INTRODUCTION

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Asthma complicates up to 4% of all pregnancies (1). The natural history of asthma is extremely variable among pregnant women: symptom severity may improve, worsen, or remain unchanged in approximately equal proportions as compared with the pregravid state (1). Some studies suggest that 11 to 18% of pregnant asthmatics have at least one emergency department (ED) visit for acute asthma (4), and that as many as 62% of pregnant women with acute asthma require hospitalization (5).

In 1993, the National Asthma Education and Prevention Program (NAEPP) expert panel developed guidelines for the treatment of asthma during pregnancy (6). The principles for managing acute asthma during pregnancy are literature-based and similar to those for management in the nonpregnant state. The guidelines include repetitive lung function measurements, maintenance of oxygen saturation above 95%, fetal monitoring, therapy with repeat doses of inhaled -agonists, and the early administration of systemic corticosteroids (2, 3, 5, 7). Rapid therapeutic intervention at the time of an exacerbation is imperative to prevent impaired maternal and fetal oxygenation. Uncontrolled asthma is associated with many maternal and fetal complications including hyperemesis, hypertension, toxemia, vaginal hemorrhage, complicated labor, intrauterine growth retardation, preterm birth, increased perinatal mortality, and neonatal hypoxemia (9, 14). If asthma is well controlled during pregnancy, however, there is little or no increased risk of adverse outcome (4, 19).

The purpose of the present study was to compare the clinical presentation, treatment, and 2-wk outcome of acute asthma among pregnant versus nonpregnant women. We sought to assess the adequacy of asthma therapy compared with published national guidelines.

	METHODS

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Design and Subject Selection

This study combines data from two prospective cohort studies performed during October through December 1996 and April through June 1997, respectively, as part of the Multicenter Asthma Research Collaboration. Using a standardized protocol, investigators at 36 EDs in 18 states provided 24-h per day coverage for a median of 2 wk and enrolled 1,281 patients with acute asthma. All patients were managed at the discretion of the treating physician. The institutional review board at each of the 36 participating hospitals approved the study. Inclusion criteria were physician diagnosis of acute asthma, age 18 to 54, and the ability to give informed consent. Repeat visits by individual subjects were excluded. For the present analysis, men (n = 438) and women age 40 to 54 (n = 292) were excluded. This left 551 women, age 18 to 39, for analysis.

Data Collection

The ED interview assessed patients' demographic characteristics, asthma history (including medication use), and details of their current asthma exacerbation. Data on ED management and disposition were obtained by chart review. Follow-up data were collected by telephone interview 2 wk later and included details of any urgent asthma visits, changes in medical management, and current asthma symptoms. All forms were reviewed by site investigators before submission to the Data Coordinating Center in Boston, where they underwent further review and double data entry by trained personnel.

Primary care provider (PCP) status was determined on the basis of the following interview question: "Do you have a primary care provider (such as a family doctor, internist, or nurse practitioner)?"; if yes, patients were asked to provide the name and address of their PCP. Peak expiratory flow rate (PEFR) is expressed as percentage of patient's predicted value, based on age, gender, and height. Changes in PEFR are expressed as the absolute change in the percentage of predicted values (e.g., an improvement from 40% predicted to 70% predicted would be expressed as a 30% change). Relapse was defined as any urgent visit to an ED, clinic, or physician office for worsening of asthma during the 2-wk follow-up period. Post-ED treatment failure (i.e., an ongoing asthma exacerbation) was assigned to patients who reported "severe symptoms" during the preceding 24 h on any one of three interview questions obtained at the 2-wk telephone follow-up (i.e., asthma symptoms "most of the time" or "severe" discomfort/distress due to their asthma or "severe" activity limitations due to their asthma). Post-ED treatment failure was also assigned to patients who stated that their asthma was "about the same" or "worse" than at the time of their ED presentation. The "severe symptoms" classification also was used to characterize symptom severity during the 24 h before ED presentation.

