial, there were no differences in asthma exacerbations or maternal or perinatal outcomes in the theophylline versus the beclomethasone dipropionate treatment groups. However, in the theophylline treatment group, there were higher levels of reported side effects and discontinuation of the medication and an increase in the proportion of women with forced expiratory volume in 1 second (FEV1) at less than 80 percent of that predicted.25Dombrowski M.P. Schatz M. Wise R. Thom E.A. Landon M. Mabie W. et al.Randomized trial of inhaled beclomethasone dipropionate versus theophylline for moderate asthma during pregnancy.Am J Obstet Gynecol. 2004; 190: 737-744Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar No data on anticholinergics were available for the current evidence review. Three experimental animal studies29Rotschild A. Solimano A. Sekhon H.S. Massoud E.A. Thurlbeck W.M. Effect of triamcinolone acetonide on the development of the pulmonary airways in the fetal rat.Pediatr Pulmonol. 1997; 23: 76-86Crossref PubMed Scopus (11) Google Scholar, 30Sakamoto M.K. Nakamura K. Handa J. Kihara T. Tanimura T. Studies of variant palatal rugae in normal and corticosteroid-treated mouse embryos.Anat Rec. 1991; 230: 121-130Crossref PubMed Scopus (11) Google Scholar, 31Wise L.D. Vetter C.M. Anderson C.A. Antonello J.M. Clark R.L. Reversible effects of triamcinolone and lack of effects with aspirin or L-656,224 on external genitalia of male Sprague-Dawley rats exposed in utero.Teratology. 1991; 44: 507-520Crossref PubMed Scopus (18) Google Scholar and 10 human studies were included. The human studies included eight studies of pregnant women. Of the eight studies, five were cohort studies;11Bracken M.B. Triche E.W. Belanger K. Saftlas A. Beckett W.S. Leaderer B.P. Asthma symptoms, severity, and drug therapy: a prospective study of effects on 2205 pregnancies.Obstet Gynecol. 2003; 102: 739-752Crossref PubMed Scopus (199) Google Scholar, 13Schatz M. Zeiger R.S. Harden K. Hoffman C.C. Chilingar L. Petitti D. The safety of asthma and allergy medications during pregnancy.J Allergy Clin Immunol. 1997; 100: 301-306Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 32Alexander S. Dodds L. Armson B.A. Perinatal outcomes in women with asthma during pregnancy.Obstet Gynecol. 1998; 92: 435-440Crossref PubMed Scopus (138) Google Scholar, 33Dombrowski M.P. Brown C.L. Berry S.M. Preliminary experience with triamcinolone acetonide during pregnancy.J Matern Fetal Med. 1996; 5: 310-313Crossref PubMed Google Scholar, 34Stenius-Aarniala B.S. Hedman J. Teramo K.A. Acute asthma during pregnancy.Thorax. 1996; 51: 411-414Crossref PubMed Scopus (165) Google Scholar one was a controlled trial;35Murphy V.E. Zakar T. Smith R. Giles W.B. Gibson P.G. Clifton V.L. Reduced 11beta-hydroxysteroid dehydrogenase type 2 activity is associated with decreased birth weight centile in pregnancies complicated by asthma.J Clin Endocrinol Metab. 2002; 87: 1660-1668PubMed Google Scholar and two were randomized controlled trials.25Dombrowski M.P. Schatz M. Wise R. Thom E.A. Landon M. Mabie W. et al.Randomized trial of inhaled beclomethasone dipropionate versus theophylline for moderate asthma during pregnancy.Am J Obstet Gynecol. 2004; 190: 737-744Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 28Wendel P.J. Ramin S.M. Barnett-Hamm C. Rowe T.F. Cunningham F.G. Asthma treatment in pregnancy: a randomized controlled study.Am J Obstet Gynecol. 1996; 175: 150-154Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar These eight studies included a total of 21,072 pregnant women, of whom 16,900 had asthma and 6,113 had taken inhaled corticosteroids. Also included were two studies of newborns from the Swedish Birth Registry—one compared the rate of abnormalities among 2,014 newborns whose mothers had taken budesonide to the rate of abnormalities in the total newborn population, although the number in that population was not reported;36Källén B. Rydhstroem H. Åberg A. Congenital malformations after the use of inhaled budesonide in early pregnancy.Obstet Gynecol. 1999; 93: 392-395Crossref PubMed Scopus (215) Google Scholar the other study compared 2,900 newborns whose mothers had taken budesonide to the total newborn population of 293,948;37Norjavaara E. de Verdier M.G. Normal pregnancy outcomes in a population-based study including 2,968 pregnant women exposed to budesonide.J Allergy Clin Immunol. 