Asthma continues to be one of the most common chronic conditions complicating pregnancy; approximately 8% of pregnant women in the United States report a current diagnosis. Asthmatic women are at increased risk of adverse birth outcomes and perinatal complications, including spontaneous abortion, preterm delivery, reduced birth weight, preeclampsia, and in selected studies, congenital anomalies. In some cases, these increased risks have been linked to specific medications (for example, oral corticosteroid use is linked with orofacial clefts). But much of the current evidence is also consistent with the interpretation that at least some of the excess risk can be attributed to the underlying severity/inadequate control of maternal asthma.
By Christina D. Chambers
However, two recently published studies suggest that beta2-agonists – mainstays of treatment and control of asthma symptoms – may be associated with increased risks of congenital anomalies.
The first, an analysis conducted with data from the National Birth Defects Prevention Study, focused specifically on orofacial clefts as the outcome and bronchodilators as the exposure. Using a case control design, researchers interviewd 2,711 mothers of infants with oral clefts and 6,482 mothers of infants with no malformations in 10 states between 1997 and 2005 about bronchodilator use for asthma during and just before pregnancy. The authors separately evaluated risks for cleft lip alone, cleft lip with cleft palate, and cleft palate alone, as each of these defect categories may have distinct etiologies. Almost 3% (247 women) reported exposure to any bronchodilator in the periconceptional period, with nearly 90% of those exposures limited to the widely used short-acting beta2-agonist, albuterol.
Significantly increased risks were noted for any bronchodilator use (without an additional anti-inflammatory drug) and cleft lip alone (adjusted odds ratio, 1.77; 95% confidence interval, 1.08-2.88); however, with the addition of an anti-inflammatory drug (four cases), the odds were attenuated and no longer statistically significant. Limiting the analysis to only those reporting use of albuterol, the estimated risks for cleft lip alone (adjusted OR, 1.79; 95% CI, 1.07-2.99) and cleft palate alone (adjusted OR, 1.65; 95% CI, 1.06-2.58) were both significantly elevated. No increased risks were noted for use of any bronchodilator and cleft lip with cleft palate. If these findings represent a causal association, the estimated odds ratios would translate to less than one excess case each of cleft lip alone and cleft palate alone for every 1,000 women using albuterol in the first trimester (Hum. Reprod. 2011;26:3147-54).
Reports of even small increased risks for asthma medications during pregnancy can further deter women from appropriate treatment, with possible unintended risks for both mother and baby.
As the authors pointed out, there was no mechanism in the study to adjust for the contribution of underlying disease severity/asthma symptom control in these mothers. However, the lack of an association between orofacial clefts and bronchodilators among those women who also used an anti-inflammatory drug suggests that perhaps women on polytherapy had more optimum treatment and therefore better control.
The second study used a retrospective cohort design drawing on administrative data collected between 1990 and 2002 in Quebec. The 13,117 pregnancies selected for the analysis were limited to those with a coded diagnosis of asthma and excluded women who received multiple prescriptions for oral corticosteroids in the year before pregnancy. The exposures evaluated were any prescription in the periconceptional period for a short-acting beta2-agonist rescue medication (such as albuterol), and any prescription in the periconceptional period for a long-acting beta2-agonist controller medication (such as salmeterol, available during the years of this study as a single active ingredient medication). In all, 17 categories of major congenital malformations were evaluated as outcomes, including orofacial clefts. More than 50% of pregnant women in the study filled a prescription for a short-acting drug in the first trimester, while only 1.3% received a prescription for one of the long-acting medications.
The authors found no significant associations with short-acting beta2-agonists for any of the congenital defect categories. Cases of cleft lip and cleft palate were combined, and the odds ratio after considering adjustment factors, was 1.50 (95% CI, 0.72-3.14). However, the authors did report that first trimester prescription for long-acting beta2-agonists was associated with significantly increased risks for major cardiac malformations (adjusted OR, 2.30; 95% CI, 1.11-5.10) based on seven infants exposed and "other or unspecified major malformations" (adjusted OR, 3.97; 95% CI, 1.29-12.20) based on three infants exposed (Birth Defects Res. Clin. Molec. Teratol. 2011;91:937-47).
In this study, the authors attempted to control for underlying disease severity using Canadian treatment guidelines as well as emergency room and other hospital admissions for asthma. However, no direct measure of disease severity or symptom control was collected, and unfortunately, the "lumping" of orofacial clefts (likely due to the small number of affected infants) makes comparison to the above-described study difficult. The findings with long-acting beta2-agonists, as the authors point out, could be influenced by the higher rate of more severe and less well-controlled asthma among these women, the expected higher rate of preterm delivery with associated prematurity-related defects, and/or multiple testing/chance. Finally, it has been suggested that some asthmatic women will reduce or discontinue medication in the first trimester of pregnancy based on fear of fetal exposure, not on remission of symptoms. If in fact this is the case, prescriptions filled may not reflect true usage of the drug.