Does treatment of premature labor with terbutaline increase the risk of autism spectrum disorders

Beta-adrenergic agents have been used in pregnant women forthetreatmentofprematurelaborandforthetreatment of asthma. Concerns have been expressed that exposure to terbutaline,whichisabeta-2adrenergicagonist,mayincreasethe riskofautismspectrumdisorders(ASDs)intheoffspring.This hypothesis deserves critical review, given the number of patients who have been exposed to the drug in the last 2 decades. Theresultsareimportanttoboththeobstetriciansandpatients who weigh the risks and benefits of interventions and to the pediatricians who counsel the families of affected children. We conducted an examination of the human and animal studies that have been used to support this hypothesis in a recentreview, 1 andwehavereachedadifferentconclusion.We findnosupportforthehypothesisthattheuseofterbutalineas a tocolytic agent is associated with the subsequent development of ASDs. The ASDs are common neurodevelopmental disorders that occur in approximately 1 of 150 to 1 of 100 children. 2 They are diagnosed by deficits in social interaction and communication and by restricted and repetitive behaviors and interests; the symptoms appear during the first 3 years of life. 3 Family and twin studies demonstrate that these disorders are heritable, with estimates of heritability approaching 90%. 4 However,thegeneticetiologyiscomplex,withmanylociinvolvedand nonethataccountsformorethanasmallfractionofcases. 5 Many developmental pathways seem to be involved and include those that have roles in initiating or maintaining synapses. 6,7 The penetranceofthegeneticliabilityfactorsisvariablesothatsymptoms differ, even in pairs of monozygotic twins. 8 The largest genome scan to date has added to this confusing picture the etiologic role of structural chromosomal anomalies (copy number variants), some of which arise de novo. 9 This unexpected result has been verified by other groups. 10 The known environmental risk factors for ASDs account for a small number of cases but are interesting because they share critical periods of exposure in the first trimester. 11 The identification of environmental risk factors is especially important because,unlikegeneticriskfactors,theyshouldbepreventable. Thus, it is reasonable to ask whether there is evidence that medications, such as terbutaline, to which pregnant women may be exposed increase the risk for an ASD outcome in the offspring. Our argument is not with the intent but with the quality of the evidence presented in the review by Witter et al, 1 which we now describe.