2003; 111: 736-742Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar there may be some overlap in the populations of these two studies. There are three major conclusions from the evidence review: (1) the risk of asthma exacerbations associated with pregnancy can be reduced and lung function (FEV1) improved with the use of inhaled corticosteroid therapy;25Dombrowski M.P. Schatz M. Wise R. Thom E.A. Landon M. Mabie W. et al.Randomized trial of inhaled beclomethasone dipropionate versus theophylline for moderate asthma during pregnancy.Am J Obstet Gynecol. 2004; 190: 737-744Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 28Wendel P.J. Ramin S.M. Barnett-Hamm C. Rowe T.F. Cunningham F.G. Asthma treatment in pregnancy: a randomized controlled study.Am J Obstet Gynecol. 1996; 175: 150-154Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 34Stenius-Aarniala B.S. Hedman J. Teramo K.A. 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Single and repetitive maternal glucocorticoid exposures reduce fetal growth in sheep.Am J Obstet Gynecol. 1998; 178: 880-885Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 44Tangalakis K. Lumbers E.R. Moritz K.M. Towstoless M.K. Wintour E.M. Effect of cortisol on blood pressure and vascular reactivity in the ovine fetus.Exp Physiol. 1992; 77: 709-717Crossref PubMed Scopus (162) Google Scholar, 45Uno H. Eisele S. Sakai A. Shelton S. Baker E. DeJesus O. et al.Neurotoxicity of glucocorticoids in the primate brain.Horm Behav. 1994; 28: 336-348Crossref PubMed Scopus (434) Google Scholar, 46Watanabe C. Ishizuka Y. Nagao T. Palatal slit and cleft palate in rats treated with glucocorticoids—II. Comparative teratogenicity of prednisolone, triamcinolone acetonide and hydrocortisone.Congenital Anomalies. 1995; 35: 133-140Crossref Scopus (2) Google Scholar and eight human studies were included. The animal studies do not change the previous understanding (Asthma and Pregnancy Report 1993)5Asthma and pregnancy report. NAEPP report of the Working Group on Asthma and Pregnancy: management of asthma during pregnancy. NIH publication no. 93-3279. Bethesda (MD): US Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute, 1993. Available from URL: http://www.nhlbi.nih.gov/health/prof/lung/asthma/astpreg.txt. Accessed July 8, 2004.Google Scholar of the steroid-mediated clefting or decreases in fetal growth in animals. The eight human studies in the current evidence review included one report of two meta-analyses:47Park-Wyllie L. Mazzotta P. Pastuszak A. Moretti M.E. Beique L. Hunnisett L. et al.Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies.Teratology. 2000; 62: 385-392Crossref PubMed Scopus (672) Google Scholar one meta-analysis used six cohort studies that included 51,380 pregnant women, of whom 535 had taken oral corticosteroids; the other meta-analysis used four case-control studies,48Carmichael S.L. Shaw G.M. Maternal corticosteroid use and risk of selected congenital anomalies.Am J Med Genet. 1999; 86: 242-244Crossref PubMed Scopus (203) Google Scholar, 49Czeizel A.E. Rockenbauer M. Population-based case-control study of teratogenic potential of corticosteroids.Teratology. 1997; 56: 335-340Crossref PubMed Scopus (169) Google Scholar, 50Robert E. Vollset S.E. Botto L. Lancaster P.A.L. Merlob P. Mastroiacovo P. et al.Malformation surveillance and maternal drug exposure: the MADRE project. 1995.Int J Risk Safe Med. 1994; 6: 75-118PubMed Google Scholar, 51Rodríguez-Pinilla E. Martinez-Frias M.L. Corticosteroids during pregnancy and oral clefts: a case-control study.Teratology. 1998; 58: 2-5Crossref PubMed Scopus (219) Google Scholar each of which was also eligible to be included in the evidence review. These four case-control studies included 52,038 pregnant women, of whom 25 had taken oral corticosteroids. The remaining three human studies included one case-control study52Perlow J.H. Montgomery D. Morgan M.A. Towers C.V. Porto M. Severity of asthma and perinatal outcome.Am J Obstet Gynecol. 1992; 167: 963-967Abstract Full Text PDF PubMed Scopus (189) Google Scholar and two prospective cohort studies11Bracken M.B. Triche E.W. Belanger K. Saftlas A. Beckett W.S. Leaderer B.P. Asthma symptoms, severity, and drug therapy: a prospective study of effects on 2205 pregnancies.Obstet Gynecol. 