The use of newer asthma and allergy medications during pregnancy

Position statement

The use of newer asthma and allergy medications during pregnancy The following statement was developed by a joint committee of the American College of Obstetricians and Gynecologists (ACOG) and the American College of Allergy, Asthma and Immunology (ACAAI). The statement was reviewed by the ACOG and approved by the ACAAI Board of Regents in April 2000. Committee members included Mitchell P. Dombrowski, MD, Dept. of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan; Robert Huff, MD, Dept of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, Texas; Myron Lipkowitz, MD, Private Practice, Howell, New Jersey; and Michael Schatz, MD, Dept. of Medicine, University of California, San Diego, California. INTRODUCTION Asthma is one of the most common potentially serious medical problems to complicate pregnancy.1 Although severe asthma may increase the risk of perinatal complications,2,3 adequately controlled asthma is associated with outcomes not significantly different from those of the non-asthmatic population.4 – 6 In 1993, the National Asthma Education Program Working Group on Asthma and Pregnancy1 published recommendations, based on the landmark Expert Panel Report,7 for the management of asthma and associated conditions during pregnancy. In 1997, the National Asthma Education and Prevention Program (NAEPP) published an update entitled Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma.8

VOLUME 84, MAY, 2000

The American College of Allergy, Asthma and Immunology (ACAAI) and the American College of Obstetricians and Gynecologists (ACOG) recently convened an Ad hoc Committee to incorporate the updated NAEPP general approach to managing asthma with specific information available since 1993 regarding asthma and allergy medications during pregnancy. This resulting position statement adapts the 1993 NAEPP Working Group on Asthma and Pregnancy’s recommendations for pharmacologic treatment to the 1997 NAEPP Expert Panel Report 2’s new classification of asthma severity (see Table 1). In addition, the ACAAI-ACOG position statement offers information and recommendations regarding the use of newer asthma and allergy medications during pregnancy. It should be noted that this position paper does not address two important non-pharmacologic aspects of therapy. As recommended in the Working Group report,1 patients should do everything they can during pregnancy to avoid asthma triggers, including cigarette smoke and allergens. In addition, allergen immunotherapy should be continued during pregnancy in patients with a positive response who are not experiencing systemic reactions, although benefit-risk considerations do not generally favor beginning immunotherapy during pregnancy.1 SHORT-ACTING BETA AGONISTS A recent report from the Kaiser-Permanente prospective study of asthma during pregnancy9 did not associate the use of beta agonists in a large number of pregnant patients with an increased risk of congenital malformations or

other adverse pregnancy outcomes. The specific beta agonists most frequently used in this study were metaproterenol (n ⫽ 309) and terbutaline (n ⫽ 316). In addition, the Michigan Medicaid study10 reported reassuring data regarding albuterol (n ⫽ 1090), as well as for a smaller number of patients receiving metaproterenol (n ⫽ 361) and terbutaline (n ⫽ 149). Another recent report showed no adverse effect of maternal inhalation of albuterol on fetal circulation.11 SALMETEROL Animal studies with systemically administered salmeterol have not been reassuring,12 although the inhaled route of administration in humans and the experience with chemically similar albuterol (animals studies suggesting adverse effects but human data reassuring) suggests that these animal studies may not be predictive of human risk. Nonetheless, no human data regarding the use of salmeterol during pregnancy has been published. Salmeterol would not generally be recommended for use during pregnancy in preference to older beta2 agonists, cromolyn or beclomethasone, but benefit-risk considerations may favor its continuation during pregnancy in patients with moderate or severe asthma who have demonstrated a very good therapeutic response prior to becoming pregnant. In addition, recent data show that, in patients not adequately controlled on inhaled corticosteroids, salmeterol is more effective than doubling the dose of inhaled corticosteroids13 and may be more effective and better tolerated than theophylline.14 This suggests that salmeterol could be considered instead of or in addition to theophylline in pregnant

475

Table 1. Working Group Recommendations for the Pharmacological Step Therapy of Chronic Asthma During Pregnancy* Category Mild intermittent

Mild persistent

Moderate persistent

Severe persistent

Frequency/Severity of Symptoms (Sx)

Pulmonary Function† (untreated)

Sx ⱕ 2 times per week Nocturnal Sx ⱕ 2/month Exacerbations brief (a few hours to a few days) Asymptomatic between episodes Sx ⬎ 2 times per week but not daily Nocturnal Sx ⬎ 2/month Exacerbations may affect activity

