Asthma during pregnancy

OBJECTIVE: To determine neonatal and maternal outcomes stratified by asthma severity during pregnancy by using the 1993 National Asthma Education Program Working Group on Asthma and Pregnancy definitions of asthma severity. The primary hypothesis was that moderate or severe asthmatics would have an increased incidence of delivery at <32 weeks of gestation compared with nonasthmatic controls. METHODS: This was a multicenter, prospective, observational cohort study conducted over 4 years at 16 university hospital centers. Asthma severity was defined according to the National Asthma Education Program Working Group on Asthma and Pregnancy classification and modified to include medication requirements. This study had 80% power to detect a 2- to 3-fold increase in delivery less than 32 weeks of gestation among the cohort with the moderate or severe asthma compared with controls. Secondary outcome measures included obstetrical and neonatal outcomes. RESULTS: The final analysis included 881 nonasthmatic controls, 873 with mild asthma, 814 with moderate, and 52 with severe asthma. There were no significant differences in the rates of preterm delivery less than 32 weeks (moderate or severe 3.0%, mild 3.4%, controls 3.3%; P =.873) or less than 37 weeks of gestation. There were no significant differences for neonatal outcomes except discharge diagnosis of neonatal sepsis among the mild group compared with controls, adjusted odds ratio 2.9, 95% confidence interval 1.2, 6.8. There were no significant differences for maternal complications except for an increase in overall cesarean delivery rate among the moderate-or-severe group compared with controls (adjusted odds ratio 1.4, 95% confidence interval 1.1, 1.8). CONCLUSION: Asthma was not associated with a significant increase in preterm delivery or other adverse perinatal outcomes other than a discharge diagnosis of neonatal sepsis. Cesarean delivery rate was increased among the cohort with moderate or severe asthma. LEVEL OF EVIDENCE: II-2

ORIGINAL RESEARCH Asthma During Pregnancy Mitchell P. Dombrowski, md, Michael Schatz, md, Robert Wise, md, Valerija Momirova, ms, Mark Landon, md, William Mabie, md, Roger B. Newman, md, Donald McNellis, md, John C. Hauth, md, Marshall Lindheimer, md, Steve N. Caritis, md, Kenneth J. Leveno, md, Paul Meis, md, Menachem Miodovnik, md, Ronald J. Wapner, md, Richard H. Paul, md, Michael W. Varner, md, Maryjo O'Sullivan, md, Gary R. Thurnau, md, and Deborah L. Conway, md, for the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network and The National Heart, Lung, and Blood Institute OBJECTIVE: To determine neonatal and maternal outcomes stratified by asthma severity during pregnancy by using the 1993 National Asthma Education Program Working Group on Asthma and Pregnancy definitions of asthma severity. The primary hypothesis was that moderate or severe asthmatics would have an increased incidence of delivery at <32 weeks of gestation compared with nonas­thmatic controls. METHODS: This was a multicenter, prospective, observa­tional cohort study conducted over 4 years at 16 university hospital centers. Asthma severity was defined according to the National Asthma Education Program Working Group on Asthma and Pregnancy classification and modified to From the Departments of Obstetrics and Gynecology at. Wayne State University, Detroit, Michigan; Allergy at Kaiser Permanente, San Diego, California; Pulmo­nary Medicine at Johns Hopkins University, Baltimore, Maryland; the Biostatis­tics Center at George Washingfon University, Washington, DC; the National Institute of Child Health, and Human Development, Bethesda, Maryland; and the Departments of Obstetrics and Gynecology at Ohio State University, Columbus, Ohio; University of Tennessee, Memphis, Tennessee; Medical College of South Carolina, Charleston, South Carolina; the University of Alabama, Birmingham, Alabama; the University of Chicago, Chicago, Illinois; the University ofPttsburgh- Magee Women's Hospital, Pittsburgh, Pennsylvania; UT Southwestern Medical Center, Dallas Texas; Wake Forest University, Winston-Salem, North. Carolina; the University of Cincinnati, Cincinnati, Ohio; Thomas Jefferson University, Philadelphia, Pennsylvania; the University of Southern California, Los Angeles, California; University of Utah, Salt Lake City, Utah; University of Miami, Miami, Florida; University of Oklahoma, Oklahoma City, Oklahoma; and. the University of Texas, San Antonio, Texas. Supported by the National Institute of Child Health and Human Develojjment (HD21410, HD21414, HD21434, HD27S69, HD2791 7, HD27905, HD27SS9, HD27S60, HD27861, HD27915, HD27SS3, HD34122, HD34116, HD3420S, HD34136, HD36801) and the National Heart, Lung, and Blood Imtitute. Presented at the Society of Maternal Fetal Medicine 2000 Annual Meeting, January 31-February 5, 2000, Miami, Florida. The