Asthma control during pregnancy and the risk of preterm delivery or impaired fetal growth

Asthma control during pregnancy and the risk of preterm delivery or impaired fetal growth Ludmila N. Bakhireva, MD, PhD, MPH*; Michael Schatz, MD, MS†; Kenneth Lyons Jones, MD‡; and Christina D. Chambers, PhD, MPH‡§; for the Organization of Teratology Information Specialists Collaborative Research Group

Background: Concerns regarding potential harmful effect of medications on fetuses often result in inadequate treatment of asthma in pregnancy, whereas risks posed by poorly controlled maternal asthma are often underestimated. Objective: To evaluate the effect of maternal asthma on preterm delivery and fetal growth. Methods: Study participants were individuals enrolled in the Organization of Teratology Information Specialists Asthma Medications in Pregnancy Study between February 1, 1998, and December 31, 2003. Pregnant women with physician-diagnosed asthma (n ⫽ 719) evaluated their asthma control repeatedly during pregnancy based on symptom frequency and interference with daily activities and sleep and reported hospitalizations and unscheduled clinic visits for asthma exacerbations. The incidence of preterm delivery, the incidence of intrauterine growth restriction, and mean birth weight were evaluated relative to asthma symptom control and exacerbation measures. Results: The incidence of preterm delivery was significantly higher among patients with inadequate asthma symptom control during the first part of pregnancy (11.4%) compared with patients with adequate asthma control (6.3%; P ⫽ .02). Similarly, patients who were hospitalized for asthma during pregnancy had a higher incidence of preterm delivery (16.4%) compared with asthmatic women without a history of hospitalization (7.6%; P ⫽ .02). The effect seemed independent from use of systemic corticosteroids and other covariates. Neither the incidence of intrauterine growth restriction nor mean birth weight varied by any measures of asthma symptom control or exacerbations. Conclusions: This study demonstrates a substantial risk for preterm delivery posed by poorly controlled maternal asthma and provides additional evidence regarding the importance of adequate treatment of asthma in pregnancy to maintain optimal asthma control. Ann Allergy Asthma Immunol. 2008;101:137–143.

INTRODUCTION Asthma is a chronic disorder that affects up to 8% of pregnant women in the United States.1 Previous data suggest that women with asthma, especially severe asthma, have a higher rate of adverse perinatal outcomes, including preterm delivery and impaired fetal growth.2 Intrauterine growth restriction (IUGR) and preterm delivery are common pregnancy complications that are associated with increased mortality and

morbidity in the neonatal period and might have long-term consequences, such as neurologic and developmental disability and chronic health problems.3,4 Preterm labor and IUGR have also been reported to occur more often in corticosteroid-dependent asthmatic patients,5– 8 making it difficult to separate the effect of severe or uncontrolled asthma from the effects of asthma medications.9 Concerns regarding the safety of gestational drug therapy and the

Affiliations: *Division of Pharmacy Practice and Department of Family/ Community Medicine, University of New Mexico, Albuquerque, New Mexico; †Department of Allergy-Immunology, Kaiser-Permanente Medical Center; San Diego, California; ‡Department of Pediatrics, University of California, San Diego, La Jolla, California; §Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, California. Disclosures: Dr Jones has consulting arrangements with Merck. Dr Chambers has consulting arrangements with Cephalom Pharmaceutical. Drs Jones and Chambers have received grant support from Sanofi-Aventis, Sanofi-Pasteur, Abbott Laboratories, Amgen, Apotex, Barr Laboratories, Kali Laboratories, Sandoz Pharmaceutical, Teva Pharmaceutical, and Bristol Myers Squibb. Dr Schatz has received grant support from GlaxoSmithKline and Sanofi-Aventis and has received honoraria from GlaxoSmithKlein, Genentech, and Merck. Dr Bakhireva has no conflict of interest. Funding Sources: This research was supported by a grant from Aventis Pharmaceutical. Received for publication December 19, 2007; Received in revised form February 25, 2008; Accepted for publication March 19, 2008.