Statistical Analysis

All analyses were performed using Stata 5.0 (StataCorp, College Station, TX). Data are presented as proportions, means (with standard deviation [SD]), or medians (with interquartile range [IQR]). The association between pregnancy and other factors was examined using chi-squared test, Student's t test, and Wilcoxon rank sum test, as appropriate. Variables associated with failure at a p value < 0.1 were evaluated for inclusion in multivariate logistic regression models. All odds ratios (OR) are presented with 95% confidence intervals (CI). All p values are two-sided, with p < 0.05 considered statistically significant.

	RESULTS

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The study group was comprised of 51 pregnant women (9%) and 500 nonpregnant women (91%). Demographic and chronic asthma characteristics are noted in Table 1. Pregnant women were slightly younger than nonpregnant women and less likely to have a primary care provider. Otherwise, the groups were similar in terms of race/ethnicity and a variety of factors related to chronic asthma.

Acute asthma presentation, according to pregnancy status, is shown in Table 2. The duration of patients' asthma exacerbations was approximately 0.75 d for both pregnant and nonpregnant women (p = 0.57). Moreover, both subjective and objective markers of acute asthma severity did not differ between the two groups. Use of NAEPP criteria (20) also did not show a statistically significant difference in acute asthma severity by pregnancy status; a similar proportion of pregnant versus nonpregnant women presented with mild flares (initial PEFR  80%: 12% versus 11%, respectively), moderate flares (initial PEFR 50 to 79%: 28% versus 43%), and severe flares (initial PEFR < 50%: 60% versus 46%; overall p = 0.14).

Pregnant and nonpregnant women received comparable numbers of aerosolized -agonist treatments in the first hour as might be expected from a similar severity of acute asthma yet pregnant women were significantly less likely to be given systemic corticosteroids in the ED (44% versus 66%, p = 0.002). The relatively small number of pregnant women precludes detailed analysis, but it appears that the decrease was not due to a selective practice during the first trimester of pregnancy: 53% received corticosteroids in first trimester, 40% in the second, 50% in the third, and 66% in the not pregnant group (p = 0.03). Pregnant women exhibited a trend toward a lower final percentage of predicted PEFR (71% versus 78% predicted, p = 0.06). Although this was not statistically significant, this may contribute to the differences in risk of ongoing exacerbation that pregnant women reported. Risk of admission did not differ by pregnancy status, nor did ED length of stay. Among those admitted, pregnant women had lower final PEFR in the ED (44% versus 57% predicted, p = 0.04), and they stayed longer in the hospital (median: 3 versus 2 d, p = 0.04). Among discharged patients, the final PEFR did not differ (80% versus 83%, p = 0.38) but, once again, pregnant women were significantly less likely to be prescribed systemic corticosteroids (Table 2).

Table 2 also shows outcomes during the 2 wk after discharge from the ED. Statistical power was limited (n = 59 relapse events), but it did not appear that risk of relapse differed by pregnancy status. By contrast, pregnant women may have been more likely to report an ongoing exacerbation (p = 0.09). To further examine the association between pregnancy status and risk of ongoing asthma exacerbation (n = 93 failure events), a multivariate logistic regression was performed (Table 3). The final model, which controlled for 10 potential confounders, indicated that pregnant women were almost three times as likely as nonpregnant women to report an ongoing asthma exacerbation. Further controlling for ED treatment with systemic corticosteroids (during ED visit or prescribed at discharge) slightly attenuated pregnant women's excess risk, but the OR remained high (OR = 2.5; 95% CI, 1.0 to 6.0). When the multivariate models were repeated among only women sent home from the ED, the results were very similar: Model 4 yielded an OR of 3.3 (95% CI, 1.2 to 8.7) for pregnant women, and this excess risk was only slightly attenuated by adding a term for ED treatment with systemic corticosteroids (OR = 2.7; 95% CI, 1.0 to 7.4).

	DISCUSSION

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In this prospective multicenter study of acute asthma, we found that pregnant and nonpregnant women have the same clinical presentation to the ED. However, pregnant women are undertreated with systemic corticosteroids compared with their nonpregnant peers both while in the ED and at discharge to home. Moreover, pregnant women are three times as likely as nonpregnant women to report an ongoing asthma exacerbation at 2-wk follow-up.