authors thank the participating institutions and staff members listed in the Appendix. include medication requirements. This study had 80% power to detect a 2- to 3-fold increase in delivery lessthan32 weeks of gestation among the cohort with the moderate or severe asthma compared with controls. Secondary outcome mea­sures included obstetrical and neonatal outcomes. RESULTS: The final analysis included 881 nonasthmatic controls, 873 with mild asthma, 814 with moderate, and 52 with severe asthma. There were no significant differences in the rates of preterm delivery less than 32 weeks (moder­ate or severe 3.0%, mild 3.4%, controls 3.3%; P = .873) or less than 37 weeks of gestation. There were no significant differences for neonatal outcomes except discharge diagno­sis of neonatal sepsis among the mild group compared with controls, adjusted odds ratio 2.9, 95% confidence interval 1.2, 6.8. There were no significant differences for maternal complications except for an increase in overall cesarean delivery rate among the moderate-or-severe group com­pared with controls (adjusted odds ratio 1.4, 95% confi­dence interval 1.1, 1.8). CONCLUSION: Asthma was not associated with a significant increase in preterm delivery or other adverse perinatal outcomes other than a discharge diagnosis of neonatal sepsis. Cesarean delivery rate was increased among the cohort with moderate or severe asthma. (Obstet Gynecol 2004;103:5-12. © 2004 by The American College of Ob­stetricians and Gynecologists.) LEVEL OF EVIDENCE: 11-2 Asthma is probably the most common potentially seri­ous medical complication of pregnancy. A recent study suggests that nearly 6% of pregnant women have asthma, and the most recent asthma surveillance data suggest that approximately 9% of the U.S. population report a physician diagnosis of asthma during their life­time. 1-3 In general, the prevalence and morbidity from asthma are increasing.1,3 There have been few large prospective studies of asthma during pregnancy. Moreover, previous studies VOL. 103, NO. 1, JANUARY 2004 © 2004 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. 0029-7844/04/$30.00 doi:10.1097/01.AOG. 0000103994.75162.16 Copy r ight© Ame r ican C o l l e g e o f Ob s t e t r i c ia n s an d G y n e c o l o g i s t s have a number of methodological inadequacies, includ­ing low power; poor control for confounders; little infor­mation regarding asthma severity, management, or con­trol; and time frames not reflective of current management. Existing studies on the effects of asthma on pregnancy outcomes have had inconsistent results in regard to perinatal mortality, prematurity, low birth weight, neonatal hypoxia, cesarean delivery, hemor­rhage, and preeclampsia.3-18 Asthma has been associ­ated with preterm delivery in some,4 ~9 but not all stud­ies. 3'10 ~16 Prematurity is a leading cause of perinatal mortality and long-term neurological morbidity in chil­dren, with very early preterm births (less than 32 weeks of gestation) accounting for most of the morbidity and mortality.19 Perlow et al8 in 1992 reported a case-control study of 130 controls and 81 women with asthma, 31 of whom required long-term oral corticosteroids and 50 who had nonsteroid medication-dependent asthma. They found a 7.7-fold increase of preterm delivery less than 37 weeks and a 4-fold increase of deliveries less than 32 weeks of gestation among those with asthma com­pared with controls. In 1993, under the auspices of the National Asthma Education Program of the National, Heart, Lung, and Blood Institute, a working group on asthma and preg­nancy defined mild, moderate, and severe asthma ac­cording to symptoms and pulmonary function criteria in untreated patients.20 The relationship between National Asthma Education Program severity classification and pregnancy outcomes has not been reported 3-18 The 1993 National Asthma Education Program guide­lines did not discuss classification of asthma severity for women who were already receiving medications for their asthma.20 We previously reported asthma morbidity among the women in this study21 and modified National Asthma Education Program asthma severity criteria to include medication use. Women with moderate asthma solely on the basis of requiring daily asthma medications had significantly more asthma exacerbations than those with mild asthma, but they did not have significantly more exacerbations than those with moderate asthma based on symptoms and measurements of forced expira­tory volume of air expired in 1 second (FEV1). Women with severe asthma solely on the basis of requiring daily oral corticosteroids had significantly more exacerbations than those with moderate asthma, but they did not have significantly more exacerbations than those with severe asthma based on FEV1.21 The purpose of this study was to determine pregnancy outcomes stratified by asthma severity in a