Asthma is one of the most common complications of pregnancy,1 occurring in some 3.7–8.4% of pregnancies.2 Whether asthma, or the medications used to treat it, influence fetal and infant health has become a research question of increasing and urgent interest. Initial observations made from the Norwegian Birth Registry in 1972 suggested increased risks from bronchial asthma of preterm birth, low birth weight, preeclampsia, and neonatal death.3 Subsequently, Bertrand et al4 proposed that the hyperreactivity of smooth muscle characteristic of asthma might lead to both bronchial and uterine complications. Some evidence suggests that the more common sequelae in pregnancies complicated by asthma or asthma medication include preterm labor,5–9 preterm delivery,5,7,9–11 small for gestational age,7,11,12 low birth weight,9,11–16 preeclampsia,7,8,11 congenital malformations,11,17,18 and fetal or neonatal death.8,15 Neonates born to asthmatic mothers have also been found to be more likely to have transient tachypnea.19
It is of particular clinical importance to determine whether pregnancies that are complicated by asthma or asthma symptoms and actively managed with currently available pharmacologic therapies are at reduced risk owing to better management of the underlying disease, or whether risk is increased owing to the therapies themselves. Limited preliminary evidence suggests that risks might be reduced,20–22 but more data are needed.
In this article, we describe the results of a large, prospective study of pregnant asthmatic women, which was specifically designed to examine whether asthma, asthma symptoms, or asthma therapy influence pregnancy outcomes (specifically, preterm delivery, intrauterine growth restriction [IUGR], gestational age, or birth weight) while controlling for other known risk factors.
MATERIALS AND METHODS
Pregnant women were recruited from 56 obstetric practices and 15 clinics associated with six hospitals in Connecticut and Massachusetts. Exclusion criteria included being more than 24 weeks pregnant at interview, having insulin-dependent diabetes mellitus, not speaking English or Spanish, and intending to terminate the pregnancy.
Between April 1997 and June 2000, 11,484 women were screened for eligibility; all women with a history of physician-diagnosed asthma (n = 1343) and a simple random sample (approximately 1.5 nonasthmatics for every asthmatic subject, by geographic region and who were not selected for another study) of nonasthmatic women (n = 2070) were invited to participate. Of these, 2379 (69.7%) enrolled, 531 (15.6%) refused, 389 (11.4%) were not eligible at time of home interview (usually because they were more than 24 weeks pregnant), 73 (2.1%) miscarried before interview, and 41 (1.2%) did not participate for other reasons. After enrollment, 174 women were excluded from analysis due to stillborn fetus, molar pregnancy, planned or spontaneous abortion (n = 69), multiple birth (n = 43), and loss to follow-up or withdrawal (n = 60). Inadequate asthma status information (n = 2). These outcomes were not studied further because of the small numbers. This analysis is of the 2205 singleton births. A detailed description of how women entered the study is shown in Figure 1.
All women were interviewed at home before 24 weeks' gestation. The baseline interview collected information on respiratory symptoms and medication use; hospitalizations and emergency visits; and maternal characteristics, including age, weight, height, marital status, education, race or ethnicity, pregnancy history, cigarette smoking, and alcohol and caffeine consumption up to the time of the interview. Women who reported a history of physician-diagnosed asthma (n = 941) and a simple random sample of approximately 10% of nonasthmatics (n = 195) were reinterviewed by telephone at 20, 28, and 36 weeks' gestation to prospectively collect information on respiratory symptoms, medication use, hospitalizations, and emergency room visits. A postpartum interview, usually conducted in the hospital shortly after the birth of the baby, collected information on asthma symptoms, medication use, and changes in risk factors during the latter part of pregnancy. For those who were reinterviewed during pregnancy, the postpartum interview covered events during the last 3 months of pregnancy, whereas those who were not reinterviewed during pregnancy were asked about their pregnancy experience since the home interview. A small number of women (n = 32) could not be interviewed after pregnancy, and their entire pregnancy history was estimated from the first months of pregnancy.
A respondent was considered asthmatic if she reported ever being diagnosed with asthma by a doctor. A woman was classified as having had asthma symptoms during pregnancy if she reported chest tightness, persistent cough (“where you feel like you can't stop coughing for long periods of time”), or wheeze (“wheezing or whistling sounds when you breathe”) at least once during her pregnancy.
Among women who had asthma symptoms or used asthma medication at least once during pregnancy, we further classified them by symptom severity and medication use according to the 2002 Global Initiative for Asthma guidelines23 as being intermittent, mild persistent, moderate persistent, or severe persistent. Relatively minor modifications to the Global Initiative for Asthma guidelines were made because of differences in the way the data were collected in the current study (refer to Global Initiative for Asthma guidelines for comparison). The modified 2002 Global Initiative for Asthma guidelines we followed are described below for symptoms, treatment, and severity.