2003; 102: 739-752Crossref PubMed Scopus (199) Google Scholar, 13Schatz M. Zeiger R.S. Harden K. Hoffman C.C. Chilingar L. Petitti D. The safety of asthma and allergy medications during pregnancy.J Allergy Clin Immunol. 1997; 100: 301-306Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar that included a total of 4,321 pregnant women, of whom 1,998 had asthma and 213 had taken oral corticosteroids. The findings from the current evidence review are conflicting. Oral corticosteroid use, especially during the first trimester of pregnancy, is associated with an increased risk for isolated cleft lip with or without cleft palate (the risk in the general population is 0.1 percent; the risk in women on oral corticosteroids is 0.3 percent).47Park-Wyllie L. Mazzotta P. Pastuszak A. Moretti M.E. Beique L. Hunnisett L. et al.Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies.Teratology. 2000; 62: 385-392Crossref PubMed Scopus (672) Google Scholar However, very few pregnant women who had oral steroid-dependent asthma were included in the studies, and the length, timing, and dose of exposure to the drug were not well described. Oral corticosteroid use during pregnancy in patients who have asthma is associated with an increased incidence of preeclampsia and the delivery of both preterm and low birth weight infants.13Schatz M. Zeiger R.S. Harden K. Hoffman C.C. Chilingar L. Petitti D. The safety of asthma and allergy medications during pregnancy.J Allergy Clin Immunol. 1997; 100: 301-306Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 47Park-Wyllie L. Mazzotta P. Pastuszak A. Moretti M.E. Beique L. Hunnisett L. et al.Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies.Teratology. 2000; 62: 385-392Crossref PubMed Scopus (672) Google Scholar, 52Perlow J.H. Montgomery D. Morgan M.A. Towers C.V. Porto M. Severity of asthma and perinatal outcome.Am J Obstet Gynecol. 1992; 167: 963-967Abstract Full Text PDF PubMed Scopus (189) Google Scholar However, the available data make it difficult to separate the effects of the oral corticosteroids on these outcomes from the effects of severe or uncontrolled asthma, which has been associated with maternal and/or fetal mortality. No experimental animal studies and two human studies were included in the current review. The two human studies consisted of prospective cohort studies11Bracken M.B. Triche E.W. Belanger K. Saftlas A. Beckett W.S. Leaderer B.P. Asthma symptoms, severity, and drug therapy: a prospective study of effects on 2205 pregnancies.Obstet Gynecol. 2003; 102: 739-752Crossref PubMed Scopus (199) Google Scholar, 13Schatz M. Zeiger R.S. Harden K. Hoffman C.C. Chilingar L. Petitti D. The safety of asthma and allergy medications during pregnancy.J Allergy Clin Immunol. 1997; 100: 301-306Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar that included 4,110 pregnant women, of whom 1,917 had asthma and 318 had taken cromolyn. The safety of using cromolyn during pregnancy is supported by the current review of evidence. Leukotriene modifiers include two compounds available as oral tablets (the receptor antagonists montelukast and zafirlukast) and 5-lipoxygenase pathway inhibitors (e.g., zileuton). No animal studies and one human study were available for review. The human study was an observational study of 2,205 pregnant women, 873 with asthma, of whom 9 took leukotriene modifiers, but the specific agent was not identified.11Bracken M.B. Triche E.W. Belanger K. Saftlas A. Beckett W.S. Leaderer B.P. Asthma symptoms, severity, and drug therapy: a prospective study of effects on 2205 pregnancies.Obstet Gynecol. 2003; 102: 739-752Crossref PubMed Scopus (199) Google Scholar The conclusion is that minimal data are currently available on the use of leukotriene modifiers during pregnancy. Reassuring animal studies have been submitted to the Food and Drug Administration (FDA) for leukotriene receptor antagonists but not for the leukotriene lipoxygenase inhibitor. The Working Group recommends the following principles and stepwise approach to pharmacologic therapy for managing asthma during pregnancy. (See Fig 1, Fig 2, Fig 3, Fig 4, Fig 5, Fig 6.) The principles and approach are based on the Working Group's interpretation of the current scientific review of the evidence on the safety of asthma medications during pregnancy and consideration of previous NAEPP reports: the Asthma and Pregnancy Report 1993, the EPR-2 1997, and the EPR—Update 2002.Fig 2Usual dosages for long-term-control medications during pregnancy and lactation.