contempo­rary cohort of asthmatic women. The primary objective was to determine the frequency of preterm delivery at less than 32 weeks of gestation and other perinatal outcomes among those with asthma compared with non­asthmatic controls. METHODS This was a prospective observational cohort study that was sponsored by the National Institute of Child Health and Human Development and the National, Heart, Lung, and Blood Institute. The study was conducted at 16 centers of the Maternal-Fetal Medicine Units Net­work of the National Institute of Child Health and Human Development. The target enrollment was 900 women with mild asthma, 900 with moderate or severe (moderate-severe) asthma, and 900 control participants. Smoking status is an important determinant of both asthma morbidity and perinatal outcome. To avoid a disproportion of frequency of the smokers in the three cohorts, the control and mild-asthma cohorts were pro­spectively balanced in terms of the proportions of smok­ing status (any in the past week) with the moderate- severe cohort. Controls were also prospectively balanced for proportion of African-American ethnicity with the moderate-severe cohort. Smoking status and asthma severity were determined upon enrollment. Re­cruitment began in December 1994 and ended in March 1999. Case finding was by questioning all obstetric pa­tients about ever having physician-diagnosed asthma. Informed, written consent was obtained from all partic­ipants, and each institution's local Institutional Review Board approved the study. Exclusion criteria at enroll­ment included the following: known multiple gestation, intrauterine fetal demise, major congenital abnormali­ties, active pulmonary disease other than asthma, inabil­ity to schedule an ultrasound for gestational age confir­mation, gestational age 26 weeks or more at intake, or participation in the asthma randomized clinical trial or other interventional studies. In addition to these exclu­sion criteria, any woman who had ever had a physician diagnosis of asthma was excluded from the control group. We collected demographic, social, and medical infor­mation, including ethnicity, age, smoking status (any in the previous week), prepregnancy weight, miscarriage/ abortion, history of preterm delivery, insurance type, education, marital status, and chronic hypertension de­fined as either systolic more than 140 mm Hg or diastolic blood pressure more than 90 mm Hg on at least two occasions 4 or more hours apart when not pregnant or at less than 20 weeks of gestation or if the patient was on an antihypertensive medication when not pregnant or at less than 20 weeks of gestation. Spirometry (more than 4 hours postbronchodilator) was performed on partici­pants with asthma at enrollment. Measurements of 6 Dombrowski et al Asthma During Pregnancy OBSTETRICS & GYNECOLOGY Copy r ight© Ame r ican C o l l e g e o f Ob s t e t r i c ia n s an d G y n e c o l o g i s t s Classification of asthma Criteria Mild AH of the following: Asthma symptoms in the prior 6 months Asthma symptoms fewer than 8 days in prior 4 weeks (except with URI) FEV1 > 80% predicted Not taking daily asthma medications* Moderate Any of the following: Asthma symptoms on 8 or more days during the prior 4 weeks not attributable to a URI FEV; 60-79% predicted Use of one or more daily asthma medications* Severe Any of the following: FEV! < 60% predicted Use of daily or every other day oral corticosteroids for 4 weeks prior to enrollment FEV1 = forced expiratory volume of air expired in f second, mea sured at the time of enrollment > 4 hours post bronchodilator. * Daily medications included 2 puffs per day of inhaled |8 agonist, cromolyn, nedocromil, inhaled steroids, or 4 puffs per day of ipratropium or f dose per day of theophylline. Patients on regular oral corticosteroids were classified as severe irrespective of other criteria. FEV 1 were made while the patient was standing after a maximal inspiration. To standardize spirometry tech­niques, all centers used Collins Stead-Well (Braintree, MA) dry-seal volume displacement spirometers, and all research nurses underwent a training and quality review program. On each monthly study visit, an FEV1 was obtained, and information regarding symptom frequency, asthma medication use, and the occurrence of asthma exacerba­tions was recorded. An exacerbation was defined as asthma symptoms (cough, dyspnea, or wheezing) severe enough to result in a medical intervention, including hospitalization, unscheduled visits (physician office or emergency department), and/or treatment with oral cor­ticosteroids among subjects who were not already taking regular oral corticosteroids. The classification of asthma severity was determined upon enrollment in the study. As we previously report­ed21 and for the purposes of the current study, the National Asthma Education Program definitions of asthma