Treatment differences according to pregnancy status may be based on concerns about harmful effects of medication on the fetus (16) rather than lack of familiarity with the NAEPP recommendations. No currently approved asthma medications carry a Federal Drug Administration label of category A, which stipulates "adequate and well controlled studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy and there is no evidence of risk in later trimester." This uncertainty reflects the sparsity of data on the effects of asthma medications during pregnancy. Nevertheless, available studies give little cause for concern (5, 7, 12, 14, 21, 22). Thus, in the absence of definitive data, most experts agree that the maternal and fetal risks of uncontrolled asthma are much greater than risks from using typical asthma medications for management of acute asthma (6).

Myriad physiological changes affect respiration during pregnancy and merit a brief review. In the first trimester, minute ventilation increases while the respiratory rate remains unchanged. Arterial blood gas measurements reflect a compensated respiratory alkalosis, with pH in the range of 7.40 to 7.47, PO₂ as high as 106 mm Hg, and PCO₂ varying from 25 to 32 mm Hg (11). Hypocapnia is more consistent than alkalosis owing to renal compensation. Clinicians must be cautioned to remember that a PO₂ < 70 in a pregnant woman with acute asthma represents severe hypoxemia, and a PCO₂ > 35 represents acute respiratory failure (8). Thus, the normal alkalosis of pregnancy can be aggravated by acute asthma and lead to significant decreases in placental blood flow; furthermore, hypoxemia, if present, is usually more severe in the fetus than in the mother. Hyperventilation results from increases in circulating progesterone levels, which peak in the third trimester at levels 50 to 100 times baseline values and then fall abruptly before parturition. Changes in airway responsiveness during pregnancy do not appear related to changes in progesterone or estriol, suggesting that nonhormonal factors contribute to the control of airway smooth muscle and airway responsiveness during pregnancy (22, 23). Whereas the tidal volume is increased, there is a decrease in functional residual capacity, residual volume, expiratory reserve volume, and total lung capacity when near term (1, 24). There is some controversy regarding the effect of pregnancy on tests of airway obstruction, such as PEFR (25), but most authorities believe that airways remain essentially unchanged throughout pregnancy (8). Thus, changes in PEFR in a pregnant asthmatic complaining of exacerbation are likely caused by asthma and not by a physiological change of pregnancy.

As previously noted, the benefits of any medications used during pregnancy must be balanced against their risks to the fetus. Little debate exists over the safety of -agonist use during pregnancy. Schatz and colleagues (26) demonstrated the safety of inhaled -agonist bronchodilators in a prospective study of 259 pregnant asthmatics who were using -agonists compared with 101 pregnant asthmatics not using bronchodilators and with 295 pregnant control subjects. No differences in perinatal mortality, congenital malformations, preterm births, mean birthweight, Apgar scores, labor/delivery complications, or postpartum bleeding were noted between the groups. An increased incidence of maternal chronic and pregnancy-induced hypertension, as well as transient tachypnea of the newborn, was observed in asthmatics regularly using inhaled bronchodilators, although a logistic regression analysis did not significantly associate these outcomes with the use of inhaled bronchodilators (26). Comparing a cohort of 824 pregnant asthmatics and 678 pregnant women without asthma, Schatz and colleagues also reported that the use of theophylline, cromolyn, antihistamines, and decongestants was not associated with perinatal risks (27).

Inhaled corticosteroids also are considered safe during pregnancy and are currently recommended as part of the routine management of moderate-to-severe chronic asthma during pregnancy (6). Among pregnant women, several investigators have shown that inhaled corticosteroids reduce the overall number of asthma exacerbations (13), as well as the number of serious attacks (5). Greenberger and Patterson demonstrated the safety of inhaled beclomethasone dipropionate for the treatment of severe asthma during pregnancy for 45 pregnancies in 40 pregnant women (12). Although our study did not address issues of outpatient efficacy or medication safety, we do note with some concern, that only 40 to 45% of our patients were on inhaled corticosteroids at the time of ED presentation despite the evident severity of their disease (Table 1).