Symptom steps were defined as follows:
Step 1. Intermittent. Symptoms 1–7 days per month, or nocturnal symptoms fewer than 2 nights per month.
Step 2. Mild persistent. Symptoms more than 7 days but less than every day per month, or nocturnal symptoms 2–7 nights per month.
Step 3. Moderate persistent. Symptoms daily, and nocturnal symptoms fewer than 14 nights per month.
Step 4. Severe persistent. Symptoms daily, frequent exacerbations, and frequent nocturnal asthma symptoms, at least 14 nights per month.
Symptom steps 3 and 4 were combined to reflect all daily symptom reports because frequency of night symptoms was unavailable.
Treatment steps were defined as follows:
Step 1. Intermittent. No daily controller medications used. Short-acting inhaled bronchodilators used as needed to relieve symptoms.
Step 2. Mild persistent. One controller medication—inhaled glucocorticosteroid, or sustained-release theophylline, or cromone, or leukotriene modifier.
Step 3. Moderate persistent. Two controller medications—inhaled glucocorticosteroid plus long acting inhaled β2 agonist, or theophylline or leukotriene.
Step 4. Severe persistent. Three or more controller medications—inhaled glucocorticosteroid plus long-acting inhaled β2 agonist plus one or more of theophylline, leukotriene, or oral glucocorticosteroid.
Each asthma medication used by the women in this study was categorized according to drug class. Eight types of medications were coded: systemic steroids, inhaled steroids, short-acting β2 agonists, long-acting β2 agonists, anticholinergics, leukotriene inhibitors, chromones, and xanthine derivatives (eg, theophylline). Doses per month of each class were calculated by multiplying frequency of use by doses per day for each month of pregnancy.
Overall asthma severity was determined for each subject, regardless of a doctor's diagnosis of asthma, by cross-classifying them (with a grid provided in the 2002 Global Initiative for Asthma methodology23) on their symptom and medication steps, described above, to derive four severity categories: intermittent, mild persistent, moderate persistent, and severe persistent asthma. We averaged monthly severity scores over the number of months of pregnancy and rounded to the next highest integer to obtain an average severity grade for the entire pregnancy for preterm delivery, and over the third trimester for IUGR.
Symptoms and medication reports from the third trimester were used as the primary analysis for fetal growth restriction because this is the period most likely to influence that outcome. Because of concerns about censored data among women who delivered before term, we obtained measures of asthma severity by averaging over the woman's pregnancy when analyzing the preterm delivery outcome. For other analyses (not reported), we created alternative severity measures: for each trimester, for the entire pregnancy, or for the most severe symptomatic month, but none of these measures changed the results reported here.
Hospital charts related to the index pregnancy were abstracted to identify pregnancy outcomes. Gestational age was calculated as completed days from first day of last menstrual period (LMP) or the doctor's estimated date of delivery if LMP was uncertain. We gave preference to first or second trimester sonography estimates that confirmed gestational age in 61.2% of women. Preterm delivery was defined as delivery before 37 weeks' gestation.
Fetal growth restriction was defined as below the tenth percentile of birth weight for gestational age, according to an external standard of birth weight for gestational age developed by us from all 1999 singleton births in the United States.24 Covariates for race and ethnicity were entered into the analysis.
The primary analysis focused on the categorization of asthma diagnosis, the Global Initiative for Asthma measures of severity, and the components of severity (symptoms and medication use during pregnancy), to identify their independent effects on the perinatal outcomes. Each category of symptoms, medication, or severity was compared with the reference category of no symptoms or medication use during pregnancy. Adjusted odds ratios (ORs) for the associations between asthma status and dichotomous outcomes, preterm delivery, and IUGR were calculated from multiple logistic regression models with PC-SAS 8.02 (SAS Institute, Cary, NC). All final adjusted logistic regression models included the exposures of interest and race, education, gravidity, parity, maternal age, prepregnancy weight, marital status, third trimester cigarette smoking, and prenatal vitamin use. Models replacing third with first trimester cigarette use were run and gave essentially identical results. Additional, multivariate linear regression analyses were conducted on birth weight and gestational age as continuous variables. We also conducted analyses of the influence of asthma symptoms on pregnancy outcome stratified by diagnosis of asthma or not (Figure 2).
The human investigation committee at each participating hospital approved the study protocol.