∗View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 3Estimated comparative daily dosages for inhaled corticosteroids.∗View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 4Management of asthma exacerbations during pregnancy and lactation: home treatment.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 5Management of asthma exacerbations during pregnancy and lactation: emergency department and hospital-based care.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 6Medications and dosages for asthma exacerbations during pregnancy and lactation.∗View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 6Medications and dosages for asthma exacerbations during pregnancy and lactation.∗View Large Image Figure ViewerDownload Hi-res image Download (PPT) •The treatment goal for the pregnant asthma patient is to provide optimal therapy to maintain control of asthma for maternal health and quality of life as well as for normal fetal maturation. Asthma control is defined as:—Minimal or no chronic symptoms day or night—Minimal or no exacerbations—No limitations on activities—Maintenance of (near) normal pulmonary function—Minimal use of short-acting inhaled beta2-agonist—Minimal or no adverse effects from medications•It is safer for pregnant women with asthma to be treated with asthma medications than for them to have asthma symptoms and exacerbations. Monitoring and making appropriate adjustments in therapy may be required to maintain lung function and, hence, blood oxygenation that ensures oxygen supply to the fetus. Inadequate control of asthma is a greater risk to the fetus than asthma medications are. Proper control of asthma should enable a woman with asthma to maintain a normal pregnancy with little or no risk to her or her fetus.•The obstetrical care provider should be involved in asthma care, including monitoring of asthma status during prenatal visits. A team approach is helpful if more than one clinician is managing a pregnant woman with asthma.•Asthma treatment is organized around four components of management:—Assessment and monitoring of asthma, including objective measures of pulmonary function. Because the course of asthma changes for about two-thirds of women during pregnancy,53Schatz M. Dombrowski M.P. Wise R. Thom E.A. Landon M. Mabie W. et al.Asthma morbidity during pregnancy can be predicted by severity classification.J Allergy Clin Immunol. 2003; 112: 283-288Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 54Beam W.R. Weiner D.E. Martin R.J. Timing of prednisone and alterations of airways inflammation in nocturnal asthma.Am Rev Respir Dis. 1992; 146: 1524-1530Crossref PubMed Scopus (101) Google Scholar monthly evaluations of asthma history and pulmonary function are recommended. Spirometry tests are recommended at the time of initial assessment. For routine monitoring at most subsequent followup outpatient visits, spirometry is preferable, but measurement of peak expiratory flow (PEF) with a peak flow meter is generally sufficient. Patients should be instructed to be attentive to fetal activity. Serial ultrasound examinations starting at 32 weeks gestation may be considered for patients who have suboptimally controlled asthma and for women with moderate to severe asthma. Ultrasound examinations are also helpful after recovery from a severe exacerbation.—Control of factors contributing to asthma severity. Identifying and controlling or avoiding such factors as allergens and irritants, particularly tobacco smoke, that contribute to asthma severity can lead to improved maternal well-being with less need for medications. (See Fig 7.)—Patient education. Asthma control is enhanced by ensuring access to education about asthma and about the skills necessary to manage it—such as self-monitoring, correct use of inhalers, and following a plan for managing asthma long term and for promptly handling signs of worsening asthma.