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Abstract

We recommended limiting the use of beta 2 adrenergic agonists (B2AA) to clearly proven indications consistent with American College of Obstetricians and Gynecologists recommendations. Due to the very high placebo effects seen in the treatment of preterm labor, we have only used controlled trials to establish effectiveness. In this setting, retrospective studies have an unacceptably high type I error rate, and should not be used.The dosages utilized in the rat studies were proportionally higher due to differing pharmacokinetics in the rat.1Rhodes M.C. Seidler F.J. Abdel-Rahman A. et al.Terbutaline is a developmental neurotoxicant: effects on neuroproteins and morphology in cerebellum, hippocampus, and somatosensory cortex.J Pharmacol Exp Ther. 2004; 308: 529-537Crossref PubMed Scopus (58) Google Scholar, 2Tegner K. Nilsson H.T. Persson C.G. Ryrfeldt A. Elimination pathways of terbutaline.Eur J Respir Dis Suppl. 1984; 134: 93-100PubMed Google Scholar Rats metabolize drugs much more quickly than do human beings; for terbutaline, the half-life is 4 times shorter. In toxicology, biologic effects should be matched between species. For terbutaline, we chose doses for rat pups shown to match cardiorespiratory effects of terbutaline in the human fetus. Animal studies use closely matched subjects, unlike human studies, therefore higher doses in animals are used to identify effects that are likely to be seen in vulnerable human subpopulations. Terbutaline use in human pregnancy produces adverse outcomes in a smaller subset; higher doses in animal studies are necessary to show us the mechanisms that provide the causal links for those adverse effects.We presented data to indicate that B2AA as a class were associated with adverse neurophysiological and behavioral outcomes. As such, we utilized data on several members of this class as our proposed mechanism of action would be similar. We did, however, state which studies involved which agents. While each individual study could not stand alone, the overall pattern of association indicates a risk.References correlating terbutaline with autism included a case series3Kilburn K.H. Thrasher J.D. Immers N.B. Do terbutaline- and mold-associated impairments of the brain and lung relate to autism?.Toxicol Ind Health. 2009; 25: 703-710Crossref PubMed Scopus (13) Google Scholar and a twin study.4Connors S.L. Crowell D.E. Eberhart C.G. et al.Beta 2-adrenergic receptor activation and genetic polymorphisms in autism: data from dizygotic twins.J Child Neurol. 2005; 20: 876-884Crossref PubMed Scopus (69) Google Scholar The personal communication concerned albuterol; please see our earlier response to a letter concerning asthma therapy.5Witter F.R. Zimmerman A.W. Connors S.L. In utero beta 2 adrenergic agonist exposure and adverse neurophysiologic and behavioral outcomes [reply].Am J Obstet Gynecol. 2001; 203: e15Abstract Full Text Full Text PDF Scopus (2) Google ScholarIn the study by Pitzer et al,6Pitzer M. Schmidt M.H. Esser G. Laucht M. Child development after maternal tocolysis with beta-sympathomimetic drugs.Child Psychiatry Hum Dev. 2001; 31: 165-182Crossref PubMed Scopus (46) Google Scholar terbutaline was not mentioned, but rather fenoterol followed by nonspecified B2AA oral agents. The most significant finding in this case control study was that differences were not seen in the infants born prematurely, but rather only in those born at term consistent with effect caused by longer exposure and not related to preterm delivery. The study by Alvarez et al7Alvarez M. Pita S. Costas E. et al.Long term effects of ritodrine on blood pressure and heart rate of adolescents exposed during the prenatal stage.Eur J Obstet Gynecol Reprod Biol. 1995; 59: 137-141Abstract Full Text PDF PubMed Scopus (7) Google Scholar on prenatal exposure to ritodrine showed, by direct cardiovascular measurements, a shift in the balance of the sympathetic to parasympathetic tone with sympathetic dominance consistent with the animal data. Evidence that autism is more common in children who inherit a more active form of the beta 2 adrenergic receptor4Connors S.L. Crowell D.E. Eberhart C.G. et al.Beta 2-adrenergic receptor activation and genetic polymorphisms in autism: data from dizygotic twins.J Child Neurol. 2005; 20: 876-884Crossref PubMed Scopus (69) Google Scholar, 8Cheslack-Postava K. Fallin M.D. Avramopoulos D. et al.Beta 2-adrenergic receptor gene variants and risk for autism in the AGRE cohort.Mol Psychiatry. 2007; 12: 283-291PubMed Google Scholar is consistent with a genetic link to autism.Taken together, all the data we present do make a strong case for B2AA as functional and behavioral teratogens. We recommended limiting the use of beta 2 adrenergic agonists (B2AA) to clearly proven indications consistent with American College of Obstetricians and Gynecologists recommendations. Due to the very high placebo effects seen in the treatment of preterm labor, we have only used controlled trials to establish effectiveness. In this setting, retrospective studies have an unacceptably high type I error rate, and should not be used. The dosages utilized in the rat studies were proportionally higher due to differing pharmacokinetics in the rat.1Rhodes M.C. Seidler F.J. Abdel-Rahman A. et al.Terbutaline is a developmental neurotoxicant: effects on neuroproteins and morphology in cerebellum, hippocampus, and somatosensory cortex.J Pharmacol Exp Ther. 2004; 308: 529-537Crossref PubMed Scopus (58) Google Scholar, 2Tegner K. Nilsson H.T. Persson C.G. Ryrfeldt A. Elimination pathways of terbutaline.Eur J Respir Dis Suppl. 