The distribution of study population characteristics by asthma status is shown in Table 1. In all, 39.6% of the women had been diagnosed as having asthma, by design, a higher rate than expected in the general pregnant population. The largest proportion of women had no asthma symptoms or treatment during their pregnancy (44.4%), one third (32.2%) had intermittent asthma, and almost a quarter of women (23.4%) were in higher-severity groups. Having an asthma diagnosis and having more severe asthma symptoms and treatment during pregnancy seems related to younger age, not being currently married, Hispanic and black ethnicity, being less well educated, a prepregnancy weight of 160 lb or more, smoking any amount during pregnancy, and consuming 150 mg or more of caffeine daily in pregnancy.
Table 2 displays the frequency of asthma severity as cross-classified by current symptoms and treatment according to the 2002 Global Initiative for Asthma guidelines23 for women diagnosed with asthma. Almost half of study respondents (382 of 778, 49.1%) were in the intermittent (mildest) degree of severity, with 24.6% mild persistent, 15.2% moderate persistent, and 11.2% severe persistent.
Table 3 examines the association between population characteristics and preterm delivery (6.9 % of pregnancies) and IUGR (7.6%). A larger proportion of younger mothers and those currently unmarried, Hispanic, less well educated, shorter, smoking (particularly in the third trimester), and consuming 300 mg or more caffeine daily had preterm delivery and IUGR. In addition, IUGR was more common in black women, cigarette smokers, and women with fewer prior pregnancies.
Crude associations with preterm delivery are shown in Table 4. Preterm delivery was more common in women with a history of physician-diagnosed asthma (OR= 1.49, 95% confidence interval [CI] 1.07, 2.08), with a somewhat smaller effect among women with an asthma diagnosis and symptoms in the prior 2 years. When assessed by overall Global Initiative for Asthma severity, all levels of severity showed an approximately 50% increased risk of preterm delivery, but with no increase in risk evident by increasing severity. Women with a symptom step of 1 or 2 across pregnancy had elevated rates of preterm delivery, but those in the highest step did not. In contrast, women in treatment steps 3 and 4 had three-fold increases in risk for preterm delivery (OR = 3.15, 95% CI 1.17, 8.45; OR = 3.62, 95% CI 0.76, 17.27, respectively).
When specific medication use was considered, preterm delivery was associated with increased risks of chromone, theophylline, and oral steroid use (OR = 3.06, 95% CI 1.02, 9.14; OR= 5.02, 95% CI 1.58, 15.96; OR = 3.37, 95% CI 1.66, 6.86, respectively).
Crude associations with IUGR are also shown in Table 4. A somewhat different pattern of risk was observed for IUGR, with smaller increased risk seen for any or recent diagnosis of asthma. Steps 2 and 3 of severity showed elevated risks of IUGR (OR = 1.74, 95% CI 1.10, 2.77; OR = 1.98, 95% CI 1.16, 3.39, respectively), as did the two highest symptom steps (OR = 1.72, 95% CI 1.09, 2.73; OR = 1.92, 95% CI 1.18, 3.13, respectively).
No association was seen for IUGR and general or specific medication use.
Table 5 shows adjusted associations with preterm delivery. Preterm delivery was no longer significantly associated with a diagnosis of asthma, severity, or symptoms in the multivariate models. With each increasing treatment step, there was an increase in preterm delivery. For patients with two or three controller medications, the likelihood increased by 3.67 (95% CI 1.11, 12.16) and 4.57 (95% CI 0.75, 24.63), respectively, with an overall increased risk of preterm delivery of 32% (95% CI 0%, 76%) for every increase in treatment step. When medication type was examined in more detail, theophylline and oral steroid use increased risk (by 5% [95% CI 1%, 9%] and 11% [95% CI 3%, 18%], respectively) for every increase in dose per month. We analyzed the absolute decrease in gestational age attributable to specific medication use, adjusting for asthma severity and other confounding factors (data not shown). The reduction in gestation was 2.22 weeks in a woman using oral steroids daily across pregnancy (P = .001). The interquartile range for oral steroid use was one and 11 times per month over pregnancy, with a median of four times. The median use resulted in 2.1 days reduction in overall pregnancy. The estimate for reduced gestation owing to theophylline was 1.11 weeks (P = .002) for once-daily use across pregnancy.
Adjusted associations with IUGR are also shown in Table 5. Fetal growth restriction was associated with moderate persistent severity (OR = 2.01, 95% CI 1.11, 3.65), and although this risk declined in the highest severity group, the overall linear trend was significant (20% [95% CI 4%, 38%] increase for each step in severity). Similarly, for women with daily symptoms, the risk of IUGR increased (OR = 2.25, 95% CI 1.25, 4.06), and a linear trend suggested increased risk (24% [95% CI 5%, 47%) for each symptom step). No increased risk of IUGR was seen by treatment step or for any specific medication type. No effect on mean birth weight was observed from any of the exposure classifications.