Received for publication December 19, 2007; Received in revised form February 25, 2008; Accepted for publication March 19, 2008. The following members of the OTIS Collaborative Research Group contributed to this study: Arizona Teratogen Information Program, University of Arizona, Tucson: D. Quinn, D. Vogt; California Pregnancy Risk Information, University of California, San Diego: K. Kao; Connecticut Pregnancy Exposure Information Service, University of Connecticut Health Center, Farmington: S. Lavigne, J. Brochu; Nebraska Teratogen Project, University of Nebraska Medical Center, Omaha: Dr B. Buehler, E. Conover; Illinois Teratogen Information Service, Chicago: K. Ormond, C. Chou; Michigan Teratogen Information Service, Children’s Hospital of Michigan, Detroit: Dr Y. Johnson, S. Swerc; Missouri Teratogen Information Service, University of Missouri Hospital and Clinics, Columbia: Dr S. Braddock, P. Slusher; Pregnancy Risk Network, University of Buffalo: Dr L. Robinson, S. Gangell; Motherisk Program, Hospital for Sick Children, Toronto, Ontario: Dr G. Koren, M. Morreti; Texas Teratogen Information Service, University of North Texas, Denton: L. Wolfe; Pregnancy RiskLine Project, Utah Department of Health, Salt Lake City: Dr J. Carey; J. Robertson; CARE Northwest, University of Washington, Seattle: Dr J. Polifka, Dr E. Rudy.

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potential harmful effect of asthma medications on the fetus often result in inadequate treatment of asthma during pregnancy, presumably contributing to prolonged exacerbations of asthma in pregnant compared with nonpregnant women,10,11 whereas risks associated with severe asthma for adverse perinatal outcomes might be underestimated. It has been reported that only half of women who experience daily asthma symptoms during pregnancy take any controller medications and only half of women who take controller medications before pregnancy continue using them while pregnant.12 These findings indicate that existing reports do not provide compelling enough evidence for health care professionals and pregnant women to feel confident that optimal treatment of asthma in pregnancy can be of benefit to the mother and the infant. The purpose of this study was to evaluate the risk of preterm delivery and fetal growth deficiency associated with poorly controlled maternal asthma in a well-characterized cohort of pregnant women. METHODS Study Population Study participants were individuals enrolled in the multicenter, prospective study of Asthma Medication Use in Pregnancy conducted by the Organization of Teratology Information Specialists (OTIS) between February 1, 1998, and December 31, 2003. The methods of the study have been described elsewhere.8,13,14 Briefly, 819 pregnant women with physician-diagnosed asthma were recruited through the OTIS counseling network in North America and were followed up through a central coordinating center at the University of California, San Diego. For evaluation of preterm delivery and IUGR, the sample size was restricted to 719 pregnancies that resulted in singleton live delivery because twinning and the underlying mechanisms leading to spontaneous abortion or stillbirth could confound evaluated associations.15 For evaluation of mean birth weight, the sample size was further restricted to 659 live-born full-term singletons. To be eligible for the study, women had to be at least 18 years old, be in their first part of pregnancy (mean gestational age at enrollment was 13 weeks), have physician-diagnosed asthma, and be willing to be followed up. Women who had any prenatal diagnostic test result that indicated an abnormal pregnancy were not eligible for participation. Women between 18 and 48 years of age (mean [SD] age, 31.4 [5.4] years) were recruited. The University of California, San Diego Human Research Protection Program approved the study. All study participants provided oral informed consent before enrollment and written consent for release of medical records. Data Collection and Measurements Structured maternal interviews were conducted at enrollment, at the 26th and 32nd gestational weeks, and within 4 to 6 weeks after delivery and included information on maternal demographic and lifestyle characteristics, medication use, asthma control, and pregnancy complications. Family socio-