1984; 134: 93-100PubMed Google Scholar Rats metabolize drugs much more quickly than do human beings; for terbutaline, the half-life is 4 times shorter. In toxicology, biologic effects should be matched between species. For terbutaline, we chose doses for rat pups shown to match cardiorespiratory effects of terbutaline in the human fetus. Animal studies use closely matched subjects, unlike human studies, therefore higher doses in animals are used to identify effects that are likely to be seen in vulnerable human subpopulations. Terbutaline use in human pregnancy produces adverse outcomes in a smaller subset; higher doses in animal studies are necessary to show us the mechanisms that provide the causal links for those adverse effects. We presented data to indicate that B2AA as a class were associated with adverse neurophysiological and behavioral outcomes. As such, we utilized data on several members of this class as our proposed mechanism of action would be similar. We did, however, state which studies involved which agents. While each individual study could not stand alone, the overall pattern of association indicates a risk. References correlating terbutaline with autism included a case series3Kilburn K.H. Thrasher J.D. Immers N.B. Do terbutaline- and mold-associated impairments of the brain and lung relate to autism?.Toxicol Ind Health. 2009; 25: 703-710Crossref PubMed Scopus (13) Google Scholar and a twin study.4Connors S.L. Crowell D.E. Eberhart C.G. et al.Beta 2-adrenergic receptor activation and genetic polymorphisms in autism: data from dizygotic twins.J Child Neurol. 2005; 20: 876-884Crossref PubMed Scopus (69) Google Scholar The personal communication concerned albuterol; please see our earlier response to a letter concerning asthma therapy.5Witter F.R. Zimmerman A.W. Connors S.L. In utero beta 2 adrenergic agonist exposure and adverse neurophysiologic and behavioral outcomes [reply].Am J Obstet Gynecol. 2001; 203: e15Abstract Full Text Full Text PDF Scopus (2) Google Scholar In the study by Pitzer et al,6Pitzer M. Schmidt M.H. Esser G. Laucht M. Child development after maternal tocolysis with beta-sympathomimetic drugs.Child Psychiatry Hum Dev. 2001; 31: 165-182Crossref PubMed Scopus (46) Google Scholar terbutaline was not mentioned, but rather fenoterol followed by nonspecified B2AA oral agents. The most significant finding in this case control study was that differences were not seen in the infants born prematurely, but rather only in those born at term consistent with effect caused by longer exposure and not related to preterm delivery. The study by Alvarez et al7Alvarez M. Pita S. Costas E. et al.Long term effects of ritodrine on blood pressure and heart rate of adolescents exposed during the prenatal stage.Eur J Obstet Gynecol Reprod Biol. 1995; 59: 137-141Abstract Full Text PDF PubMed Scopus (7) Google Scholar on prenatal exposure to ritodrine showed, by direct cardiovascular measurements, a shift in the balance of the sympathetic to parasympathetic tone with sympathetic dominance consistent with the animal data. Evidence that autism is more common in children who inherit a more active form of the beta 2 adrenergic receptor4Connors S.L. Crowell D.E. Eberhart C.G. et al.Beta 2-adrenergic receptor activation and genetic polymorphisms in autism: data from dizygotic twins.J Child Neurol. 2005; 20: 876-884Crossref PubMed Scopus (69) Google Scholar, 8Cheslack-Postava K. Fallin M.D. Avramopoulos D. et al.Beta 2-adrenergic receptor gene variants and risk for autism in the AGRE cohort.Mol Psychiatry. 2007; 12: 283-291PubMed Google Scholar is consistent with a genetic link to autism. Taken together, all the data we present do make a strong case for B2AA as functional and behavioral teratogens. Beta 2 adrenergic agents and autismAmerican Journal of Obstetrics & GynecologyVol. 203Issue 4PreviewRegarding the commentary by Witter et al,1 the authors go to great lengths to emphasize the possible risks and to dismiss the possible benefits of maintenance beta 2 agonist therapy in the management of preterm labor. Indeed, the data supporting the use of maintenance tocolysis with beta 2 adrenergic agents are limited to retrospective studies, but the 2 negative prospective trials quoted by the authors are limited by their small sample size and were underpowered to avoid a type II error. Therefore, the benefit of maintenance terbutaline therapy must be considered unknown. Full-Text PDF Editors' AnnouncementAmerican Journal of Obstetrics & GynecologyVol. 205Issue 2PreviewIn response to questions from readers concerning a conflict of interest disclosure in a 2009 article,1 a letter to the editor,2 and the authors' replies to letters to the editor,3,4 the editorial board of the American Journal of Obstetrics and Gynecology wishes to inform readers that the following statement of conflict of interest was disclosed in the original submission of the article. Full-Text PDF