One of the most common conditions that complicate pregnancy is maternal asthma. Evidence continues to mount that adequate control of asthma, including appropriate use of medications, is the best approach to optimizing outcomes. Yet questions persist about the effect of asthma itself, as well as specific medications and the risk for major congenital malformations. As with any exposure during pregnancy, answering these questions is challenging because of the rarity of specific birth defects and the various and increasing number of medications that might be used to treat or prevent asthma symptoms.
Previously in this column ("Beta2-agonists for asthma, December 2011), we reviewed two studies that suggested short-acting beta-agonists used for the treatment of asthma were associated with an increased risk of oral clefts and that long-acting beta-agonists might be associated with an increased risk of cardiac anomalies (Hum. Reprod. 2011;26:3147-54; Birth Defects Res. A. Clin. Mol. Teratol. 2011;91:937-47).
What have we learned since then? Two studies published in 2013 add to the body of knowledge. The first, a database analysis using the United Kingdom’s General Practice Research Database, assessed pregnancy outcomes between 1991 and 2002 in 7,911 women exposed to asthma medications in the first trimester of pregnancy and 15,840 women who were not exposed (Pharmacotherapy 2013;33:363-8). Major anomalies were identified up to 1 year of age. Minor anomalies, chromosomal anomalies, and those associated with prematurity were excluded.
The overall risk for any exposure, compared with no exposure, for any congenital anomaly was 1.1 (95% confidence interval [CI], 1.0-1.3). No significant differences were found by class of asthma medication. Specific categories of defects also were evaluated, including musculoskeletal anomalies, oral clefts, cardiovascular defects, and multiple anomalies. Some estimates were elevated for specific medication classes.
For example, the relative risk (RR) of cleft lip or palate associated with exposure to long-acting beta-agonists was 2.4, but the confidence interval included 1 (0.3-21.8) based on 424 exposed pregnancies. The authors concluded that they found no significant increased risk of congenital anomalies associated with exposure to asthma, asthma medications, or any specific asthma medication classes in the first trimester. Limitations of the study included the inability to verify that exposure took place and insufficient data to adjust for confounding by vitamin supplementation, alcohol use, socioeconomic status, or markers of disease severity (other than number of medications prescribed).
The second study addressed the issue of maternal asthma itself and the risk for congenital anomalies (BJOG 2013;120:812-22). Using a meta-analysis approach, 21 cohort studies published between 1975 and 2012 met the criteria for inclusion. Combining major and minor congenital anomalies, the authors found a slight but statistically significant increased risk for any defect (RR, 1.11; 95% CI, 1.01-1.68), but when the analysis was restricted to major defects alone, the summary estimate was elevated but no longer significant (RR, 1.31; 95% CI, 0.57-3.02). When the specific defect grouping of oral clefts was examined, however, there was a significantly elevated overall relative risk of 1.30 (95% CI, 1.01-1.68). Limitations of this study include differing quality of studies and the appropriateness of combining data to derive a summary estimate.
Although both studies provide reassurance about the overall risk of major defects in the offspring of women with asthma, both suggest that more work needs to be done to follow up on the risk for oral clefts and whether this is linked to underlying disease severity and/or use of specific medications. Furthermore, safety of specific long-acting beta-agonist medications in pregnancy should be further examined.
The take-home message, however, continues to be that the risk for major defects in the offspring of pregnant women with asthma appears to be low, which supports the recommendation to follow guidelines for appropriate treatment of women with asthma both during and outside of pregnancy to control symptoms.
Dr. Chambers is professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. She said that she had no relevant financial disclosures.