ⱖ80% Normal pulmonary function between episodes ⱖ80%

Daily Sx Nocturnal Sx ⬎ 1/week Exacerbations affect activity Continual Sx Limited activity Frequent nocturnal symptoms Frequent acute exacerbations

60–80%

⬍60%

Step Therapy Inhaled beta2-agonists as needed (for all categories)

Inhaled cromolyn Substitute inhaled beclomethasone if not adequate Inhaled beclomethasone Add oral theophylline Above ⫹ oral corticosteroids (burst for active symptoms, alternate day or daily if necessary)

* Based on the recommendations of the National Asthma Education Program Report of the Working Group on Asthma During Pregnancy1 updated to use the terminology of the Expert Panel Report 2.8 † FEV1 or PEFR based on the norm for the patient, which may be standardized norms or personal best.

patients inadequately controlled by medium-dose inhaled corticosteroids. NEBULIZED IPRATROPIUM Although ipratropium by metered dose inhaler was available earlier, nebulized ipratropium became available in 1993. Several studies suggest that nebulized ipratropium provides additional bronchodilation to high dose inhaled beta agonist therapy in patients presenting with acute asthma.15–17 Although there is no published human gestational data, the inhaled route and reassuring animal studies12 suggest that nebulized ipratropium could be considered in women presenting with acute asthma who do not improve substantially with the first inhaled beta agonist treatment. NEDOCROMIL Animal studies with nedocromil have not revealed teratogenicity,12 but no human data has been published. Efficacy data comparing cromolyn to nedocromil in general have been conflicting, but most of the available data suggests that nedocromil is less effective than inhaled corticosteroids.18 Nedocromil probably would not be recommended over cromolyn or beclomethasone for use during pregnancy in general, although the reassuring animal studies and inhalational

476

route of delivery suggest that benefitrisk considerations might favor its continuation during pregnancy in patients responding well to it prior to gestation. INHALED CORTICOSTEROIDS Six studies regarding the gestational use of inhaled corticosteroids have been published since 1993. Four of these specifically assessed safety issues;9,10,19,20 of the 573 subjects described in three of these reassuring reports,9,10,19 546 used beclomethasone. In the other study from the Swedish Medical Birth Registry, 2014 infants whose mothers had used inhaled budesonide for asthma in early pregnancy were evaluated.20 No increase in the general rate of congenital malformations or in the rate of orofacial clefts was observed in the infants of budesonide-treated mothers. Two of the studies provide information regarding the efficacy of inhaled steroids during pregnancy. SteniusAarniala et al21 evaluated 504 pregnant asthmatic patients, 47 (9.3%) of whom experienced acute exacerbations. Of the 257 patients treated with inhaled beclomethasone or budesonide from the start of pregnancy, only 4% experienced acute exacerbations compared with 17% of the 177 patients not initially treated with inhaled steroids

(P ⬍ .0001). Wendel et al22 evaluated 84 non-steroid-dependent subjects who presented with 105 asthma exacerbations, 65 of which required hospitalization. Hospitalized patients were randomized upon discharge to one of the following two regimens: (1) albuterol and an oral steroid taper (31 patients) or (2) albuterol, an oral steroid taper, and inhaled beclomethasone (34 patients). Of the patients who received beclomethasone, 12% were readmitted compared with 33% of those who did not receive beclomethasone (P ⬍ .05). These unique efficacy data suggest that inhaled corticosteroids should generally be considered the prophylactic medications of choice for use in pregnant women with persistent asthma, unless they are well-controlled by cromolyn or nedocromil. Since 1993, two higher potency steroids, budesonide and fluticasone, have become available in the United States. Some data have suggested that these medications have less systemic effects than equivalent doses of beclomethasone;23–29 however, definitive comparisons of the systemic effects of equally efficacious doses of inhaled steroids are lacking. Considering the totality of published data available, beclomethasone or budesonide could be considered the inhaled steroids of

ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

choice for use during pregnancy. Thus, if an inhaled corticosteroid is to be newly initiated in a woman who is pregnant or is likely to become pregnant, beclomethasone or budesonide should generally be chosen. However, since conventional doses of all of the available inhaled steroids seem to be associated with minimal systemic effects,30 it would not be unreasonable to continue a different inhaled steroid in a patient well-controlled by that drug prior to pregnancy. Budesonide would be a particularly good choice during pregnancy for women requiring high doses of inhaled steroids; in such patients, it may maximize adherence, minimize the need for systemic steroids, and possibly minimize systemic effects. ORAL CORTICOSTEROIDS Since 1993, two reassuring studies have been reported regarding the teratogenicity of oral corticosteroids. Fraser and Sajoo31 performed a systematic review of the literature and reported a 3.5% incidence of congenital malformations in 457 infants of mothers receiving systemic corticosteroids. In a large case-control study of 20,830 infants with congenital malformations, the proportion of mothers receiving oral corticosteroids (n ⫽ 323) was not significantly different than in mothers of normal controls.32 However, a recent case-control study33 found a significant association between the first trimester use of systemic corticosteroids and an increase in oral clefts (OR ⫽ 6.55, 95% CI ⫽ 1.44 –29.76). The authors of this report conclude that the use of systemic corticosteroids during the first trimester should be restricted to “life-threatening situations” or “diseases without any other safe therapeutic alternatives”; severe asthma would certainly meet these criteria. Maternal use of oral corticosteroids for gestational asthma has also recently been independently associated with an increased risk of preeclampsia (odds ratio ⫽ 2.0, P ⫽ .027), after controlling for potential demographic, medication, and asthma severity confound-

VOLUME 84, MAY, 2000

ers.9 Oral corticosteroids were not independently associated with an increased risk of congenital malformations, preterm birth, or low birthweight infants in this study. Although the mechanism of the association is uncertain, the authors concluded that the benefits of oral corticosteroids when indicated for the management of severe asthma during pregnancy still outweigh the risks. LEUKOTRIENE MODIFIERS The leukotriene modifier drugs montelukast, zafirlukast, and zileuton have recently been released in the United States. Although all three drugs have been shown to be more effective than placebo in the management of mildmoderate asthma, only preliminary comparative data with other prophylactic medications have been published.34 Animal reproduction studies

have demonstrated adverse effects with zileuton,12 and there are no available human data. Zileuton therefore cannot be recommended for use during pregnancy at this time. Although there is no gestational human data for the receptor antagonists zafirlukast or montelukast either, animal studies have been reassuring.12 While one would not generally recommend using these medications during pregnancy, their use could be considered in patients with recalcitrant asthma who have shown a uniquely favorable response prior to becoming pregnant. SECOND-GENERATION ANTIHISTAMINES Chlorpheniramine and tripelennamine were recommended by the Working Group as the antihistamines of choice for use during pregnancy based on duration of availability as well as reassuring animal12 and human10,35,36 data.

Table 2. Summary of ACAAI-ACOG Recommendations for the Use of Newer Asthma and Allergy Medications During Pregnancy Medication

Year Introduced

Salmeterol

1994

Nebulized ipratropium Nedocromil Budesonide

1993

Fluticasone Zileuton Zafirlukast

1996 1996 1996

Montelukast

1998

Cetirizine

1995

Loratadine

1993

Azelastine Fexofenadine Intranasal steroids (see text)

1996 1996 —

1993 1997

Consider Use in Pregnant Women With moderate-severe asthma who have shown a very good response prior to pregnancy Who are inadequately controlled by medium-dose inhaled corticosteroids Presenting with acute asthma who do not improve substantially with the first inhaled b agonist treatment Who have shown a good response prior to pregnancy Who have shown a good response prior to pregnancy; Who are starting inhaled corticosteroids during pregnancy; Who require high doses of inhaled corticosteroids for adequate control Who have shown a good response prior to pregnancy No indication at this time With recalcitrant asthma who have shown a uniquely favorable response prior to pregnancy With recalcitrant asthma who have shown a uniquely favorable response prior to pregnancy Who do not tolerate chlortrimeton or tripelennamine and who need an antihistamine in spite of optimal topical therapy (ideally after 1st trimester) Who do not tolerate chlortrimeton or tripelennamine and who need an antihistamine in spite of optimal topical therapy (ideally after 1st trimester) Based on animal studies, better choices available Based on animal studies, better choices available Who have shown a good response prior to pregnancy and who continue to require such therapy

477

Table 3. ACAAI-ACOG Recommendations for the Pharmacologic Step Therapy of Chronic Asthma During Pregnancy* Category Mild Intermittent Mild Persistent

