Asthma in Pregnancy - NEJM 2009.pdf - AInotes

The new england journal of medicineclinical practiceAsthma in PregnancyMichael Schatz, M.D., and Mitchell P. Dombrowski, M.D.This Journal feature begins with a case vignette highlighting a common clinical problem.Evidence supporting various strategies is then presented, followed by a review of formal guidelines,when they exist. The article ends with the authors’ clinical recommendations.A 23-year-old nonsmoking woman (gravida 1, para 0) presents at 11 weeks’ gestationwith an 8-year history of asthma, which has worsened over the past year. She reportsasthma symptoms requiring albuterol two or three times per day and interfering withsleep two or three nights per week. A corticosteroid inhaler was prescribed beforepregnancy, but she has been afraid to use it. Cleaning her house triggers asthma, andshe has had a cat at home for 1 year. Her forced expiratory volume in 1 second (FEV 1 )is 75% of the predicted value; it increases to 88% of the predicted value after administrationof albuterol. How should her case be managed?The Clinical ProblemFrom the Department of Allergy, KaiserPermanente Medical Center, San Diego,CA (M.S.); and the Department of Obstetricsand Gynecology, St. John Hospital,and Wayne State University MedicalCenter (M.P.D.) — both in Detroit. Addressreprint requests to Dr. Schatz atthe Department of Allergy, Kaiser PermanenteMedical Center, 7060 ClairemontMesa Blvd., San Diego, CA 92111, or atmichael.x.schatz@kp.org.N Engl J Med 2009;360:1862-9.Copyright © 2009 Massachusetts Medical Society.An audio versionof this articleis available atNEJM.orgAsthma is probably the most common potentially serious medical problem that occursduring pregnancy, and approximately 8% of pregnant women reported currentasthma in recent national surveys. 1 In several studies, even after adjustment for potentialconfounders, women with asthma have been reported to have higher risks ofseveral complications of pregnancy, including preeclampsia, 2-7 preterm birth, 2-4,6 infantswith low birth weight or intrauterine growth restriction, 2-4,6,7 infants with congenitalmalformations, 3,8,9 and perinatal death 2,4,10 than women without a history ofasthma. Residual confounding 11 or common pathogenetic factors 12-14 may explainsome of these associations. Nevertheless, observational data showing strong associationsbetween poor asthma control during pregnancy (as evidenced by symptoms,impaired pulmonary function, or exacerbations) and these increased risks 15-19suggest that better asthma control may improve pregnancy outcomes. Treatmentalso may reduce serious risks to the mother resulting from uncontrolled asthma, includingdeath. However, the choice among medications must take into account theirpotential adverse effects on the fetus.In addition to the effect of maternal asthma on pregnancy outcomes, pregnancymay affect the course of asthma. The severity of asthma may improve, worsen, orremain unchanged during pregnancy 20,21 ; the mechanisms underlying changes inthe severity of asthma during pregnancy remain undefined.Strategies and EvidenceDiagnosis and EvaluationThe diagnosis of asthma is usually straightforward, since most patients have a knownhistory of asthma antedating pregnancy. However, diagnostic testing is warrantedin patients whose clinical picture or response to therapy is atypical or who presentwith respiratory symptoms during pregnancy in the absence of a history of asthma.The most common alternative diagnosis is dyspnea of pregnancy, which is not associatedwith cough, wheezing, chest tightness, or airway obstruction. Other po-1862n engl j med 360;18 nejm.org april 30, 2009The New England Journal of MedicineDownloaded from nejm.org at LSU HEALTH SCIENCES CENTER LIBRARY on January 18, 2011. For personal use only. No other uses without permission.Copyright © 2009 Massachusetts Medical Society. All rights reserved.

clinical practicetential diagnoses include cough due to reflux orpostnasal drip, bronchitis, laryngeal dysfunction,hyperventilation, pulmonary edema, and pulmonaryembolism. 22,23 The demonstration of a reducedFEV 1 or ratio of FEV 1 to forced vital capacitywith a 12% or greater improvement in FEV 1after the administration of inhaled albuterol confirmsa diagnosis of asthma in pregnancy. 23,24Methacholine testing, which is used to confirmbronchial hyperreactivity in patients with normalpulmonary function, is contraindicated duringpregnancy because of the lack of data on the safetyof such testing in pregnant patients. Thus, womenwith a clinical picture that is consistent withnew-onset asthma in whom the diagnosis is notconfirmed on the basis of testing for reversibilityof impairment in pulmonary function should betreated for asthma until methacholine testing canbe performed post partum if indicated. 23 Exhalednitric oxide has not been studied as a diagnosticmeasure of asthma in pregnant women.Patients with persistent asthma who have notpreviously been tested for allergies should undergoblood testing for specific IgE antibodies to allergenssuch as dust mites, cockroaches, mold spores,and pets. Skin tests are not generally recommendedduring pregnancy because skin testing withpotent antigens may be associated with systemicreactions.Current asthma control should be assessed accordingto the frequency and severity of symptoms(including their interference with sleep and normalactivity), the frequency of use of rescue therapy, thehistory of exacerbations requiring the use of systemiccorticosteroids, and the results of pulmonary-functiontests (Table 1). Spirometry is thepreferred method of assessing pulmonary function,but peak flow measurement is an acceptablealternative. FEV 1 and peak flow rates do notchange substantially as a result of pregnancy, 23 sothese measures can be used for assessing asthmacontrol in patients who are pregnant just as theyare in patients who are not pregnant. Patients whohave asthma that is well controlled and who arenot receiving controller medications can be classifiedas having intermittent rather than persistentasthma.Women who have previously received prescriptionsfor asthma medications should be askedabout their use in order to classify their currentlevel of therapy (according to a stepped-care approach,with step 1 indicating no treatment andstep 6 indicating the most aggressive treatment)(Table 2) and to assess potential problems withand barriers to adherence. Adherence to treatmentwith inhaled corticosteroids has been reported tobe poor in many studies. For example, the reportedadherence rate was approximately 50% in onestudy involving adults with asthma; decreased adherencewas associated with an increased frequencyof asthma exacerbations. 26 Women with asthmahave been reported to decrease their use of inhaledcorticosteroids during early pregnancy, ascompared with their use of these agents in the20 weeks before their last menstrual period 27 ; thismay be due to their reported concern regarding thesafety of inhaled corticosteroids during pregnancy.28 Moreover, a substantial proportion of asthmaticexacerbations during pregnancy have beenassociated with nonadherence to treatment withinhaled corticosteroids. 29 In addition to assessingadherence, asking about past medications andtheir effectiveness and any side effects can help toguide subsequent management decisions.Management of AsthmaAll patients should be educated regarding the relationshipbetween asthma and pregnancy, andthey should be taught about self-treatment, includinginhaler techniques, adherence to medication,and control of potential environmental triggers(Table 3). The appropriate management of commoncoexisting conditions that can aggravate asthma,such as rhinitis, sinusitis, and gastroesophagealreflux, can improve asthma control. Women whosmoke must be informed of the potential adverseeffects of smoking on the fetus, which may addto the fetal effects of uncontrolled asthma, 15 andshould be strongly encouraged to quit. Advice onenvironmental control measures for reducing exposureto allergens can be provided on the basisof the results of allergy testing (Table 4).Medications for asthma are divided into longtermcontroller medications that prevent the manifestationsof asthma (inhaled corticosteroids,long-acting β-agonists, leukotriene modifiers, cromolyn,and theophylline) (Table 5) and rescuetherapy that provides quick relief of symptoms(primarily short-acting inhaled β-agonists). Instudies involving patients who were not pregnant,inhaled corticosteroids were the most effectivecontroller medications in terms of reducing symptomsand exacerbations and improving pulmonaryfunction, and all controller medications have beenn engl j med 360;18 nejm.org april 30, 2009 1863The New England Journal of MedicineDownloaded from nejm.org at LSU HEALTH SCIENCES CENTER LIBRARY on January 18, 2011. For personal use only. No other uses without permission.Copyright © 2009 Massachusetts Medical Society. All rights reserved.