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economic status (SES) was evaluated using a Hollingshead 4-factor index (unpublished data, 1975). Self-reported dates of last menstrual period, expected date of delivery, and gestational age were subsequently confirmed by review of ultrasound reports and obstetrician records. Preterm delivery was defined as birth before 37 completed gestational weeks. Information about the newborn included birth weight, length, head circumference, sex of the child, and birth complications. Percentiles for each measure of fetal growth were determined based on the National Center for Health Statistics 2000 standard US growth curves for fullterm infants16 and growth charts adjusted for gestational age for preterm infants.17 Gestational age– and sex-specific percentiles for birth weight were defined as small for gestational age if they were in the 10th percentile or less. Asthmatic women were asked at each interview to categorize their symptoms during the previous 2-week period using a 5-point scale, developed by 1 of the coauthors (M.S.). The scale is based on asthma symptoms and their interference with daily activities and sleep. Asthma control was categorized as adequate if no symptoms occurred or symptoms did not interfere with sleep or activity (score, 0 –1), fair if symptoms occasionally interfered with sleep or activity (score, 2), and poor if symptoms frequently or constantly interfered with sleep or activity (score, 3– 4). At the time of initiation of the study, no validated asthma control tools had been published; however, frequency of symptoms and their interference with sleep and activity are the major components of subsequently published validated asthma control tools.18 –20 To evaluate asthma exacerbations during pregnancy, women were asked to report the number of unscheduled asthma visits and hospitalizations for asthma since their last menstrual period. Although this study was completed before the 2007 National Asthma Education and Prevention Program guidelines,21 the control scale determined by patient interview in the current study corresponds to the impairment domain of asthma control, and the exacerbations that required unscheduled care are related to the risk domain. At each interview, participants reported actual use, frequency, duration, and dosage of all medications, with a particular emphasis on asthma medications. Information collected by questionnaires was supplemented and validated by review of maternal and infant medical records. Statistical Analysis The distribution of maternal characteristics was compared among women with adequate and fair to poor asthma control at the time of enrollment using ␹2 tests. Average daily doses of specific inhaled corticosteroids (ICSs) were converted into beclomethasone equivalent doses as previously described22 and compared among patients with adequate and inadequate asthma control and patients with and without exacerbations by analysis of variance. The incidences of preterm delivery and IUGR were compared among women with adequately controlled asthma relative to women with fair to poor control of their asthma as

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measured at each maternal interview by ␹2 tests in univariate analyses. The incidences were also compared among patients who had been hospitalized for asthma during pregnancy or had unscheduled clinic visits vs patients who did not. The distribution of mean birth weight by asthma control and exacerbation measures was compared by analysis of variance. Multiple logistic regression analysis was used to evaluate the effect of asthma control and asthma exacerbation on preterm delivery and IUGR after adjustment for important covariates. Covariates that are known to affect both asthma and the evaluated perinatal outcomes were selected a priori and included maternal age, body mass index, gravidity, parity, ethnicity, tobacco use, and SES. The information on common comorbidities (ie, hypertension, diabetes mellitus, maternal infection) and other asthma medications was collected, but none met a definition of a confounder. Since the use of systemic corticosteroids during pregnancy has been reported to increase the risk of adverse perinatal outcomes, it was included in the models in addition to other covariates. RESULTS Among 719 women with asthma, 396 (56.3%) reported adequate control of asthma at their first maternal interview, whereas 308 (43.7%) reported fair to poor control of asthma, and 15 women had missing values for this variable (Table 1). At subsequent maternal interviews, a slightly smaller proportion of patients reported poor to fair control of their asthma (35.3% and 30.4%, respectively). During pregnancy 8.5% of patients were hospitalized for asthma and 21.3% had unscheduled asthma clinic visits. Some differences were observed in demographic, reproductive health, and lifestyle characteristics of participants, depending on the level of asthma control (Table 2). Patients with inadequately controlled asthma were more likely to be younger (P ⫽ .02), multigravida (P ⬍ .001), multipara (P ⬍ Table 1. Distribution of Asthma Symptom Control and Exacerbation Measures Among Women With Asthma in the Organization of Teratology Information Specialists Study Measures of maternal asthma control Asthma symptom control at ⱕ20 gestational weeks Adequate Poor to fairb Asthma symptom control at 26 gestational weeks Adequate Poor to fairb Asthma symptom control at 32 gestational weeks Adequate Poor to fairb Hospitalization(s) for asthma during pregnancy Unscheduled asthma visits during pregnancy

No. (%)a 396 (56.3) 308 (43.7) 419 (64.7) 224 (35.3) 445 (69.6) 194 (30.4) 61 (8.5) 153 (21.3)

a Sample size varies from 635 to 719 because of pairwise deletion of missing data. b Defined as the presence during the prior 2 weeks of asthma symptoms that interfered with sleep or activity occasionally, frequently, or constantly.