severity were modified to include medication use Table 1)- Daily medication was defined as at least 2 puffs per day of inhaled /3-agonist, cromolyn, nedocromil, or inhaled steroids, or at least 4 puffs per day inhaled ipratropium, or at least f dose per day of theophylline. Regular oral corticosteroid use was defined as daily or every other day dosing for at least 4 weeks before entry in the study. Table 1. Classification of Asthma Severity The gestational age at the time of randomization was determined from the last menstrual period if it correlated with the first ultrasound. Dating was based upon first ultrasound if the last menstrual period estimate varied by more than 7 days from the ultrasound gestational age estimate if the first ultrasound was performed less than 20 weeks of gestation or more than f 4 days if the first ultra­sound was performed at or after 20 weeks of gestation. The primary hypothesis was that the cohort with moderate-severe asthma would have an increased inci­dence of delivery at less than 32 weeks of gestation compared with nonasthmatic controls.8 From previous studies, we estimated that the rate of preterm delivery at less than 32 weeks would be between 2% and 3°/o.22 We felt that a 2- to 3-fold increase of preterm delivery among the moderate-severe cohort would be plausible and clin­ically relevant. We estimated that a sample size of 900 per group would be sufficient, with power of at least 80%, 2-sided type I error of 0.05, and allowing for a loss to follow-up rate of as much as f 0%. Secondary analyses included the incidence of gesta­tional diabetes, preeclampsia, premature preterm rup­ture of membranes, induced for fetal indication, cliorio- amnionitis, oligohydramnios, cesarean delivery for fetal distress, total cesarean delivery, wheezing during labor, gestational age, preterm delivery (less than 37 weeks), labor duration, postpartum hemorrhage (more than 500 mL for vaginal delivery or more than f,000 mL for cesarean delivery), birth weight, small for gestational age (less than fOth percentile, Brenner et al23), perinatal mortality, hyaline membrane disease, bronchopulmo­nary dysplasia, discharge diagnosis of neonatal sepsis, major congenital anomalies, patent ductus arteriosis, neonatal intensive care unit admission, intraventricular hemorrhage, necrotizing enterocolitis, and transient tachypnea of newborn. These data were obtained at postpartum chart reviews. The Biostatistics Center of George Washington Uni­versity maintained the data and performed the statistical analysis using SAS 8.2 (SAS Institute, Cary, NC) statis­tical software. The data were analyzed by using Kruskal-Wallis for continuous variables and x2 test and logistic regression analysis for dichotomous variables. Logistic regression covariates included asthma severity, previous preterm delivery, smoking status, African American versus other race, previous elective or sponta­neous abortion, type of insurance, and minimum of high school education. For sparse outcomes, a reduced co- variate set consisting of the first 4 covariates was used. Body mass index and oral corticosteroid use were also covariates for the model for gestational diabetes. Logistic regression results are reported as odds ratios and 95% VOL. 103, NO. 1, JANUARY 2004 Dombrowski et al Asthma During Pregnancy 7 Copy r ight© Ame r ican C o l l e g e o f Ob s t e t r i c ia n s an d G y n e c o l o g i s t s Table 2. Demographic and Baseline Inform ation Moderate-severe (N = 866) Mild (N = 873) Control (N = 881) Overall P Race .002 African American 447(51.6) 518 (59.3) 458 (52.0)* Caucasian 325 (37.5) 269 (30.8) 324 (36.8) Hispanic 77 (8.9) 78 (8.9) 74 (8.4) Other 17 (2.0) 8 (0.9) 25 (2.8) Age (y) _ 24.2 ± 6.1 22.4 ± 5.3 24.8 ± 6.1 < .001 Mean gestational age at enrollment (wk) 18.9 ± 4.8 18.1 ± 4.9 19.8 ± 4.3 < .001 Previous preterm delivery 142 (16.4) 111 (12.7) 136 (15.4) .081 Previous miscarriages/abortions 363 (41.9) 323 (37.0) 345 (39.2) .110 At least 12 years of schooling 522 (60.3) 509 (58.3) 584 (66.4) .002 Smoked at enrollment 162 (18.7) 164 (18.8) 166 (18.8) .998 Chronic hypertension 46 (5.3) 23 (2.6) 39 (4.4) .017 Mean prepregnancy body mass index 27.9 ± 7.9 27.3 ± 7.6 26.5 ± 7.1 .002 Married 300 (34.6) 213 (24.4) 343 (38.9) < .001 Insurance .001 Government 680 (78.5) 702 (80.4) 644 (73.1) Private 136 (15.7) 100 (11.4) 164 (18.6) None 50 (5.8) 71 (8.1) 73 (8.3) Data presented as ./V(%) or mean ± standard deviation. * Not significant compared with moderate severe cohort, P= .764. confidence intervals (95% CIs) with the control group as the referent. Significance was defined at P< .05 without correction for multiple comparisons. RESULTS A total of 2,171 patients with asthma were asked to enroll in the study; 359 (16.5%) declined participation. We recruited 906 women with mild asthma, 906 with mod­erate- severe asthma, and 928 controls. One