The new england journal of medicineTable 1. Assessment of Asthma Control in Pregnant Women.*VariableWell-ControlledAsthmaAsthma NotWell ControlledVery PoorlyControlled AsthmaFrequency of symptoms ≤2 days/wk >2 days/wk Throughout the dayFrequency of nighttime awakening ≤2 times/mo 1–3 times/wk ≥4 times/wkInterference with normal activity None Some ExtremeUse of short-acting β-agonist for symptomcontrolFEV 1 or peak flow (% of the predicted orpersonal best value)Exacerbations requiring use of systemiccorticosteroid (no.)≤2 days/wk >2 days/wk Several times/day>80 60–80

clinical practiceof long-acting β-agonists during pregnancy, althoughthe inhalational route and the generallyreassuring data on short-acting β-agonists suggestthat these agents are probably safe. 25 A possibleassociation between long-acting β-agonistsand an increased risk of severe and even fatalasthma exacerbations has been observed in patientswho were not pregnant. Although the dataare sparse, expert panels suggest that the benefitsof the use of long-acting β-agonists appearto outweigh the risks as long as they are usedconcurrently with inhaled corticosteroids. 44,45Overall, the risks associated with asthma medicationsin current use are considered to be definitelylower than the risks associated with uncontrolledasthma.It is appropriate for pregnant patients with wellcontrolledasthma to continue taking their medications.In patients who are not pregnant and whohave asthma that has been controlled for at least3 months with the use of controller medications,guidelines recommend consideration of a stepdown in therapy 24 ; however, it may be prudent tomaintain the current level of therapy during pregnancyin order to reduce the risk of a loss of control.For patients at step 5 or 6 (Table 2), a carefulreduction in therapy may be considered if theprevious course of asthma and the course duringpregnancy suggest that a reduction is likely to betolerated without a loss of control.Therapy should be increased by one step (Table2) in patients with asthma that is not well controlleddespite consideration of the nonpharmacologicstrategies described above. A two-step increase,a course of oral corticosteroids, or bothshould be recommended for women with asthmathat is very poorly controlled.Monthly visits to assess asthma control arerecommended for women who require controllertherapy during pregnancy. This assessmentmay be performed as part of routine obstetricalvisits or by the primary care physician or asthmaspecialist who is managing the patient’s asthma.Patients with very poorly controlled asthmashould be seen every 1 to 2 weeks until controlis achieved.Table 2. Steps of Asthma Therapy during Pregnancy.*StepPreferredController MedicationAsthma ExacerbationsAn asthma exacerbation in a pregnant patient, asin any adult, should be managed with inhaledβ-agonists, inhaled anticholinergic drugs, andsystemic corticosteroids. 23,24 Maintenance of anarterial oxygen saturation of at least 95%, measuredby means of pulse oximetry, is recommendedto ensure sufficient oxygenation in both themother and the fetus. 22 Assessment of the fetusduring an acute asthma episode depends on thestage of the pregnancy, but continuous electronicfetal monitoring, a biophysical profile, or bothshould be considered if the fetus has reached thestage of viability. 23 A biophysical profile includesa nonstress test for a reactive fetal heart rate, ul-AlternativeController Medication1 None —2 Low-dose inhaled corticosteroid LTRA, theophylline, or cromolyn3 Medium-dose inhaled corticosteroid4 Medium-dose inhaled corticosteroidplus LABA5 High-dose inhaled cortico steroidplus LABA6 High-dose inhaled corticosteroidplus LABA plus oral prednisoneLow-dose inhaled corticosteroidplus LABA, LTRA, or theophyllineMedium-dose inhaled corticosteroidplus either LTRA or theophylline* Data are from the National Asthma Education and Prevention Program. 24,25We have modified step 3 to reflect the choice of a medium-dose inhaled corticosteroidover a low-dose inhaled corticosteroid plus a long-acting β-agonist(LABA) because of the lack of safety data on the use of LABA during pregnancy.LTRA denotes leukotriene-receptor antagonist.Table 3. Patient Education for Self-Treatment of Asthma during Pregnancy.SubjectGeneral informationUse of inhaler deviceAdherence to treatmentSelf-treatment actionplanRecommendationProvide basic information about asthma and relationshipbetween asthma and pregnancyDemonstrate proper technique for specific deviceand ask patient to perform the technique; demonstrateuse of spacer device for metered-doseinhaler if patient’s inhaler technique is suboptimalDiscuss self-reported adherence to treatment withcontroller medication and, if needed, addressbarriers to optimal adherence (e.g., cost, convenience,concern about side effects)Provide schedule for maintenance medication anddoses of rescue therapy for increased symptoms;explain when and how to increase controllermedication and when and how to useprednisone (for patients with previous prednisoneuse or poorly controlled asthma); explainhow to recognize a severe exacerbationand when and how to seek urgent or emergencycare——n engl j med 360;18 nejm.org april 30, 2009 1865The New England Journal of MedicineDownloaded from nejm.org at LSU HEALTH SCIENCES CENTER LIBRARY on January 18, 2011. For personal use only. No other uses without permission.Copyright © 2009 Massachusetts Medical Society. All rights reserved.

The new england journal of medicineTable 4. Environmental Control Measures to Reduce Exposure to Allergens.*Allergen Instructions Level of EvidenceAnimal danderDust mitesCockroachesRemove pet from house;if removal not acceptable,keep pet out ofbedroomEncase pillow and mattresswith impermeable covers;wash sheets andblankets weekly in hotwaterDo not leave food or garbageexposed; use poisonbaits or traps ratherthan chemical agents,which can aggravateasthmaConsensus judgmentData from several randomized,controlled trialsFew randomized, controlledtrials* Data are from the National Asthma Education and Prevention Program. 24These data are not specific to pregnancy.trasonographic measurement of amniotic-fluidvolume, observation of the presence or absenceof fetal breathing movements, and observation ofgross body movements and fetal tone. If oxygensaturation remains below a level of at least 95%(as measured by means of pulse oximetry) whilethe patient is breathing ambient air, if FEV 1 or peakexpiratory flow remains below 70% of the predictedvalue, or if there is evidence of fetal compromise,the patient should be hospitalized, withcareful medical and obstetrical surveillance. 22,23This pulmonary-function criterion, which is basedon general recommendations for asthmatic exacerbations,is supported by some observationaldata, 24 although we are aware of no specific datain pregnant women with asthma.Obstetrical CareIn general, data are lacking on the optimal obstetricalcare of patients with asthma, and recommendationsare based on extrapolation of datafrom other clinical settings and expert opinion.Women with asthma that is not well controlled maybenefit from increased fetal surveillance. Ultrasonographicexaminations can be helpful to establishaccurate pregnancy dating and monitorfetal growth, which (as described above) can beaffected by uncontrolled asthma. Assessment offetal well-being, usually by means of nonstress testing,should be considered, starting at 32 weeks’gestation. 23Adequate hydration and analgesia should bemaintained during labor and delivery; analgesiashould not compromise the patient’s respiratorystatus, and insufficient pain control could triggerbronchospasm. Use of asthma medications shouldbe continued during labor and delivery. It is commonlyrecommended that women who are currentlytaking systemic corticosteroids or who havereceived several short courses of systemic corticosteroidsduring pregnancy receive intravenouscorticosteroids (e.g., hydrocortisone at a dose of100 mg every 8 hours) during labor and for 24hours after delivery in order to prevent adrenalcrisis. 22 Prostaglandin E 1 or E 2 can be used forcervical ripening, management of spontaneous orinduced abortions, or postpartum hemorrhage,although the patient’s respiratory status shouldbe monitored for bronchospasm. 46 In contrast,carboprost (15-methyl prostaglandin F 2 α) and ergonovinemay trigger bronchospasm and shouldbe avoided, if possible. 22 If tocolysis is required,magnesium sulfate and terbutaline are preferablebecause they are bronchodilators; in contrast, indomethacincan induce bronchospasm in a patientwith aspirin-sensitive asthma. 22Cesarean delivery is rarely required in patientswith an acute asthmatic exacerbation; maternaland fetal compromise usually responds to aggressivemedical management. Lumbar anesthesia canreduce oxygen consumption and minute ventilationduring labor. 47 The obstetrician, anesthesiologist,and pediatrician should coordinate intrapartumand postpartum care. In general, onlysmall amounts of the asthma medications listedin Table 5 enter breast milk; none are a contraindicationto breast-feeding. 23,25Areas of UncertaintyThe mechanisms linking poorly controlled asthmato adverse perinatal outcomes remain unclear. Itis not possible in observational studies to definitelydistinguish the potential contributions ofincreased asthma severity and poor asthma controlfrom the potential effects of medications usedin more severe cases. Because of the ethical issuesraised, controlled trials cannot be performed todetermine the effects of asthma control, as comparedwith lack of control, on perinatal outcomes.Controlled trials are unlikely to be large enoughto determine the absolute safety of various asthmamedications during pregnancy, especially with regardto uncommon outcomes such as specific congenitalmalformations.1866n engl j med 360;18 nejm.org april 30, 2009The New England Journal of MedicineDownloaded from nejm.org at LSU HEALTH SCIENCES CENTER LIBRARY on January 18, 2011. For personal use only. No other uses without permission.Copyright © 2009 Massachusetts Medical Society. All rights reserved.