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.001), and of a race/ethnicity other than white (P ⫽ .046) and more likely to have a below average SES (P ⬍ .001) compared with women with adequately controlled asthma. Similarly, women who were hospitalized for asthma during pregnancy were more likely to be multigravida, multipara, and of an ethnicity other than white, whereas no differences in other characteristics were observed (data not shown). Women in the study had inadequate symptom control despite higher average daily doses of ICSs (P ⫽ .01). Patients who reported unscheduled clinic visits for asthma also took higher mean [SD] daily doses of ICSs (538.1 [379] ␮g) compared with patients who did not require urgent care (413.4 [342] ␮g; P ⫽ .002). The observed incidence of preterm delivery in the entire sample was 8.3%. Most of these births (7.9%) were moderately preterm (32 to 36 gestational weeks), and only 3 (0.42%) were very preterm (28 to 31 gestational weeks). As presented in Table 3, the incidence of preterm delivery was significantly higher among patients with inadequate asthma control during the first part of pregnancy (11.4%) compared with patients with adequate control (6.3%; P ⫽ .02). However, no association was observed between preterm delivery and asthma symptom control during the second and third trimesters (P ⫽ .48 and P ⫽ .32, respectively). In a subset of women who delivered very preterm infants, all had inadequate asthma symptom control early in pregnancy (data not shown). The incidence of preterm delivery was much higher (16.4%) among patients who experienced hospitalizations for asthma during pregnancy compared with only 7.6% among asthmatic patients who were not hospitalized for asthma during pregnancy (P ⫽ .02). The degree of asthma control at entry into the study or later in pregnancy was not a significant predictor of fetal growth. The incidence of infants born small for gestational age was similar among patients with inadequate asthma control anytime in pregnancy compared with patients with adequate asthma control (all P ⬎ .10; Table 4). The incidence of infants born small for gestational age also did not vary by asthma exacerbation measures in this study population (Table 4). Additionally, no difference in mean birth weight of fullterm infants by asthma symptom control or exacerbation measures was observed (data not shown). Preterm delivery remained significantly associated with asthma symptom control during the first part of pregnancy (odds ratio [OR], 1.93; 95% confidence interval [CI], 1.10 – 3.40) and hospitalizations for asthma (OR, 2.29; 95% CI, 1.06 – 4.94) after adjustment for maternal age, body mass index, gravidity, parity, SES, smoking, and ethnicity (Table 5). The risk of preterm delivery among patients with inadequate asthma control was independent from systemic steroid use (OR, 1.83; 95% CI, 1.04 –3.25). Even though an association between hospitalizations for asthma and preterm delivery became of borderline statistical significance (P ⫽ .08) after adjustment for systemic corticosteroid use, the magnitude of association did not change considerably (OR, 2.02; 95% CI, 0.92– 4.42). In addition, no interaction was detected

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Table 2. Maternal Characteristics by Asthma Symptom Control at the Time of Enrollment Women with adequate symptom control, (n ⴝ 396) No. (%)a

Maternal characteristics

Maternal age, y ⬍25 25–34 ⱖ35 BMI ⬍24 24–28 ⬎28 Gravidity ⬎1 Parity ⬎0 White non-Hispanic Any tobacco use in pregnancy Any alcohol use in pregnancy SES status above averageb Mean (SD) daily dose of inhaled corticosteroids, ␮gc

Women with poor to fair symptom control, (n ⴝ 308) No. (%)a

Overall P value

.02 29 (7.3) 240 (60.6) 127 (32.1)

42 (13.6) 179 (58.1) 87 (28.3)

208 (52.5) 94 (23.7) 94 (23.7) 223 (56.3) 153 (38.6) 360 (91.4) 38 (9.6) 187 (50.0) 304 (77.9) 399.3 (314)

141 (45.8) 81 (26.3) 86 (27.9) 215 (69.8) 169 (54.9) 267 (86.7) 38 (12.3) 132 (45.4) 190 (62.5) 481.1 (88)

.11

⬍.001 ⬍.001 .046 .24 .24 ⬍.001 .01

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); SES, socioeconomic status. Data are presented as number (percentage) of patients unless otherwise indicated. b Hollingshead 4-factor SES category 1 or 2 on a scale of 1 to 5, with 1 being the highest. c Expressed in beclomethasone equivalent dose. a

Table 3. Incidence of Preterm Delivery by Asthma Control and Exacerbation Measures Measures of asthma control and exacerbation Asthma control during first part of pregnancy Adequate Fair to poor Asthma control at 26 gestational weeks Adequate Fair to poor Asthma control at 32 gestational weeks Adequate Fair to poor Hospitalization(s) for asthma during pregnancy Yes No Unscheduled clinic visit(s) for asthma during pregnancy Yes No

Incidence of preterm delivery, No. (%)a

Table 4. Incidence of Small for Gestational Age (SGA) by Asthma Control and Exacerbation Measuresa

P value

Measures of asthma control and exacerbation

.02 Asthma control in first part of pregnancy Adequate Fair to poor Asthma control at 26 gestational weeks Adequate Fair to poor Asthma control at 32 gestational weeks Adequate Fair to poor Hospitalization(s) for asthma during pregnancy Yes No Unscheduled clinic visit(s) for asthma during pregnancy Yes No

25 (6.3) 35 (11.4) .48 34 (8.3) 15 (6.7) .32 35 (7.9) 11 (5.7) .02 10 (16.4) 50 (7.6) .56 11 (7.2) 49 (8.7)

a

Sample size varies from 635 to 719 because of pairwise deletion of missing data.

Incidence of SGA, No. (%)b

P value .85

23 (5.9) 17 (5.5) .73 21 (5.2) 13 (5.8) .41 28 (6.3) 9 (4.7)

4 (6.6) 37 (5.7)

.78 .63

10 (6.5) 31 (5.5)

a

Birth weight in 10th percentile or less for gestational age and sex. Sample size varies from 635 to 719 because of pairwise deletion of missing data. b

between hospitalizations for asthma and systemic corticosteroid use (P ⫽ .16) or between asthma symptom control and systemic corticosteroid use (P ⫽ .90) relative to preterm delivery.

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DISCUSSION In this study, poor maternal asthma symptom control early in pregnancy and a history of hospitalizations for asthma any-

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Table 5. Multivariate Analysis for Preterm Delivery. Asthma control measures Poor to fair vs adequate asthma symptom control in first part of pregnancy Unadjusted Model 1a Model 2b Any vs no hospitalization(s) for asthma during pregnancy Unadjusted Model 1a Model 2b

OR (95% CI)

Overall P value

1.90 (1.11–3.25) 1.93 (1.10–3.40) 1.83 (1.04–3.25)

.02 .02 .04

2.39 (1.14–4.98) 2.29 (1.06–4.94) 2.02 (0.92–4.42)

.02 .03 .08

Abbreviations: CI, confidence interval; OR, odds ratio. Adjusted for maternal age, body mass index, gravidity, parity, socioeconomic status, smoking in pregnancy, and ethnicity. b Adjusted for maternal age, body mass index, gravidity, parity, socioeconomic status, smoking in pregnancy, ethnicity, and use of systemic corticosteroids in pregnancy. a

time during pregnancy were each associated with a doubling of the risk of preterm delivery independent of other risk factors. Increased risk of preterm delivery might be attributed to hypoxia secondary to severe and uncontrolled asthma or to an effect of asthma therapy during pregnancy: 2 factors that are often difficult to disentangle. Systemic corticosteroids are a class of asthma medications that presents a particular concern for safety in pregnancy. They have been found to increase the risk of preterm delivery independent of other factors in 3 large cohort studies.5,6,8 In our study, inadequate maternal asthma symptom control remained significantly associated with preterm delivery after adjustment for use of systemic corticosteroids. The association between hospitalizations for asthma and preterm delivery became of borderline statistical significance after adjustment for systemic corticosteroids, possibly indicating a statistical power issue since the magnitude of association was not notably affected. Furthermore, no effect modification of systemic corticosteroids on the relationship between asthma control (as defined by hospitalization or symptom control) and preterm delivery was detected. Thus, the effect of maternal asthma on preterm delivery seems to be independent from the effect of systemic corticosteroids and other evaluated risk factors. Similar to our findings, the risk of preterm delivery among asthmatic patients in previous studies ranged from 1.15 to 2.2.23–27 However, most previous studies compared the risk in asthmatic women with nonasthmatic controls and could not evaluate any change in asthma severity or control during pregnancy.23–25,27 A few studies reported that an association between maternal asthma and preterm delivery was only limited to patients with severe asthma26 or was stronger in those patients,24 suggesting a dose-response trend. Interestingly, in our study asthma symptom control later in pregnancy (ie, at 26 and 32 gestational weeks) was not associated with preterm delivery. Although preterm labor is a