hundred twenty (4.4%) patients were lost to follow-up. Compared with the cohort remaining in the study, women lost to follow-up were significantly different with respect to age (24 ± 6 years versus 22 ± 5 years; P = .002), weeks of gestational age at enrollment (19 ± 5 weeks versus 18 ± 5 weeks; P = .006), and government insurance (77.3% versus 84.2%; P = .014). Losses to follow-up did not affect the relative balance of smoking or ethnicity among the 3 cohorts. The final analysis included 881 controls, 873 with mild asthma, and 866 with moderate-severe asthma. Of the moderate-severe cohort, 52 (6.0%) were classified as having severe asthma. Demographic and baseline information and length of follow-up by initial severity group are presented in Table 2. There were significant differences in ethnicity, age, level of educa­tion, body mass index, marital status, chronic hyperten­sion, and type of insurance. The mean gestational age at study entry was 19.3 ± 4.7 weeks. Women with moder­ate- severe asthma were treated with the following medi­cations during the 4 weeks before enrollment: inhaled /3-agonist (n = 377, 41.6%), inhaled corticosteroids (n = 194,21.4%), theophylline (n = 54, 6.0%), oral corticoste­roids (n = 18,2.0%), inhaled ipratropium (n = 19,2.1%), inhaled cromolyn or inhaled nedocromil (n = 15,1.7%), and oral /3-agonist (n = 11, 1.2%). Patients could be on more than one medication. During this study, 4 women were intubated for asthma exacerbations, but there were no maternal deaths. Patients with mild asthma had an asthma exacerbation rate of 12.6% (n = 110), and asthma hospitalization rate of 2.3% (n = 20) .21 Those with moderate asthma had an exacerbation rate of 25.7% (n = 209) and hospitalization rate of 6.8% (n = 55). Severe asthmatics had exacerba­tion and hospitalization rates of 51.9% (n = 27) and 26.9% (n = 14), respectively. During this study, 23% of women had an improvement in asthma severity, and 30.3% had an increase of asthma severity.21 Among women with asthma, we found no significant differences in the rates of preterm delivery less than 32 weeks or delivery less than 37 weeks (Table 3). Neither asthma nor asthma severity (moderate-severe or mild) was significantly related to preterm delivery by logistic regression analysis. There were no significant differences for antepartum, delivery or postpartum outcomes com­pared with controls except increased cesarean delivery rate among the moderate-severe group. Wheezing dur­ing labor was significantly associated with asthma sever­ity. There were no significant differences in neonatal outcomes (Table 4), except for a discharge diagnosis of neonatal sepsis among the mild group compared with controls. 8 Dombrowski et al Asthma During Pregnancy OBSTETRICS & GYNECOLOGY Copy r ight© Ame r ican C o l l e g e o f Ob s t e t r i c ia n s an d G y n e c o l o g i s t s Table 3. Ante p a rtum , Delivery, and Postpartum Outcomes Moderate- severe (n = 866) Mild (n=873) Control (n=881) Overall P Moderate- severe versus controls [Unadjusted OR (95% Cl)] Mild versus controls [Unadjusted OR (95% Cl)] Delivery < 32 weeks 26 (3.0) 30 (3.4) 29 (3.3) .873 0.9 (0.5, 1.6) 1.0 (0.6, 1.8) Delivery < 37 weeks 137 (15.8) 141 (16.1) 139 (15.8) .973 1.0 (0.8, 1.3) 1.0 (0.8, 1.3) Gestational diabetes 57 (6.6) 29 (3.3) 42 (4.8) .007 1.4 (0.9, 2.1) 0.7 (0.4, 1.1) Preeclampsia 107 (12.4) 106 (12.2) 98 (11.2) .703 1.1 (0.8, 1.5) 1.1 (0.8, 1.5) Preterm premature rupture of 100 (11.6) 113 (13.0) 98 (11.2) .484 1.0 (0.8, 1.4) 1.2 (0.9, 1.6) membranes Induced for fetal indication 21 (2.4) 23 (2.6) 15(1.7) .386 1.4 (0.7, 2.8) 1.6 (0.8, 3.0) Chorioamnionitis 44 (5.1) 59 (6.8) 44 (5.0) .197 1.0 (0.7, 1.6) 1.4 (0.9, 2.1) Oligohydramnios 71 (8.2) 44 (5.1) 52 (5.9) .021 1.4 (1.0, 2.1) 0.8 (0.6, 1.3) Cesarean delivery 203 (23.4) 160 (18.3) 160 (18.2) .007 1.4 (1.1, 1.7)* 1.0 (0.8, 1.3) Cesarean delivery for fetal distress 35 (4.0) 35 (4.0) 35 (4.0) .997 1.0 (0.6, 1.6) 1.0 (0.6, 1.6) Wheezing during labor 195 (22.7) 116 (13.4) 3 (0.3) <.001 Gestational age at delivery (wk) 38.5 ± 3.1 38.3 ± 3.7 38.3 ± 3.6 .950 Mean hours of labor 12.1 ± 9.2 12.9 ± 12.6 11.7 ±9.4 .181 Postpartum hemorrhage 60 (7.5) 63 (7.8) 44 (5.3) .091 1.5 (1.0, 2.2) 1.5 (1.0, 2.2) OR = odds ratio; Cl = confidence interval. Data presented as ,/Y'(%j or mean ± standard deviation. * Logistic regr ession adjusted OR = 1.4 (95% Cl 1.1, 1.8). Based on univariate analysis indicating significance, diabetes and delivery at less than 37 weeks of gestation we performed a post hoc logistic regression analysis for remained si .gnificantly increased compared to controls gestational diabetes, oligohydramnios, and cesarean de­by adjusted odds ratio. livery with severe asthma considered as a separate cate­gory (Table 5). We also included preterm delivery and small for gestational age because they have been in­IJIbUUbblUN creased