clinical practiceTable 5. Controller Medications for the Management of Asthma during Pregnancy.*Drug Usual Dose Potential Adverse EffectsInhaled corticosteroidsBudesonideBeclomethasoneFluticasoneLow: 180–600 µg/day; medium:>600–1200 µg/day;high: >1200 µg/dayLow: 80–240 µg/day; medium:>240–480 µg/day; high:>480 µg/dayLow: 100–300 µg/day; medium:>300–500 µg/day;high: >500 µg/dayCough, dysphonia, thrush; potentialsystemic effects athigh doses; local side effectsdecreased with valvedholding chamber (spacer)for metered-dose inhalersthat are not breath-actuatedand with mouth washingand spitting after inhalationFDAPregnancyClass†Long-acting β-agonistsTachycardia, skeletal-muscleSalmeterol 1 blister twice dailytremor, hypokalemia; possibleincrease in risk ofsevere, life-threatening,or fatal exacerbationCFormoterol 1 capsule twice daily CLeukotriene- receptor antagonistsMontelukast 10 mg daily No major adverse effects identifiedZafirlukast 20 mg twice daily Cases of hepatitis reported B∥Recommended Use‡Preferred controller therapyB§ Preferred inhaled corticosteroidbecause of more reassuringdata in humansCCPreferred add-on therapy tomedium- or high-doseinhaled corticosteroidsAlternative for mild asthmaor as add-on therapy toinhaled corticosteroids,especially in patientswith good responsebefore pregnancyCromolyn 2 puffs four times daily Cough B∥ Alternative for mild asthmaTheophylline400–600 mg/day (based ontheophylline level)Insomnia, gastric upset, aggravationof gastroesophagealrefluxB∥C Alternative for mild asthmaor as add-on therapy toinhaled corticosteroids* Data are from the National Asthma Education and Prevention Program. 24,25 FDA denotes Food and Drug Administration.† A pregnancy rating of B indicates that reassuring data from studies in animals or humans have been submitted to the FDA, and a ratingof C that a risk to the fetus cannot be ruled out on the basis of submitted data.‡ Data are based on relative efficacy in all patients with asthma and safety data in pregnant women.§ Data are based on nonreassuring studies of systemic administration in animals, but reassuring data in humans have been submitted tothe FDA. Data are based on nonreassuring studies of systemic administration in animals, and no data in humans have been submitted to the FDA.∥ Data are based on reassuring studies in animals, but no data in humans have been submitted to the FDA.GuidelinesNational guidelines for the management of asthmaduring pregnancy were most recently updatedin 2004, 25 and general guidelines for the managementof asthma in all patients were updatedin 2007. 24 The American College of Obstetriciansand Gynecologists published guidelines on theclinical management of asthma during pregnancyin 2008. 23 The recommendations in this articleare consistent with these guidelines.Conclusionsand RecommendationsAlthough uncontrolled asthma may increase therisk of adverse perinatal outcomes, women withwell-controlled asthma in pregnancy generally havegood pregnancy outcomes. 48-50 The patient describedin the vignette has poorly controlled asthma,as evidenced by daily symptoms and daily useof rescue therapy, asthma that interferes with sleepmore than once a week, and an FEV 1 of less thann engl j med 360;18 nejm.org april 30, 2009 1867The New England Journal of MedicineDownloaded from nejm.org at LSU HEALTH SCIENCES CENTER LIBRARY on January 18, 2011. For personal use only. No other uses without permission.Copyright © 2009 Massachusetts Medical Society. All rights reserved.