Moderate Persistent

Severe Persistent

Step Therapy Inhaled beta2-agonists as needed (for all categories)† Inhaled cromolyn Continue inhaled nedocromil in patients who have shown a good response prior to pregnancy Substitute inhaled corticosteroids‡ if above not adequate Inhaled corticosteroids‡ Continue inhaled salmeterol in patients who have shown a very good response prior to pregnancy Add oral theophylline and/or inhaled salmeterol for patients inadequately controlled by medium-dose inhaled corticosteroids Above ⫹ oral corticosteroids (burst for active symptoms, alternate-day or daily if necessary)

* Based on the recommendations of the National Asthma Education Program Report of the Working Group on Asthma During Pregnancy,1 updated to incorporate newer information, including the Expert Panel Report 2.8 † Most published human data using albuterol, metaproterenol, or terbutaline. ‡ Beclomethasone or budesonide if inhaled corticosteroids are being initiated during pregnancy; continuation of other inhaled corticosteroid if patient well-controlled by it prior to pregnancy; consider budesonide if patient requires high dose inhaled corticosteroids for adequate control.

Regarding second generation antihistamines, human data do not suggest an association between congenital malformations and first trimester exposure to terfenadine10,37 which is no longer being manufactured in the United States. However, maternal exposure to terfenadine was associated with lower infant birth weight in the most recent study.37 The existing human data are reassuring for astemizole (n ⫽ 114)38 which is also no longer available in the United States, and for cetirizine (n ⫽ 33).39 Because of the small sample sizes, however, these studies do not exclude as much as a sevenfold increased risk of congenital malformations with 95% certainty.40 Animal studies have been reassuring for cetirizine and loratadine, but not reassuring for astemizole, azelastine, fexofenadine, or terfenadine.12 Second generation antihistamines generally produce less anticholinergic, sedative, or performance-impairment effects than their predecessors.41 In patients who do not tolerate chlorpheniramine or tripelennamine and in whom maximal topical therapy is being utilized, second generation antihistamines with reassuring animal studies (cetirizine

478

and loratadine) could be considered, but ideally after the first trimester.40 ORAL DECONGESTANTS Pseudoephedrine was recommended by the Working Group as the oral decongestant of choice for use during pregnancy.1 Animal studies12 and a large prospective human experience with pseudoephedrine have been reassuring (n ⫽ 2509),7,10,35,36 but recent case control studies have found a significant association between the use of pseudoephedrine42 or phenylpropanolamine43 and the occurrence of a rare birth defect, gastroschisis. It is important to point out that, even if the relative increased risk is 10-fold, since gastroschisis occurs at a rate of 1 or 2 per 10,000 live births in the general population,42,43 the absolute risk of gastroschisis in infants of mothers ingesting oral decongestants during the first trimester would not be higher than 20 per 10,000 live births. Pending additional data, it would probably be prudent to avoid oral decongestants during the first trimester unless the expected benefit is large and unique.

INTRANASAL CORTICOSTEROIDS Since 1993, budesonide (1994), fluticasone (1994), and mometasone (1997) have become available for intranasal use, joining beclomethasone, flunisolide, and triamcinolone. All of the intranasal corticosteroids cause adverse effects when injected into animals,12 and no study has specifically evaluated the human safety of intranasal corticosteroids during pregnancy. Based on the human data for inhaled beclomethasone and budesonide described above, beclomethasone or budesonide would be recommended if an intranasal corticosteroid is to be initiated during pregnancy. However, none of the intranasal corticosteroids appears to have substantial systemic effects at recommended doses in adults, and no substantial differences in efficacy or safety have been demonstrated among the available intranasal corticosteroids.44 – 48 It would therefore not seem unreasonable to continue an intranasal corticosteroid different than beclomethasone or budesonide in a patient who is well-controlled on that drug prior to pregnancy and continues to require such therapy. CONCLUSION Based on a review of recent safety and efficacy information, this ACAAIACOG position paper provides recommendations regarding the use of newer asthma and allergy medications during pregnancy (Table 2). It is hoped that these ACAAI-ACOG recommendations, used in conjunction with the NAEPP Working Group on Asthma and Pregnancy report and the NAEPP Expert Panel Report 2, will promote optimal management of pregnant patients with asthma and allergy (Table 3). As newer information and medications become available, these recommendations will need to be further updated. It is also important for both medical and medical-legal reasons that these general recommendations are individualized for each patient, and that informed consent is obtained and documented.49

ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

REFERENCES 1. National Asthma Education Program Report of the Working Group on Asthma and Pregnancy: Management of asthma during pregnancy. NIH Publication number 93-3279A, Sept. 1993. 2. Gordon M, Niswander KR, Berendes H, Kantor AG. Fetal morbidity following potentially anoxigenic obstetric conditions. VII Bronchial asthma. Am J Obstet Gynec 1970;106: 421– 429 3. Perlow JH, Montgomery D, Morgan MA, et al. Severity of asthma and perinatal outcome. Am J Ob Gyne 1992; 167:963–967. 4. Schatz M, Zeiger RS, Hoffman CP, et al. Perinatal outcomes in the pregnancies of asthmatic women: a prospective controlled analysis. Am J Respir Crit Care Med 1995;151:1170 5. Stenius-Aarniala B, Riikonen S, Teramo K. Slow-release theophylline in pregnant asthmatics. Chest 1995;107: 642– 647. 6. Jana N, Vasishta K, Saha SC, Khunnu B. Effect of bronchial asthma on the course of pregnancy, labour and perinatal outcome. J Obstet Gynaecol 1995;21:227–232. 7. National Asthma Education Program Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma. NIH Publication No. 913042, August, 1991. 8. National Asthma Education and Prevention Program Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. NHLBI, NIH Publication No. 97-4051, April, 1997. 9. Schatz M, Zeiger RS, Harden K, et al. The safety of asthma and allergy medications during pregnancy. J Allergy Clin Immunol 1997;100:301–306. 10. Briggs GG, Freeman RA, Yaffe SJ. Drugs in pregnancy and lactation, 5th edition. Baltimore: Williams and Wilkins, 1998. 11. Rayburn WF, Atkinson BD, Gilbert K, Turnbull GL. Short-term effects of inhaled albuterol on maternal and fetal circulations. Am J Obstet Gynecol 1994;171:770 –773. 12. Physicians desk reference. Montvale New Jersey: Medical Economics Company, 1998 13. Woolcock A, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled ste-

VOLUME 84, MAY, 2000

14.

15.

16.

17.

18. 19.

20.

21. 22.

23.

24.

25.

26.

roids. Am J Respir Crit Care Med 1996;153:1481–1488. Pollard SJ, Spector SL, Yancey SW, et al. Salmeterol versus theophylline in the treatment of asthma. Ann Allergy Asthma Immunol 1997;78:457– 464. Schuh S, Johnson DW, Callahan S, et al. Efficacy of frequent nebulized ipratropium bromide added to frequent high-dose albuterol therapy in severe childhood asthma. J Pediatr 1995;126: 639 – 645. Garrett JE, Town GI, Rodwell P, Kelly AM. Nebulized salbutamol with and without ipratropium bromide in the treatment of acute asthma. J Allergy Clin Immunol 1997;100:165–170. Lin RY, Pesola GR, Bakalchuk L, et al. Superiority of ipratropium plus albuteral over albuterol alone in the emergency department management of adult asthma: a randomized clinical trial. Ann Emerg Med 1998;31:208 –213. Brogden RN, Sorkin EM. Nedocromil sodium. Drugs 1993;45:693–715. Dombrowski MP, Brown CL, Berry SM. Preliminary experience with triamcinolone acetonide during pregnancy. J Mat Fet Med 1996;5: 310 –313. Kallen B, Rydhstroem H, Aberg A. Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol 1999;93: 392–395. Stenius-Aarniala BSM, Hedman J, Teramo KA. Acute asthma during pregnancy. Thorax 1996;51:411– 414. Wendel PJ, Ramin SM, Barnett-Hamm C, et al. Asthma treatment in pregnancy: a randomized controlled study. Am J Obstet Gynecol 1996;175: 150 –154. Pederson S, Fuglsang G. Urine cortisol excretion in children treated with high doses of inhaled corticosteroids: a comparison of budesonide and beclomethasone. Eur Respir J 1988;1: 433– 435. Bisgaard H, Damkjaer Nielson M, Anderson B, et al. Adrenal function in children with bronchial asthma treated with beclomethasone diproprionate or budesonide. J Allergy Clin Immunol 1988;81:1088 –1095. Wolthers OD, Pedersen S. Short-term growth during treatment with inhaled fluticasone proprionate and beclomethasone diproprionate. Arch Dis Child 1993;68:673– 676. Leblanc P, Mink S, Keistinen T, et al.

27.

28.

29.

30. 31. 32.

33.

34.

35. 36. 37.

38.

39.

40.

