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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