The new england journal of medicine80% of the predicted value. This patient shouldbe educated regarding the potential risks of uncontrolledasthma for herself and her pregnancy.We would recommend testing for sensitivity tomites, cat dander, and cockroach allergens andinitiate medium-dose inhaled corticosteroids(a two-step therapy increase). We would chooseinhaled budesonide (180 µg per puff, two puffstwice a day) over other inhaled corticosteroids becausemore safety data are available on the use ofthis drug during the gestational period. The patientshould also be instructed in the use of anoptimal inhaler technique, and she should be givena personalized self-treatment action plan forasthma that includes instructions regarding themaintenance medication schedule, doses of rescuetherapy for increased symptoms, and whenand how to seek urgent or emergency care. Wewould recommend follow-up every 1 to 2 weeksinitially to ensure that asthma control is achievedand then, once the patient’s condition is stable,at least monthly throughout the pregnancy.Dr. Schatz reports receiving consulting fees from Glaxo-SmithKline and grant support from Aerocrine, Genentech,GlaxoSmithKline, and Merck. No other potential conflict of interestrelevant to this article was reported.References1. Kwon HL, Triche EW, Belanger K,Bracken MB. The epidemiology of asthmaduring pregnancy: prevalence, diagnosis,and symptoms. Immunol Allergy ClinNorth Am 2006;26:29-62.2. Bahna SL, Bjerkedal T. The course andoutcome of pregnancy in women withbronchial asthma. Acta Allergol 1972;27:397-406.3. Demissie K, Breckenridge MB, RhoadsGG. Infant and maternal outcomes in thepregnancies of asthmatic women. Am JRespir Crit Care Med 1998;158:1091-5.4. Källén B, Rydhstroem H, Aberg A.Asthma during pregnancy — a populationbased study. Eur J Epidemiol 2000;16:167-71.5. Wen SW, Demissie K, Liu S. Adverseoutcomes in pregnancies of asthmaticwomen: results from a Canadian population.Ann Epidemiol 2001;11:7-12.6. Liu S, Wen SW, Demissie K, MarcouxS, Kramer MS. Maternal asthma andpregnancy outcomes: a retrospective cohortstudy. Am J Obstet Gynecol 2001;184:90-6.7. Enriquez R, Griffin MR, Carroll KN,et al. Effect of maternal asthma and asthmacontrol on pregnancy and perinataloutcomes. J Allergy Clin Immunol 2007;120:625-30.8. Tamási L, Somoskövi A, Müller V, etal. A population-based case-control studyon the effect of bronchial asthma duringpregnancy for congenital abnormalitiesin the offspring. J Asthma 2006;43:81-6.9. Källén B, Otterblad Olausson P. Useof anti-asthmatic drugs during pregnancy.3. Congenital malformations in the infants.Eur J Clin Pharmacol 2007;63:383-8.10. Breton MC, Beauchesne M-F, LemièreC, Rey E, Forget A, Blais L. Risk of perinatalmortality associated with asthma duringpregnancy. Thorax 2009;64:101-6.11. Hendler I, Schatz M, Momirova V, etal. Association of obesity with pulmonaryand nonpulmonary complications of pregnancyin asthmatic women. Obstet Gynecol2006;108:77-82.12. Bertrand J-M, Riley SP, Popkin J,Coates AL. The long-term pulmonary sequelaeof prematurity: the role of familialairway hyperreactivity and the respiratorydistress syndrome. N Engl J Med 1985;312:742-5.13. Riedel F, Achenbach U, Rieger CHL.Prematurity and