The clearest difference between pregnant and nonpregnant women with acute asthma involved treatment with systemic corticosteroids. The reluctance of emergency physicians to use corticosteroids is particularly disconcerting, as corticosteroids are strongly recommended for the treatment of acute asthma (28, 29). Furthermore, compelling evidence exists that maternal and fetal outcomes are directly related to the quality of asthma control during pregnancy (15). In a study of 352 pregnant asthmatic women, Schatz and colleagues reported that lower maternal FEV₁ during pregnancy was related to intrauterine growth retardation (15). Jana and Fitzsimons also noted that the mean birthweight in infants of steroid-dependent mothers requiring hospitalization for asthma during pregnancy was significantly lower than the mean birthweight of infants whose steroid-dependent mothers did not require emergency treatment for gestational asthma (14, 18).

Chronic oral or high-dose steroid use during pregnancy does carry some risk. Perlow and coworkers reported an increased incidence of diabetes mellitus, preterm labor, premature rupture of membranes, preterm delivery, and low-birthweight infants in 31 steroid-dependent pregnant asthmatics (9). Schatz noted an association with preeclampsia (27), while Alexander and coworkers described an increased incidence of pregnancy-induced hypertension in pregnant asthmatic women taking corticosteroids in comparison to nonsteroid-treated asthmatics (30). Cleft lip occurs in rats, mice, and rabbits exposed to high doses of corticosteroid in utero, and has recently been associated with first-trimester use of oral corticosteroids (31). Of note, Reinisch and coworkers reported a decrease in birth weight among 119 women treated throughout pregnancy with 10 mg/d of prednisone but not in 152 women treated only during the first trimester (32). Lee and Smith documented that discontinuation of prednisone after the first trimester was not associated with this effect (33, 34). Unfortunately, the data are not clear-cut regarding the safety of short-term use of corticosteroids, especially in regard to cleft lip, hypertension, and eclampsia.

The majority of women in our studyboth pregnant and nonpregnantresponded well to treatment in the ED. This is contrary to the findings of Wendel and colleagues, who reported that 62% of exacerbations experienced by pregnant women necessitated hospitalization and that one-third required readmission for subsequent exacerbations (5). Possible explanations for these divergent results include different patient populations, as well as differences in the assessment and treatment of acute asthma between obstetricians and emergency physicians. There also may be differences in the severity of asthma exacerbation between patients who seek asthma care in the ED and those who seek asthma care from their obstetricians. However, we did find that pregnant women were more likely than their nonpregnant counterparts to report an ongoing exacerbation at the 2-wk follow-up. Although lack of corticosteroid treatment in the ED contributed to this outcome, the finding was not due to this difference alone. These results suggest that we might pay greater attention in the post-ED period to quality-of-life issues, as opposed to more traditional endpoints such as "relapse."

The present study has several potential limitations. First, our statistical power is limited by the relatively small number of pregnant women presenting to the ED for acute asthma (n = 51). This may reflect a policy at some medical centers to triage all pregnant patients to "labor and delivery" for any type of medical emergency. Second, our patients were enrolled only from urban, academic EDs and they may not be representative of the community at large. However, because emergency physicians in academic centers are more likely to have been exposed to the NAEPP guidelines than emergency physicians elsewhere (35), this situation more likely led to an underestimation of our primary finding (the failure to use systemic steroids) rather than an overestimation. Third, PEFR measurement was not standardized across sites. There is, however, no reason to believe that there are pregnancy-related differences in the accuracy of PEFR measurement. Lastly, we are unable to confirm self-reports of ongoing asthma exacerbation (e.g., by comparing the patient's outpatient PEFR with that at time of ED discharge). This shortcoming does not allow us to comment on the biology of patients' disease, but quality-of-life issues, such as "severe" discomfort and "severe" activity limitations, are surely worthy of concern.

In conclusion, pregnancy should be an indication for maximizing therapy during an asthma exacerbation, rather than withholding therapy, because neonatal outcomes are clearly superior when maternal symptoms are controlled, and oxygenation and pulmonary function are optimized. Potential harm to the fetus is more likely to result from severe uncontrolled asthma rather than from the medications used to treat it. Pregnant women also are more likely than nonpregnant women to experience an ongoing asthma exacerbation at 2-wk after their ED visit. Emergency physicians and other specialists must work together to ensure optimal care of the pregnant asthmatic.