among women who received oral corticosteroids Asthma was not associated with an increase in preterm treatment of asthma during pregnancy.8:16 Gestational delivery at less than 32 weeks of gestation. We chose Table 4. Neonatal Outcomes Moderate-severe Mild versus versus controls controls Moderate- [unadjusted OR [unadjusted OR severe Mild Control Overall P " (95% Cl)] " (95% Cl)] Birth weight (g) 3146 ± 667 3116 ± 699 3160 ± 706 0.291 Small for gestational age 60 (7.1) 59 (6.9) 51 (5.9) 0.579 1.2 (0.8, 1.8) 1.2 (0.8, 1.7) Perinatal mortality 4 (0.5) 3 (0.3) 4 (0.5) 0.935 1.0 (0.2, 4.1) 0.7 (0.2, 3.4) Hyaline membrane disease 18 (2.1) 21 (2.5) 13 (1.5) 0.365 1.4 (0.7, 2.9) 1.6 (0.8, 3.3) Bronchopulmonary disease 8 (0.9) 6 (0.7) 2 (0.2) 0.165 4.1 (0.9, 19.3) 3.0 (0.6, 15.1) Discharge diagnosis of neonatal 14 (1.7) 20 (2.3) 7 (0.8) 0.048 2.0 (0.8, 5.1) 2.9 (1.2, 7.0)* sepsis Congenital anomaly 36 (4.2) 33 (3.9) 34 (3.9) 0.919 1.1 (0.7, 1.7) 1.0 (0.6, 1.6) Patent ductus arteriosus 7 (0.8) 6 (0.7) 3 (0.4) 0.429 2.4 (0.6, 9.2) 2.0 (0.5, 8.1) Neonatal intensive care unit 147 (17.3) 152 (17.8) 133 (15.4) 0.379 1.1 (0.9, 1.5) 1.2 (0.9, 1.5) admission Intraventricular hemorrhage 1 (0.1) 7 (0.9) 4 (0.5) 0.099 0.2 (0.0, 2.3) 1.8 (0.5, 6.1) Necrotizing enterocolitis 3 (0.3) 4 (0.5) 3 (0.3) 0.928 1.0 (0.2, 5.0) 1.3 (0.3, 6.0) Transient tachypnea of 34 (4.0) 37 (4.3) 35 (4.0) 0.934 1.0 (0.6, 1.6) 1.1 (0.7, 1.7) newborn OR = odds ratio; Cl = confidence interval. Data presented as ,/Y'(%j or mean ± standard deviation. * Logistic regression adjusted OR = 2.9 (95% Cl 1.2, 6.8) VOL. 103, NO. 1, JANUARY 2004 Dombrowski et al Asthma During Pregnancy 9 Copy r ight© Ame r ican C o l l e g e o f Ob s t e t r i c ia n s an d G y n e c o l o g i s t s Table5. Logistic Regression Analysis for Severe Asthma Cohort Compared With Controls (N = 52) Severe asthma [N (%)] Unadjusted odds ratios (95% Cl) Adjusted odds ratios (95% Cl) Gestational diabetes 8 (15.4) 3.6 (1.6, 8.2) 3.0 (1.2, 7.8) Oligohydramnios 6 (11.5) 2.1 (0.8, 5.1) 2.1 (0.9, 5.3) Cesarean delivery 14 (26.9) 1.7 (0.9, 3.1) 1.6 (0.8, 3.1) Delivery < 32 weeks 3 (5.8) 1.8 (0.5, 6.1) 1.6 (0.5, 5.5) Delivery < 37 weeks 16 (30.8) 2.4 (1.3, 4.4) 2.2 (1.2, 4.2) Small for gestational age 5 (9.8) 1.7 (0.7, 4.5) 1.6 (0.6, 4.4) Discharge diagnosis of neonatal sepsis 2 (3.9) 5.0 (1.0, 24.7) 4.6 (0.9, 22.8) Cl = confidence interval. Adjusted odds ratio covariates: previous preterm delivery, smoking status, African American versus other. Body mass index was also included in the model for gestational diabetes. severe prematurity as our primary outcome for several reasons. The association of prematurity and asthma is biologically plausible; both are characterized by chronic processes that are mediated in part by increased inflam­matory cytokines and increased smooth muscle reactiv­ity. Preterm delivery at less than 32 weeks of gestation is clinically important, accounts for most of the perinatal morbidity and mortality due to prematurity,19 and was reported to be increased among asthmatics receiving regular medications.8 There have been inconsistent find­ings of an increased risk of prematurity among women with asthma.3-16 We found an increased frequency of delivery at less than 37 weeks of gestation limited to the subset (n = 52) with severe asthma. This finding should be interpreted with caution; we could not control for the potential confounding effects of oral corticosteroid use because we used the need for oral corticosteroids as part of our definition to classify severe asthma. A large retro­spective database study of 36,985 asthmatic patients did find an increased incidence of preterm births less than 37 weeks; the incidence of preterm births at less than 32 weeks was not reported.9 The largest prospective studies have not found a significant association of preterm birth and asthma.10,14 Other than increased frequencies of cesarean delivery among patients with moderate-severe asthma, discharge diagnosis of neonatal sepsis among those with mild asthma, and gestational diabetes and delivery less than 37 weeks among the subset with severe asthma, we did not find increased perinatal or obstetrical morbidity com­pared with controls. Because a discharge diagnosis of neonatal sepsis was found only among the cohort with mild asthma, the clinical importance of this outcome is not clear; this finding maybe related to type 1 error. Our findings are generally reassuring, despite a relatively high prevalence of asthma morbidity. After enrollment, 27.3% of women in the moderate-severe cohort had asthma exacerbations, and 8% of these required hospi­talization. 