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complication that occurs late in pregnancy, it has been suggested to originate early in gestation because of defective implantation and placental development.28 We hypothesize that poor asthma control in early pregnancy could potentially negatively affect placentation, leading to the increased risk of preterm delivery even if the poor control of asthma does not persist into the later part of pregnancy. Similar to our results, in another prospective study preterm delivery was associated with severe asthma as classified during the first part of pregnancy at the time of enrollment.26 Poor control of asthma could be a result of inappropriate management, increased severity, reduced responsiveness to therapy, or poor adherence. To at least partially address the question about disease management, we compared the use of the most common controller therapy among these patients. Patients who had inadequate asthma symptom control, hospitalizations for asthma, or unscheduled clinic visits all used higher daily doses of ICSs. Higher doses of controller medications in patients with exacerbations and poor symptom control suggest decreased responsiveness to therapy or inadequate therapy in patients with more severe asthma. Dose of ICSs, which may be a marker for severity, was not an independent predictor of preterm delivery or growth restriction (data not shown). This suggests that asthma control is still more important than inherent severity in determining the risk of preterm birth in asthmatic women. Although poor asthma control was associated with preterm delivery in our study, no increased risk of fetal growth restriction was observed. Several factors could account for these results. First, measures of asthma control and exacerbation used in this study may not be adequately sensitive or specific to identify severe asthma or asthma that is sufficiently uncontrolled to substantially increase the risk of fetal growth restriction. In some earlier reports, lower pulmonary function but not increased asthma symptoms was associated with adverse perinatal outcomes.29 Nevertheless, repeated measures of asthma symptom control and multiple asthma exacerbation measures used in our study allowed evaluation of the effect of both the impairment and risk domains of maternal asthma control on preterm delivery and fetal growth. Second, factors that determine gestational length and preterm birth may be more sensitive to uncontrolled asthma than factors that influence fetal growth. The Bertrand hypothesis suggests that hyperactivity of bronchial and uterine smooth muscles might have common pathophysiologic mechanisms.30 Similar to our results, in the Maternal Fetal Medicine Unit study, lower pulmonary function affected prematurity but not IUGR.29 However, another large prospective study found asthma symptom severity to be predictive of IUGR but not of preterm delivery in multivariate analysis.6 In that study, average severity scores for the entire pregnancy were used in the analysis, whereas in our study asthma control at each trimester was evaluated relative to perinatal outcomes. Furthermore, although Bracken et al6 evaluated the risk of IUGR separately by symptom severity and medication use, an association between symptom severity and IUGR

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could be potentially influenced by use of asthma medications, particularly systemic corticosteroids, among patients with more severe asthma since no adjustment for medication use was done in that analysis. Finally, an association with mean or low birth weight reported in some previous studies could be confounded by the effect of asthma on the length of gestation. Without attention to gestational age, these measures inappropriately combine distinct outcomes with potentially different causes and clinical consequences.31 Several limitations of the study should be mentioned. The study design did not allow for collection of pulmonary function data. Potential selection bias could be introduced if women with a history of adverse outcomes in previous pregnancies or women who have better access to Internet resources (eg, women of higher socioeconomic class) were more likely to contact OTIS or to enroll in the study. However, an earlier study demonstrated that women who enroll in OTIS studies do not substantially differ from nonparticipants with respect to numerous pregnancy and lifestyle risk factors.32 Study design did not allow collecting information on prepregnancy asthma severity or control and prepregnancy medication use; thus, we could not examine whether poor asthma control during pregnancy is a result of intentional decrease of asthma therapy, poor compliance, or physiologic changes increasing asthma severity. Generalizability of results might be limited since most patients were of white/nonHispanic ethnicity with household SES above average. Most previous studies that reported an increased risk of preterm delivery in asthmatic women used nonasthmatic controls for comparison, making it difficult to conclude whether the observed effect is due to poor control of maternal asthma, other factors associated with asthma, or asthma therapy. In our large sample of asthmatic women, incidence of preterm delivery was compared among asthmatic patients with adequate and inadequate symptom control and patients with and without exacerbations in pregnancy. Information about asthma control level, use of asthma medications, and relevant covariates was ascertained before evaluation of perinatal outcomes, thus limiting recall and misclassification bias. Information collected through self-reports was validated by review of maternal and pediatric medical records. In summary, this is the first report, to our knowledge, that links hospitalizations for asthma during pregnancy with a significant risk of preterm delivery. Furthermore, this is the first study, to our knowledge, to separately evaluate the effect of maternal asthma control in each trimester of pregnancy relative to preterm delivery. Results demonstrate that the risk posed by poorly controlled asthma for preterm delivery is substantial and independent from use of systemic corticosteroids or other risk factors. In contrast, our study finds no evidence of an association between maternal asthma control and fetal growth restriction, suggesting that length of gestation might be more sensitive to poorly controlled maternal asthma than fetal growth. These findings provide additional evidence to health care professionals and patients regarding the importance of adequate treatment of asthma in pregnancy,

