Witter et al suggest that beta adrenergic receptor agonists act as functional and behavioral teratogens and that use of these agents should be severely curtailed in pregnancy. The basis of this conclusion is, in our view, a selective and flawed review of animal and human data.

Animal studies cited conclude that beta adrenergic receptor agonists lead to abnormalities in brain development and behavior similar to those found in autism. In these rat studies, a dose of 10 mg/kg of terbutaline was administered as a single subcutaneous injection daily from neonatal days 2-5. Each injection is 2000-3000 times the equivalent single human dose (250 μg subcutaneously or roughly 3-4 μg/kg for a 60-80 kg woman). Beta adrenergic receptor agonists have dramatic effects on blood pressure, heart rate, and numerous metabolic functions. A huge nonpharmacologic or nonphysiologic dose will likely lower blood pressure and affect metabolic functions so dramatically that injury is not only possible but likely. An agent should not be viewed as harmful when the dose administered as a single injection is 2000-3000 times the usual pharmacologic dose.

Witter et al also cite clinical literature that purportedly demonstrates that terbutaline use is associated with poor neurophysiologic and behavioral outcome including autism. One such report was a discussion focused on a child with delayed language development whose mother had received terbutaline (dose, route of administration, and duration unstated). The 4 discussants of the case do not mention terbutaline as a cause of the language delay but point out how cases like this can be approached by pediatricians. Each parent had a sibling with a similar language acquisition delay. Thus, the assertion that terbutaline is associated with delayed language development or expressive delay is not supported by the case cited.

Witter et al also suggest that in utero exposure to terbutaline, whether administered for tocolysis or as an aerosol for asthma is “correlated” with autism. The only reference cited for this assertion is a personal communication.

Witter et al also suggests an increase in psychiatric disorders with poor cognitive and motor performance in subjects exposed to terbutaline. Data retrievable from charts were limited and data on drug dose, duration, or route of administration were not available. Significant differences in risk factors were noted between exposed and unexposed groups and outcomes were not fully adjusted for those covariates that might affect the outcomes of interest. The authors appropriately caution about interpretation of their data pointing out that their findings may be due to those factors that cause preterm labor and suboptimal placental perfusion. Thus, the assertion that beta adrenergic agonist therapy is associated with psychiatric disorder along with poor cognitive and motor performance overstates the findings and conclusions of the investigators.

Witter et al also cite a retrospective review of 78 children suggesting that intrauterine exposure to ritodrine for ≥1 week is associated with poor school performance. Neurologic examinations carried out at delivery and at 6 years of age demonstrated no significant differences in neurologic diagnoses, degree of developmental delay, or behavior between ritodrine-treated subjects and controls. Analysis of school performance however reported fewer “bright pupils” in the control groups, but no adjustments appeared to be made for gestational age at birth, pregnancy complications, and childhood events or social status.

The laboratory and clinical evidence provided by Witter et al suggesting beta adrenergic receptor agonists are functional and behavioral teratogens is therefore unsupported or supported by weak or flawed data. Many studies are retrospective, lack key clinical information, or do not adjust for covariates that might impact outcome. Laboratory studies in rats utilizing massive doses of a vasoactive agent cannot be extrapolated to human beings. We do not believe the literature supports the assertion that beta adrenergic receptor agonists are functional or behavioral teratogens. Further, linkage of beta adrenergic receptor agonists to autism is, in our view, not justified or supported.