21 A potential explanation for the inconsistencies among previous studies regarding the effect of asthma on obstet­rical and neonatal outcomes may include the fact that most studies of asthma during pregnancy did not attempt to classify asthma severity. Classification of asthma se­verity has important clinical implications with respect to asthma morbidity and tailoring optimal treatment regi­mens. 1'20 Failure to classify severity may result in sub- optimal asthma control, thereby increasing risks for adverse maternal or neonatal outcomes. Oral corticoste­roid treatment per se may confound maternal and neo­natal outcomes. Some positive findings of our study and previous studies maybe due to chance. In general, larger prospective studies have tended to find fewer significant adverse associations.10,14 Our study has the strengths of being large, multicentered, prospective, stratified by asthma severity; including high-quality spirometry; and controlling for confounders, such as African-American ethnicity and smoking status. The prospective nature of this study may have led to better surveillance and treatment. The low prevalence of adverse obstetrical and perinatal outcomes may have in part been the result of dissemination of the 1993 Na­tional Asthma Education Program guidelines for treating asthma during pregnancy. These include 4 integral com­ponents of asthma management, including using objec­tive measures of pulmonary function, mitigating asthma triggers, patient education, and pharmacological man­agement tailored for asthma severity with anti-inflamma­tory therapy for moderate or severe asthma.20 This was an observational study in which our investigators were not mandated to follow National Asthma Education Program guidelines. However, they were familiar with the guidelines, and this study was conducted in parallel with a prospective randomized clinical trial in which all patients were managed using these guidelines. Aspects of asthma management, including medications, pulmonary function, compliance, and other outcomes, will be re­ported in future articles. 10 Dombrowski et al Asthma During Pregnancy OBSTETRICS & GYNECOLOGY Copy r ight© Ame r ican C o l l e g e o f Ob s t e t r i c ia n s an d G y n e c o l o g i s t s In 1997, the National Asthma Education Program published the Expert Panel Report II, in which the definitions of asthma severity were modified to include mild persistent asthma; however, these recommenda­tions were not specific to pregnancy.1 Based on the new classification, our moderate cohort would include sub­jects with both mild persistent and moderate persistent asthma. Our study has several important limitations. Because this was an observational study, the management of asthma was not standardized. The diagnosis of asthma was attained primarily by eliciting a history of physician- diagnosed asthma, although this has been found to be a valid definition in epidemiological studies.24 Control participants were not rigorously evaluated for absence of asthma. We did not take into account possible changes in asthma severity before enrollment in the study. Our enrolled population was heavily weighted toward single mothers and enriched for African Americans and those with subsidized insurance. This likely reflects the urban centers that make up the Maternal-Fetal Medicine Units network. However, because asthma is more common and more severe in African Americans2 and more severe in patients with lower socioeconomic status,20'26 this is an important population to study. This study controlled for confounding factors, such as ethnicity and type of insurance, and had a large sample size and wide geo­graphic representation; these strengths should increase the generalizability of our reassuring findings to other populations. However, one should be cautious about inferring the generalizability of our results in our partic­ipants with severe asthma because of the relatively small size of this cohort in our study. In conclusion, we had excellent maternal and perinatal outcomes despite a high frequency of asthma exacerba­tions. These findings do not contradict the possibility that suboptimal control of asthma during pregnancy is associated with increased risk to the mother or baby. REFERENCES 1. National Asthma Education and Prevention Program Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. NHLBI, NIH Publication No. 97-4051, Washington, DC: April, 1997. 2. Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn C, Redd SC. Surveillance for Asthma- United States, 1980-1999. MMWR Surveill Summ 2002;5I: 1-13. 3. Alexander S, Dodds L, Armson BA. Perinatal outcomes in women with asthma during pregnancy. Obstet Gynecol 1998;92:435-40. 4. Liu S, Wen SW, Demissie K, Marcoux S, Kramer M. Maternal asthma and pregnancy outcomes: a retrospective cohort study. Am J Obstet Gynecol 2001 ;184:90-6. 5. Bahna SL, Bjerkedal T. The course and outcome of preg­nancy in women with bronchial asthma. Acta Allergol 1972;27:397-406. 6. Doucette JT, Bracken MB. Possible role of asthma in the risk of preterm labor and delivery. Epidemiology 1993 ;4: 143-50. 