A comparison of fluticasone proprionate 200 ␮g/day with beclomethasone diproprionate 400 ␮g/day in adult asthma. Allergy 1994;49:380 –385. Birkebaek NH, Esberg G, Anderson K, et al. Bone and collagen turnover during treatment with inhaled dry powder budesonide and beclomethasone diproprionate. Arch Dis Child 1995;73: 524 –527. Bootsma GP, Dekhuijzen PNR, Festen J, et al. Fluticasone proprionate does not influence bone metabolism in contrast to beclomethasone diproprionate. Am J Respir Crit Care Med 1996;153: 924 –930. Pauwels RA, Yernault JC, Demedts MG, Geusens P. Safety and efficacy of fluticasone and beclomethasone in moderate to severe asthma. Am J Respir Crit Care Med 1998;157:827– 832. Barnes PJ. Inhaled glucocorticoids for asthma. New Engl J Med 1995;332: 868 – 875. Fraser FC, Sajoo A. Teratogenic potential of corticosteroids in humans. Teratology 1995;51:45– 46. Czeizel AE, Rockenbauer M. Population-based case control study of teratogenic potential of corticosteroids. Teratology 1997;56:335–340. Rodriguez-Pinilla E, Martinez-Frias ML. Corticosteroids during pregnancy and oral clefts: a case control study. Teratology 1998;58:2–5. Horwitz RJ, McGill KA, Busse WW. The role of leukotriene modifiers in the treatment of asthma. Am J Respir Crit Care Med 1998;157:1363–1371. Heinonen OP, Slone D, Shapiro S. Birth defects and drugs in pregnancy. Littleton, Mass: PSG Publishing, 1977. Aselton P, Jick H, Milunsky A, et al. First trimester drug use and congenital disorders. Obstet Gynecol 1985;65:45. Loebstein R, Lalkin A, Addis A, et al. Pregnancy outcome after gestational exposure to terfenadine: a multicenter, prospective controlled study. J Allergy Clin Immunol 1999;104:953–956. Pastuszak A, Schick B, D’Alimonte D, et al. The safety of astemizole during pregnancy. J Allergy Clin Immunol 1996;98:748 –750. Einasson A, Bailey B, Jung G, et al. A prospective controlled study of hydroxyzine and cetirizine during pregnancy. Ann Allergy 1997;78:183–186. Schatz M, Petitti D. Antihistamines and pregnancy. Ann Allergy 1997;78: 157–159.

479

41. Simons FER. The therapeutic index of newer H1-receptor antagonists. Clin Exp Allergy 1994;24:707–723. 42. Werler MM, Mitchell AA, Shapiro S. First trimester maternal medication use in relation to gastroschisis. Teratology 1992;45:361–367. 43. Torfs CP, Katz EA, Bateson TF, et al. Maternal medications and environmental exposures as risk factors for gastroschisis. Teratology 1996;54: 84 –92. 44. Ratner PH, Paull BR, Findlay SR, et al. Fluticasone proprionate given once daily is as effective for seasonal allergic rhinitis as beclomethasone diproprionate given twice daily. J Allergy Clin Immunol 1992;90:285–291. 45. Andersson M, Berglund R, Greiff L, et al. A comparison of budesonide nasal

480

dry powder with fluticasone proprionate aqueous nasal spray in patients with perennial allergic rhinitis. Rhinology 1995;33:18 –21. 46. Graft D, Aaronson D, Chervinsky P, et al. A placebo- and active-controlled randomized trial of prophylactic treatment of seasonal allergic rhinitis with mometasone furoate aqueous nasal spray. J Allergy Clin Immunol 1996; 98:724 –731. 47. Mandl M, Nolop K, Lutsky BN. Comparison of once daily mometasone furoate (Nasonex) and fluticasone propionate aqueous nasal sprays for the treatment of perennial rhinitis. 194079 study group. Ann Allergy Asthma Immunol 1997;79:370 –378. 48. Small P, Houle PA, Day JH, et al. A comparison of triamcinolone acetonide

nasal aerosol spray and fluticasone proprionate aqueous solution spray in the treatment of spring allergic rhinitis. J Allergy Clin Immunol 1997;100: 592–595. 49. Fern FH, Orlando CP. Medical-legal aspects of prescribing during pregnancy. In: Schatz M, Zeiger RS, Claman HN, eds. Asthma and immunologic diseases in pregnancy and early infancy. New York: Marcel Dekker, Inc. 1998:229. Request for reprints should be addressed to: Mary Lou Callaghan ACAAI 85 W Algonquin Suite 550 Arlington Heights, IL 60005

ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY