Abstract
This study aims to investigate the association between prenatal exposure to terbutaline and other β2 adrenergic receptor (B2AR) agonists and autism spectrum disorders (ASDs). The methodology used is a case–control study among children born from 1995 to 1999 at Kaiser Permanente Northern California hospitals. Cases (n = 291) were children with an ASD diagnosis; controls (n = 284) were children without ASDs, randomly sampled and frequency-matched to cases on sex, birth year, and delivery hospital. Exposure to B2AR agonists during 30 days prior to conception and each trimester of pregnancy was ascertained from prenatal medical records and health plan databases. The frequency of exposure to any B2AR agonist during pregnancy was similar for mothers of children with ASD and mothers of controls (18.9% vs. 14.8%, P = 0.19). Exposure to B2AR agonists other than terbutaline was not associated with an increased risk for ASDs. However, terbutaline exposure for >2 days during the third trimester was associated with more than a fourfold increased risk for ASDs independent of indication although the limited sample size resulted in an imprecise and nonsignificant effect estimate (ORadj = 4.4; 95% confidence interval, 0.8–24.6). This analysis does not offer evidence linking B2AR exposure in pregnancy with autism risk. However, exposure to terbutaline during the third trimester for >2 days may be associated with an increased risk of autism. Should this result be confirmed in larger samples, it would point to late pregnancy as an etiologic window of interest in autism risk factor research.
Highlights
Key pathophysiologic changes observed in the brain of autistic individuals provide compelling evidence that autism begins during fetal development (Casanova 2007; Bauman and Kemper 2005; Rodier 2000)
The frequency of exposure to B2AR agonists during pregnancy was higher among women carrying twins compared with singletons (45.5% vs. 13.6%, P
Further review of our results indicates that maternal treatment with B2AR agonists during pregnancy does not explain our previous observation of increased autism spectrum disorders (ASDs) risk among asthmatic mothers (Croen et al 2005)
Summary
Key pathophysiologic changes observed in the brain of autistic individuals provide compelling evidence that autism begins during fetal development (Casanova 2007; Bauman and Kemper 2005; Rodier 2000). When administered to rats at a neurodevelopmental stage equivalent to the mid-second to early third trimester in humans (Rice and Barone 2000), terbutaline dysregulates function of the enzyme adenylyl cyclase and leads to abnormal generation (excess and deficiency) of the signaling molecule cyclic adenosine monophosphate (cAMP) in different brain regions at different stages of development (Rhodes et al 2004; Slotkin et al 2001, 2003; Meyer et al 2005) Terbutaline exposure during this prenatal window results in changes in the rat central nervous system similar to those found in autism postmortem studies such as cerebellar abnormalities (delays in synaptogenesis and reduction in Purkinje cell number), deficient hippocampal development, and neuroimmune activation (Rhodes et al 2004; Zerrate et al 2007; Bauman and Kemper 1985; Vargas et al 2005; Casanova et al 2006). The relative risk increased to 4.4 (p=0.035) in those twin sets who were both male and without a family history of ASDs
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