—A stepwise approach to pharmacologic therapy. In this approach to achieving and maintaining asthma control, the dose and number of medications and the frequency of administration are increased as necessary, based on the severity of the patient's asthma, and are decreased when possible. Stepwise approach for managing asthma. To develop recommendations for the stepwise approach to the pharmacologic treatment of asthma in pregnant women, the Working Group first considered the stepwise approach in the EPR—Update 2002, which was based on systematic review of the evidence from medication effectiveness studies in nonpregnant adults and children. The Working Group also considered EPR-2 1997 and the Asthma and Pregnancy Report 1993. The effectiveness of medications is assumed to be the same in pregnant women as in nonpregnant women, although there are no studies that directly test this assumption. Based on their current systematic review of evidence from safety studies of asthma medications during pregnancy, the Working Group then tailored existing recommendations for stepwise therapy. Refer to Fig 1, Fig 2, Fig 3 for a complete list of recommended therapies and medication dosages in the stepwise approach to managing asthma. The following information highlights the rationale for the preferred medications.•Step 1: Mild Intermittent Asthma. Short-acting bronchodilators, particularly short-acting inhaled beta2-agonists, are recommended as quick-relief medication for treating symptoms as needed in patients with intermittent asthma. Albuterol is the preferred short-acting inhaled beta2-agonist because it has an excellent safety profile and the greatest amount of data related to safety during pregnancy of any currently available inhaled beta2-agonist. Women's experience with these drugs is extensive, and no evidence has been found either of fetal injury from the use of short-acting inhaled beta2-agonists or of contraindication during lactation.•Step 2: Mild Persistent Asthma. The preferred treatment for long-term-control medication in Step 2 is daily low-dose inhaled corticosteroid. This preference is based on the strong effectiveness data in nonpregnant women6EPR-2. NAEPP expert panel report 2: guidelines for the diagnosis and treatment of asthma. NIH publication no. 97-4051. Bethesda (MD): US Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute, 1997. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed July 8, 2004.Google Scholar, 7EPR—Update 2002. NAEPP expert panel report: guidelines for the diagnosis and treatment of asthma—update on selected topics 2002. NIH publication no. 02–5074. Bethesda (MD): US Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute, 2003. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthupdt.htm. Accessed July 8, 2004.Google Scholar as well as effectiveness and safety data in pregnant women that show no increased risk of adverse perinatal outcomes. Budesonide is the preferred inhaled corticosteroid because more data are available on using budesonide in pregnant women than are available on other inhaled corticosteroids, and the data are reassuring. It is important to note that there are no data indicating that the other inhaled corticosteroid preparations are unsafe during pregnancy. 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. Cromolyn, leukotriene receptor antagonists, and theophylline are listed as alternative but not preferred therapies. Cromolyn has an excellent safety profile, but it has limited effectiveness compared with inhaled corticosteroids. Leukotriene receptor antagonists have been demonstrated to provide statistically significant but modest improvements in children and nonpregnant adults with asthma, although in studies comparing overall efficacy of the two drugs, most outcomes clearly favor inhaled corticosteroids. Published data are minimal on using leukotriene receptor antagonists during pregnancy; however, animal safety data submitted to the FDA are reassuring. Thus, leukotriene receptor antagonists are an alternative but not preferred treatment for pregnant women whose asthma was successfully controlled with this medication prior to their pregnancy. Theophylline has demonstrated clinical effectiveness in some studies and has been used for years in pregnant women with asthma. It also, however, has the potential for serious toxicity resulting from excessive dosing and/or select drug–drug interactions (e.g., with erythromycin). Using theophylline during pregnancy requires careful titration of the dose and regular monitoring to maintain the recommended serum theophylline concentration range of 5-12 mcg/mL.