We repeated the analyses in Table 5, excluding non-asthmatic women who had symptoms or medication use during pregnancy, to examine whether the associations observed for reported symptoms or medication use were influenced by whether the patient also had a diagnosis of asthma. Among patients with an asthma diagnosis and symptoms (n = 778), compared with women without asthma symptoms or medication use (n = 978, Figure 2), the medication and symptom associations observed for preterm delivery and IUGR delivery remained essentially unchanged. For one controller medication the risk was OR = 4.04 (95% CI 1.26, 12.89), for three or more controller medications OR = 3.57 (95% CI 0.57, 22.56), with OR = 1.42 (95% CI 1.04, 1.93) for the linear trend. Theophylline use (OR = 1.05, 95% CI 1.01, 1.09) and oral steroid use (OR = 1.12 95%, CI 1.04, 1.20) remained essentially unchanged and statistically significant. In contrast, the associations between severity and symptoms with IUGR seen in the overall group of women were no longer statistically significant in this subset.
For those women with asthma symptoms or treatment but no diagnosis of asthma (n = 449), compared with women without asthma diagnosis or symptoms or treatment (n = 884, Figure 2), there was no association between preterm delivery and severity or symptoms. The effects of treatment and medication type could not be estimated in these women because only 32 women with asthma symptoms but no diagnosis were observed to have received any asthma medications (30 of whom received only bronchodilators). As seen in the entire group of women, the associations for IUGR were increased among these non–asthma-diagnosed women. Global Initiative for Asthma severity step 3 was associated with a three-fold increase in IUGR (OR = 3.44, 95% CI 1.29, 9.17) and step 4 with a smaller increased risk (OR = 1.53, 95% CI 0.31, 7.46). The linear trend for severity was 30% (95% CI 4%, 62%) increased risk of IUGR for each increase in severity step. When the symptom and medication use components of the severity scale are examined independently, symptom step 2 and symptom step 3 increased IUGR risk in a linear fashion (OR = 1.82, 95% CI 0.82, 4.08 and OR = 2.83, 95% CI 1.21, 6.62, respectively; linear trend OR = 31%, 95% CI 4%, 65%). The effect of treatment step could not be analyzed because the models did not converge owing to the small numbers of nonasthmatic women who took medication.
This study examines the independent associations of asthma diagnosis, severity, symptoms, treatment, and medication type with two different perinatal outcomes (preterm delivery and fetal growth assessed by IUGR). We found a modest increased risk of preterm delivery in women with an asthma diagnosis, but this was not distinguishable from chance when other risk factors were considered. No evidence of a relationship between preterm delivery and asthma symptoms or severity was observed. Interestingly, we did observe increased likelihood of preterm delivery with greater medication use, which appeared to be restricted to theophylline and oral steroids.
In contrast, increasing asthma severity and symptoms appeared to significantly decrease fetal growth, particularly when they occurred in the absence of an asthma diagnosis. A possible causal effect on these outcomes due to a hypoxic effect from chronic reduced pulmonary function in the asthmatic pregnant mother has been suggested.25,26 A limitation of the study is that we could not delineate preterm labor due to spontaneous preterm rupture of membranes and onset of spontaneous preterm labor from induced or iatrogenic preterm labor. The medical records did not permit a clear classification of these entities. We also did not study alternative causes of fetal growth restriction, though we did control for potential confounding from other risk factors in multivariate models. We found little support for the Bertrand hypothesis, which proposes that hyperreactivity of smooth muscle might lead to both bronchial and uterine complications.4 If it can be validly assessed, onset of preterm labor would offer a superior way to examine the Bertrand hypothesis, because it should be less influenced by treatment modalities or the need to consider risk factors for early labor leading to delivery than is needed when studying preterm delivery itself.