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particularly with respect to prematurity, and the need to optimize asthma control and prevent asthma exacerbations. Adequate asthma control during pregnancy can be achieved by avoidance of triggering factors, self-management education, and optimal pharmacotherapy.33 REFERENCES 1. Kwon HL, Belanger K, Bracken MB. Asthma prevalence among pregnant and childbearing-aged women in the United States: estimates from national health surveys. Ann Epidemiol. 2003;13:317–324. 2. Tan KS, Thomson NC. Asthma in pregnancy. Am J Med. 2000;109: 727–733. 3. Slattery MM, Morrison JJ. Preterm delivery. Lancet. 2002;360: 1489 –1497. 4. Levy-Marchal C, Jaquet D, Czernichow P. Long-term metabolic consequences of being born small for gestational age. Semin Neonatol. 2004; 9:67–74. 5. Schatz M, Dombrowski MP, Wise R et al. The relationship of asthma medication use to perinatal outcomes. J Allergy Clin Immunol. 2004; 113:1040 –1045. 6. Bracken MB, Triche EW, Belanger K, Saftlas A, Beckett WS, Leaderer BP. Asthma symptoms, severity, and drug therapy: a prospective study of effects on 2205 pregnancies. Obstet Gynecol. 2003;102:739 –752. 7. Perlow JH, Montgomery D, Morgan MA, Towers CV, Porto M. Severity of asthma and perinatal outcome. Am J Obstet Gynecol. 1992;167(4 pt 1):963–7. 8. Bakhireva LN, Jones KL, Schatz M, Johnson D, Chambers CD. Asthma medication use in pregnancy and fetal growth. J Allergy Clin Immunol. 2005;116:503–509. 9. Schatz M. The efficacy and safety of asthma medications during pregnancy. Semin Perinatol. 2001;25:145–152. 10. Cydulka RK, Emerman CL, Schreiber D, Molander KH, Woodruff PG, Camargo CA. Acute asthma among pregnant women presenting to the emergency department. Am J Respir Crit Care Med. 1999;160:887– 892. 11. Enriquez R, Wu P, Griffin MR, et al. Cessation of asthma medication in early pregnancy. Am J Obstet Gynecol. 2006;195:149 –153. 12. Kwon HL, Triche EW, Belanger K, Bracken MB. The epidemiology of asthma during pregnancy: prevalence, diagnosis, and symptoms. Immunol Allergy Clin North Am. 2006;26:29 – 62. 13. Scialli AR. The Organization of Teratology Information Services (OTIS) Registry Study. J Allergy Clin Immunol. 1999;103(2 pt 2):S373–S376. 14. Bakhireva LN, Jones KL, Schatz M, et al. Safety of leukotriene receptor antagonists in pregnancy. J Allergy Clin Immunol. 2007;119:618 – 625. 15. Hall JG. Twinning. Lancet. 2003;362:735–743. 16. Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, et al. CDC growth charts: United States. Adv Data. 2000;314:1–27. 17. Lubchenko L, Hansman C, Boyd E. Intrauterine growth in length and head circumference as estimated from live births at gestational ages from 26 to 42 weeks. Pediatrics. 1966;37:403. 18. Vollmer WM, Markson LE, O’Connor E, et al. Association of asthma control with health care utilization and quality of life. Am J Respir Crit Care Med. 1999;160(5 pt 1):1647–52. 19. Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14:902–907. 20. Nathan RA, Sorkness CA, Kosinski M, et al. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol. 2004;113:59 – 65. 21. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol. 2007;120(5 suppl):S94 –138. 22. Namazy J, Schatz M, Long L, et al. Use of inhaled steroids by pregnant asthmatic women does not reduce intrauterine growth. J Allergy Clin Immunol. 2004;113:427– 432. 23. Demissie K, Breckenridge MB, Rhoads GG. Infant and maternal outcomes in the pregnancies of asthmatic women. Am J Respir Crit Care Med. 1998;158:1091–1095.

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Requests for reprints should be addressed to: Ludmila Bakhireva, MD, PhD, MPH College of Pharmacy and Department of Family/Community Medicine University of New Mexico MSC09 5360 1 University of New Mexico Albuquerque, NM 87131-0001 E-mail: [email protected]

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