maternal bronchial hyperresponsiveness.J Perinat Med 1989;17:151-5.14. Siddiqui S, Goodman N, McKenna S,Goldie M, Waugh J, Brightling CE. Preeclampsiais associated with airway hyperresponsiveness.BJOG 2008;115:520-2.15. Schatz M, Zeiger RS, Hoffman CP. Intrauterinegrowth is related to gestationalpulmonary function in pregnant asthmaticwomen. Chest 1990;98:389-92.16. Bracken MB, Triche EW, Belanger K,Saflas A, Beckett WS, Leaderer BP. Asthmasymptoms, severity, and drug therapy:a prospective study of effects on 2205pregnancies. Obstet Gynecol 2003;102:739-52.17. Bakhireva LN, Schatz M, Jones KL,Chambers CD. Asthma control duringpregnancy and the risk of preterm deliveryor impaired fetal growth. Ann AllergyAsthma Immunol 2008;101:137-43.18. Schatz M, Dombrowski MP, Wise R,et al. Spirometry is related to perinatal outcomesin pregnant women with asthma.Am J Obstet Gynecol 2006;194:120-6.19. Murphy VE, Clifton VL, Gibson PG.Asthma exacerbations during pregnancy:incidence and association with adversepregnancy outcomes. Thorax 2006;61:169-76.20. Gluck JC, Gluck PA. The effect of pregnancyon the course of asthma. ImmunolAllergy Clin North Am 2006;26:63-80.21. Schatz M, Dombrowski MP, Wise R, etal. Asthma morbidity during pregnancycan be predicted by severity classification.J Allergy Clin Immunol 2003;112:283-8.22. National Asthma Education Programreport of the Working Group on Asthmaand Pregnancy: management of asthmaduring pregnancy. Bethesda, MD: NationalHeart, Lung, and Blood Institute, September1993. (NIH publication no. 93-3279.)23. ACOG practice bulletin: clinical managementguidelines for obstetrician-gynecologistsnumber 90, February 2008: asthmain pregnancy. Obstet Gynecol 2008;111:457-64.24. National Asthma Education and PreventionProgram. Expert panel report 3:guidelines for the diagnosis and managementof asthma: full report 2007. (AccessedApril 6, 2009, at http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.)25. NAEPP expert panel report: managingasthma during pregnancy: recommendationsfor pharmacologic treatment — 2004update. J Allergy Clin Immunol 2005;115:34-46. [Erratum, J Allergy Clin Immunol2005;115:477.]26. Williams LK, Pladevall M, Xi H, et al.Relationship between adherence to inhaledcorticosteroids and poor outcomesamong adults with asthma. J Allergy ClinImmunol 2004;114:1288-93.27. Enriquez R, Wu P, Griffin MR, et al.Cessation of asthma medication in earlypregnancy. Am J Obstet Gynecol 2006;195:149-53.28. Chambers K. Asthma education andoutcomes for women of childbearing age.Case Manager 2003;14:58-61.29. Murphy VE, Gibson P, Talbot PI, CliftonVL. Severe asthma exacerbations duringpregnancy. Obstet Gynecol 2005;106:1046-54.30. Dombrowski MP, Schatz M, Wise R, etal. Randomized trial of inhaled beclomethasonedipropionate versus theophyllinefor moderate asthma during pregnancy.Am J Obstet Gynecol 2004;190:737-44.31. Wendel PJ, Ramin SM, Barnett-HammX, Rowe TF, Cunningham FG. Asthma1868n engl j med 360;18 nejm.org april 30, 2009The New England Journal of MedicineDownloaded from nejm.org at LSU HEALTH SCIENCES CENTER LIBRARY on January 18, 2011. For personal use only. No other uses without permission.Copyright © 2009 Massachusetts Medical Society. All rights reserved.