Asthma has been reported to be associated with increased preterm labor and delivery in several studies3,5,8–10,13,15,16,19 and with low birth weight in others.3,9,13,15,16,19 Only a very few studies have considered the effect of asthma medication or, if examined, which specific medications were used. It is difficult to disentangle the influence of asthma from the effect of medications in many studies of treated women. Greenberger and Patterson16 reported that avoiding acute asthma attacks by use of steroids and theophylline resulted in low birth weight rates equal to the normal population. Lao and Huengsburg13 reported a low birth weight rate of 5.6% in asthmatic women treated with β2 agonists and 18.2% in untreated women, but this was based on a total of only 87 women. Schatz et al12 reported that inhaled or oral steroid therapy had no effect on birth weight. In a later article, Schatz et al21 found that actively managed patients (which included the use of oral prednisone for the most severe cases) had no increased risk of IUGR, low birth weight, or preterm delivery, though uncertainty as to the effect of severe asthma remained because of small study numbers. Stenius et al27 reported no increased risk of preterm delivery in patients managed with β2 agonists and theophylline for acute episodes. No inhaled or systemic steroids were used. Several earlier studies indicate a reduction in perinatal complications when asthma is well controlled.21,27 Recently, Olesen et al20 reported that Danish women who received prescription drugs for asthma during pregnancy had newborns with birth weight and birth length within expected ranges, but both outcomes worsened when the “intensity” of asthma therapy was reduced.
The study by Perlow et al9 is one of the few others to consider asthma severity.9 Severe asthmatics treated with systemic steroids all had higher rates of preterm labor, preterm delivery, and low birth weight infants than nonsteroid-treated severe asthma patients, which is in accord with our study. In addition to having different definitions of severity from ours, Perlow et al's study did not control for other risk factors, did not model the independent effect of each drug regimen while controlling for the other, and did not report whether the steroid exposures, which appeared to result in poor outcomes, were associated with inadequate asthma management rather than the therapy itself. Other studies have found that prednisone therapy to support pregnancy in women with an infertility history decreased birth weight.28
The observation that preterm delivery might be associated with oral steroid use rather than an with underlying risk of asthma is of particular interest. It remains possible that this result is due to residual confounding from misclassification of extreme asthma severity. However, there is also emerging evidence that administration of multiple courses of the steroid betamethasone to women at risk of preterm delivery, to stimulate fetal lung maturation, does not benefit the fetus beyond administration of a single dose and may have negative effects. Several observational studies reported reductions in birth weight after multiple steroid courses,29,30 but other studies have found no such effect.31–35 In the studies that did find an association with birth weight, it is unclear whether this is owing to reduced gestational age or to fetal growth restriction. Perhaps, because these studies were carried out in women who were all at risk for preterm delivery, the focus has been on birth weight. Unless the observational studies were carried out with meticulous attention to selection bias, they risk confounding by the fact that women given multiple doses of steroid will necessarily have larger birth weights and longer pregnancies, simply because women who deliver earlier have less opportunity to receive multiple steroid doses. This bias may explain why some studies actually report significantly greater birth weights and longer pregnancies in the multiple-dose groups.36
There are only three randomized, controlled trials on this topic, and the largest one37 did report a significant reduction (P = .02) of 0.8 weeks in the period from the first unblinded corticosteroid injection to delivery in women given weekly courses of steroids; there was also a nonsignificant reduction in birth weight, of 130 g (P = .10). Two smaller trials38,39 did not report on fetal growth or gestational age. Taken together, this evidence is judged to be inconclusive and requiring more randomized evidence.40–44
Oral steroid therapy for asthma is usually 40 mg (typical range, 30–50 mg) daily of prednisone, whereas the treatment for preterm delivery is usually by intramuscular betamethasone for 1 day (two 12-mg doses) each week. Given relative potencies of approximately 1 to 8.3 for prednisone to betamethasone (if both used orally), a weekly dose of prednisone approximates the weekly dose of betamethasone.
From a US national survey (1997–2000), we have estimated a current asthma prevalence of 5.0–9.4% in pregnant women aged 18–44 years.2 If these estimates are extrapolated to the almost 4 million births delivered in the United States in 1999, the number of pregnancies complicated by asthma is some 200,000–376,000 annually, making asthma one of the most common complications of pregnancy. Larger studies are needed to more confidently disentangle any risks associated with asthma and medication use in pregnancy. In the meantime, these findings lend support to recent guidelines advocating the need to consider more active management of pregnant patients with mild or moderate asthma with β2 agonists, adding oral corticosteroids only if asthma severity increases.45
In our sample of nondiagnosed women, fully one third (33.5%) had asthma symptoms, and of these, 22.2% had mild persistent symptoms or worse. This group of women seemed to be at particularly increased risk of IUGR with increasing symptom severity. Of note, among the entire group of 449 symptomatic women with no diagnosis, only 30 women were using short-acting inhaled bronchodilators as needed to relieve symptoms, and only two were using a controller medication. These preliminary findings suggest that further research is needed to understand whether this is a group of women who should be more actively managed for their asthma symptoms, even in the absence of an asthma diagnosis, to reduce their risk of pregnancy complications.
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