•Step 3: Moderate Persistent Asthma. Two preferred treatment options are noted: either a combination of low-dose inhaled corticosteroid and a long-acting inhaled beta2-agonist, or increasing the dose of inhaled corticosteroid to the medium dose range. No data from studies during pregnancy clearly delineate that one option is recommended over the other. Limited data describe the effectiveness and/or safety of using combination therapy during pregnancy, but strong evidence from randomized controlled trials in nonpregnant adults shows that adding long-acting inhaled beta2-agonist to a low dose of inhaled corticosteroid provides greater asthma control than only increasing the dose of corticosteroid.7EPR—Update 2002. NAEPP expert panel report: guidelines for the diagnosis and treatment of asthma—update on selected topics 2002. NIH publication no. 02–5074. Bethesda (MD): US Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute, 2003. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthupdt.htm. Accessed July 8, 2004.Google Scholar The pharmacologic and toxicologic profiles of long-acting and short-acting inhaled beta2-agonists are similar; there is justification for expecting long-acting inhaled beta2-agonists to have a safety profile similar to that of albuterol, for which there are data related to safety during pregnancy. Two long-acting inhaled beta2-agonists are available—salmeterol and formoterol. Limited observational data exist on their use during pregnancy; salmeterol might be chosen because it has been available longer in the United States. Increasing the dose of inhaled corticosteroid to medium dose will benefit many patients, and, as noted previously, the data on using inhaled corticosteroids during pregnancy—including studies of large birth registries—are reassuring.•Step 4: Severe Persistent Asthma. If additional medication is required after carefully assessing patient technique and adherence with using Step 3 medication, then the inhaled corticosteroid dose should be increased within the high-dose range, and the use of budesonide is preferred. If this is insufficient to manage asthma symptoms, then the addition of systemic corticosteroid is warranted; although the data are uncertain about some risks of oral corticosteroids during pregnancy, severe uncontrolled asthma poses a definite risk to the mother and fetus. Management of acute exacerbations. Asthma exacerbations have the potential to lead to severe problems for the fetus. Therefore, asthma exacerbations during pregnancy should be managed aggressively. Refer to Fig 4 for home treatment of asthma exacerbation, Fig 5 for emergency department and hospital management, and Fig 6 for medications and dosages. Pharmacologic management of allergic rhinitis. Rhinitis, sinusitis, and gastroesophageal reflux are conditions that are often associated with asthma, are frequently more troublesome during pregnancy, and may exacerbate coexisting asthma. If these conditions are present, appropriate treatment is an integral part of asthma management. These topics were outside the scope of the current evidence-based review, but relevant studies on the safety of rhinitis medications during pregnancy were reviewed in order to present the following recommendations.•Intranasal corticosteroids are the most effective medications for the management of allergic rhinitis and have a low risk of systemic effect when used at recommended doses. Montelukast, a leukotriene receptor antagonist, can be used for the treatment of allergic rhinitis—but minimal data are available on the use of this medication during pregnancy.•The current second-generation antihistamines of choice are loratadine or cetirizine.•There may be a relationship between use of oral decongestants in early pregnancy and a rare birth defect, gastroschisis; however, the absolute risk of gastroschisis in exposed fetuses is still extremely small. If nasal decongestion is indicated in early pregnancy, an external nasal dilator, short-term topical oxymetazoline, or intranasal corticosteroid can be considered before use of oral decongestants. CorrectionJournal of Allergy and Clinical ImmunologyVol. 115Issue 3PreviewWith regard to the January 2005 Quick Reference article entitled “Managing asthma during pregnancy: Recommendations for pharmacologic treatment—2004 update” (2005;115:34-46): The full version of this NAEPP Expert Panel Report, including all of the evidence tables, is available at http://www.nhlbi.nih.gov/health/prof/lung/asthma/astpreg.htm . Full-Text PDF