7. Demissie K, Breckenridge MB, Rhoads GG. Infant and maternal outcomes in the pregnancies of asthmatic women. Am J Respir Crit Care Med 1998;158:1091-5. 8. PerlowJH, Montgomery D, Morgan MA, Towers CV, Porto M. Severity of asthma and perinatal outcome. AmJ Obstet Gynecol 1992:167:963-7. 9. Kallen B, Rydhstroem H, Aberg A. Asthma during preg­nancy: a population based study. Eur J Epidemiol 2000: 16:167-71. 10. Schatz M, Zeiger RS, Hoffman CP, Harden K, Forsythe A, Chilingar L, et al. Perinatal outcomes in the pregnancies of asthmatic women: a prospective controlled analysis. AmJ Respir Crit Care Med 1995:151:1170-4. 11. Dombrowski MP, Bottoms SF, Boike GM, WaldJ. Inci dence of preeclampsia in asthmatics lower with theophyl­line. AmJ Obstet Gynecol 1986;155:265-7. 12. Jana N, Vasishta K, Saha SC, Khunnu B. Effect of bron­chial asthma on the course of pregnancy, labour and perinatal outcome. J Obstet Gynaecol 1995:21:227-32. 13. Minerbi-Codish I, Fraser D, Avnun L, Glezerman M, Heimer D. Influence of asthma in pregnancy on labor and the newborn. Respiration. 1998:65:130-5. 14. Stenius Aamiala BS, Hedman J, Terarno KA. Acute asthma during pregnancy. Thorax 1996;51:411-4. 15. Lao TT, Huengsburg M. Labour and delivery in mothers with asthma. Eur I Obstet Gynecol Reprod Biol 1990;35: 183-90. 16. Mabie WC, Barton JR, Wasserstrum N, Sibai BM. Clini­cal observations on asthma in pregnancy. J Mat Fet Med 1992;1:45-50. 17. Wen SW, Demissie K, Liu S. Adverse outcomes in preg­nancies of asthmatic women: results from a Canadian population. Ann Epidemiol 2001;11:7-12. 18. Stenius Aamiala BS, Piirila P, Terarno KA. Asthma and pregnancy: a prospective study of 198 pregnancies. Tho­rax 1988:43:12-8. 19. March of dimes updates: Taking action against prematu­rity. Contemp Ob/Gyn 2003;48:92-104. 20. National Asthma Education Program Report of the Work­ing Group on Asthma and Pregnancy: Management of asthma during pregnancy. NIH Publication number 93-3279A, Washington, DC: September, 1993 21. Schatz M, Dombrowski MP, Wise R, Thom EA, Landon M, Mabie W, et al. Asthma morbidity during pregnancy can be predicted by severity classification. J Allergy Clin Immunol 2003:112:283-8. VOL. 103, NO. 1, JANUARY 2004 Dombrowski et al Asthma During Pregnancy 11 Copy r ight© Ame r ican C o l l e g e o f Ob s t e t r i c ia n s an d G y n e c o l o g i s t s 22. Dombrowski MP, Wolfe HM, Brans YW, Saleh AA, Sokol iy. Neonatal morphometry: relation to obstetric, pediatric, and menstrual estimates of gestational age. Am J Dis Child 1992;146:852-6. 23. Brenner WE, Edelman DA, Hendricks CH. A standard of fetal growth for the United States of America. AmJ Obstet Gynecol 1976;126:555-564. 24. Toren K, Brisman J, Jarvholm B. Asthma and asthma-like symptoms in adults assessed by questionnaires: a literature review. Chest 1993;104:600-608. 25. Gottlieb DJ, Beiser AS, O'Connor GT. Poverty, race, and medication use are correlates of asthma hospitalization rates. Chest 1995;108:28-35. 26. Castro M, Schechtman KB, Halstead J, Bloomberg G. Risk factors for asthma morbidity and mortality in a large metropolitan city.J Asthma 2001;38:625-35. Address reprint requests to: Mitchell P. Dombrowski, St.John Hospital, Department of Obstetrics and Gynecology, 22151 Moross Road, Suite 313, Detroit MI 48236; e-mail: [e-mail]. Received July 24, 2003. Received in revised form September 8, 2003. Accepted September 11, 2003. Appendix. P a rtic ip a tin g In s titu tio n s and S ta ff Members National Heart, Lung, and Blood Institute [J. Kiley), National Institute of Child Health and Human Development Network of Matemal-Fetal Medicine Units: University of Pittsburgh Magee Women's Hospital (P. Heine, M. Cotroneo, E. Daugherty); University of Tennessee (B. Sibai, R. Ramsey); University of Southern California (Y. Rabello); University of Alabama at Birmingham (W. Andrews, R. Copper, S. Tate, A. Northen); Wayne State University (Y. Sorokin, G. S. Norman, A. Millinder); University of Cincinnati (T. A. Siddiqi, N. Elder, V. Pemberton); University of Oklahoma [J. C. Carey, A. Meyer); Wake Forest University (M. Harper, M. Swain, A. Luper); University of Chicago (A. H. Moawad, P. Jones, M. E. Brown, G. Mallett); Ohio State University (J. D. lams, F. Johnson, S. Meadows); Medical University of South Carolina (J. P. Van Dorsten, B. A. Collins); University of Miami (S. Beydoun, C. Alfonso, J. Potter, R. Washington, F. Doyle); LJniversity of Texas Southwestern (M. L. Sherman); LJniversity of Texas San Antonio (O. Langer, S. Barker); University of Utah (D. J. Dudley, L. Reynolds); Thomas Jefferson University (M. DiVito, Michelle, C. Smith); and George Washington University Biostatistics Center (E. Thom, E. Rowland, S. Brancolini) 12 Dombrowski et al Asthma During Pregnancy OBSTETRICS & GYNECOLOGY Copy r ight© Ame r ican C o l l e g e o f Ob s t e t r i c ia n s an d G y n e c o l o g i s t s