clinical practicetreatment in pregnancy: a randomizedcontrolled trial. Am J Obstet Gynecol1996;175:150-4.32. Schatz M, Zeiger RS, Harden K, HoffmanCC, Chilingar L, Petitti D. The safetyof asthma and allergy medications duringpregnancy. J Allergy Clin Immunol 1997;100:301-6.33. Schatz M, Dombrowski MP, Wise R,et al. The relationship of asthma medicationuse to perinatal outcomes. J AllergyClin Immunol 2004;113:1040-5.34. Martel M-J, Rey E, Beauchesne M-F, etal. Use of inhaled corticosteroids duringpregnancy and risk of pregnancy-inducedhypertension: nested case-control study.BMJ 2005;330:230-6.35. Bakhireva LN, Jones KL, Schatz M, etal. Asthma medication use in pregnancyand fetal growth. J Allergy Clin Immunol2005;116:503-9.36. Martel M-J, Rey E, Beauchesne M-F, etal. Use of short-acting β 2-agonists duringpregnancy and the risk of pregnancyinducedhypertension. J Allergy Clin Immunol2007;119:576-82.37. Källén B, Rydhstroem H, Aberg A.Congenital malformations after the useof inhaled budesonide in early pregnancy.Obstet Gynecol 1999;93:392-5.38. Norjavaara E, de Verdier MG. Normalpregnancy outcomes in a populationbasedstudy including 2,968 pregnantwomen exposed to budesonide. J AllergyClin Immunol 2003;111:736-42.39. Lin S, Munsie JPW, Herdt-Losavio ML,et al. Maternal asthma medication useand the risk of gastroschisis. Am J Epidemiol2008;168:73-9.40. Blais L, Forget A. Asthma exacerbationsduring the first trimester of pregnancyand the risk of congenital malformationsamong asthmatic women. J AllergyClin Immunol 2008;121:1379-84.41. Stothard KJ, Tennant PWG, Bell R,Rankin J. Maternal overweight and obesityand the risk of congenital anomalies:a systematic review and meta-analysis.JAMA 2009;301:636-50.42. Yang J, Carmichael SL, Canfield M,Song J, Shaw GM. Socioeconomic statusin relation to selected birth defects in alarge multicentered US case-control study.Am J Epidemiol 2008;167:145-54.43. Bakhireva LN, Jones KL, Schatz M, etal. Safety of leukotriene receptor antagonistsin pregnancy. J Allergy Clin Immunol2007;119:618-25.44. Jaeschke R, O’Byrne PM, Mejza F, etal. The safety of long-acting β-agonistsamong patients with asthma using inhaledcorticosteroids: systematic reviewand metaanalysis. Am J Respir Crit CareMed 2008;178:1009-16.45. Nelson HS, Carr W, Nathan R, PortnoyJM. Update on the safety of long-actingβ-agonists in combination with inhaledcorticosteroids for the treatment ofasthma. Ann Allergy Asthma Immunol2009;102:11-5.46. Towers CV, Briggs GG, Rojas JA. Theuse of prostaglandin E2 in pregnant patientswith asthma. Am J Obstet Gynecol2004;190:1777-80.47. Hägerdal M, Morgan CW, Sumner AE,Gutsche BB. Minute ventilation and oxygenconsumption during labor with epiduralanalgesia. Anesthesiology 1983;59:425-7.48. Schatz M, Zeiger RS, Hoffman CP, etal. Perinatal outcomes in the pregnanciesof asthmatic women: a prospective controlledanalysis. Am J Respir Crit Care Med1995;151:1170-4.49. Stenius-Aarniala BSM, Hedman J,Teramo KA. Acute asthma during pregnancy.Thorax 1996;51:411-4.50. Dombrowski MP, Schatz M, Wise R,et al. Asthma during pregnancy. ObstetGynecol 2004;103:5-12.Copyright © 2009 Massachusetts Medical Society.COLLECTIONS OF ARTICLES ON THE JOURNAL’S WEB SITEThe Journal’s Web site (NEJM.org) sorts published articles intomore than 50 distinct clinical collections, which can be used as conveniententry points to clinical content. In each collection, articles are cited in reversechronologic order, with the most recent first.n engl j med 360;18 nejm.org april 30, 2009 1869The New England Journal of MedicineDownloaded from nejm.org at LSU HEALTH SCIENCES CENTER LIBRARY on January 18, 2011. For personal use only. No other uses without permission.Copyright © 2009 Massachusetts Medical Society. All rights reserved.