In Utero Exposure to B2AR Agonists and Risk for Autism Spectrum Disorders

Background: Certain medications taken in the prenatal period have been documented as risk factors for autism spectrum disorders (ASD).  The teratogenic potential of most drugs with respect to neurodevelopmental outcomes is generally understudied, and it is important to consider prenatal prescription drug use as neurodevelopmental risk factors in order to weigh these potential risks with known benefits.  For women with asthma, the use of prescription drugs in pregnancy can still be the recommended standard of care.  Beta-2-adrenergic receptor (B2AR) agonist drugs such as salmeterol and formoterol are used to reduce asthma exacerbations.  In addition, the B2AR within the catecholamine system is essential for normal nervous system development.   Since B2AR agonists drugs are known to cross the placenta and cause an increase of B2AR signaling or overstimulation of the receptor it may result in the disruption, replication or differentiation of developing neurons in the fetus.

Objectives: The objective of this study was to investigate associations between use of B2ARs during pregnancy and risk for ASD. 

Methods: The matched case-control study sample consisted of 5,203 ASD cases and 52,030 controls born in Denmark between January 1, 1997 and December 31, 2006 with ASD case status ascertainment through March 11, 2011.  Data from Denmark’s health registers were linked using unique individual civil-registry number and provided detailed information regarding prescription drugs used during pregnancy, ASD diagnosis as well as health and socioeconomic status.  Ten controls per ASD case were individually matched on birth month and year.  Conditional logistic regression models were adjusted for parental age and child gender.  Estimates were calculated for any exposure during pregnancy, preconception and by trimester.  Separate analyses were conducted to address confounding by indication.

Results: Of the 5,203 cases of ASD, 177 children were exposed to B2ARs during pregnancy.  In adjusted conditional regression models, we found an increased risk for ASD associated with exposure to B2ARs anytime during pregnancy (adjusted OR, 1.28 [95% CI, 1.09-1.51]). The largest increase in risk was associated with exposure in the second trimester (adjusted OR, 1.39 [95% CI, 1.11-1.74]).  Two separate analyses were performed to control for confounding by indication for exposure anytime during pregnancy.  Statistical adjustment for maternal asthma resulted in consistently elevated estimates (adjusted OR, 1.28 [95% CI, 1.08-1.52]).  Restriction to only mothers with asthma also resulted in estimates suggesting elevated risk (adjusted OR, 1.35 [95% CI, 0.86-2.12]).

Conclusions: B2AR agonist exposure during pregnancy, especially during the second trimester, may be associated with an increased risk for ASD.  Limitations include lack of data regarding in-hospital terbutaline use, though this is unlikely to affect 2^nd trimester exposure estimates.  Under-reporting of asthma in the registry may lead to imperfect control of confounding by indication since not all asthmatics on B2ARs are identified.  Sensitivity analyses will be performed to examine the impact of misclassification of exposure and indicating condition.  Results from this study add to the limited knowledge on prenatal pharmacological exposures as potential ASD risk factors which need to be balanced against the benefits of indicated medication use by pregnant mothers.