In utero beta 2 adrenergic agonist exposure and adverse neurophysiologic and behavioral outcomes REPLY

Division of Maternal-Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
American journal of obstetrics and gynecology (Impact Factor: 4.7). 12/2009; 201(6):553-9. DOI: 10.1016/j.ajog.2009.07.010
Source: PubMed


Beta 2 adrenergic receptor overstimulation during critical periods of prenatal development can induce a permanent shift in the balance of sympathetic-to-parasympathetic tone. This is a biologically plausible mechanism whereby beta 2 adrenergic agonists can induce functional and behavioral teratogenesis, which explains their association with increases in autism spectrum disorders, psychiatric disorders, poor cognitive, motor function and school performance, and changes in blood pressure in the offspring. The use of beta 2 adrenergic agonists should be limited to proven indications when alternate drugs are ineffective or unavailable; the risks of untreated disease to the mother and fetus are greater than the risk of the beta 2 adrenergic agonist.

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Available from: James P Reichmann, Mar 19, 2015
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    • "Based on aggregated evidence from animal and human studies, Witter et al. proposed that permanent changes in autonomic tone could result in neurological changes in the fetus, especially after two or more weeks of high dose í µí»½2 adrenergic receptor agonist exposure. These functional and behavioral changes may contribute to the signs and symptoms of autism [27] "
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    ABSTRACT: Autism is a neurodevelopmental disorder marked by severe deficits in social communication and interactions. It is a complex condition that lacks an established preventive method, warranting a need for research to identify possible environmental triggers. The identification of external factors particularly perinatal risk factors forms the initial critical step in preventing and alleviating risks. We conducted a literature review to assess evidence suggested in the worldwide literature. Perinatal risk factors that have a suggested association include íµí»½2 adrenergic receptor agonists, labor induction and augmentation, maternal infection and disease (i.e., antiphospholipid syndrome), antiepileptic drugs, cocaine use, and oral supplements. Smoking has not been found to have a direct association. Pollutants, selective serotonin reuptake inhibitors, artificial insemination, and fertility medications may have a link, but results are often conflicted. Factors related to the delivery room experience may be associated with meconium aspiration syndrome, birth weight, and labor time. Several risk factors during the pregnancy and labor periods have been associated with autism; yet further studies with large populations are needed to establish definitive associations. The fact that several risk factors during the prenatal and labor periods are implicated in autism should prompt the medical community to focus on the pregnancy and labor periods as preventive measures to curb the incidence of autism.
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    • "Beta-2 adrenergic agonists are the cornerstones of tocolytic agents. However, Witter et al., (2009) illustrated that these agents when given during critical periods of prenatal development, poor neurophysiological and behavioral teratogenesis can be induced, this may explain the increased risk of autism, psychiatric disorders, poor cognitive, motor functions, and school performance changes in blood pressure "
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    ABSTRACT: Statistical association between congenital autism and prenatal exposure to ritodrine (4-(2-((1R,2S)-1-hydroxy-1-(4-hydroxyphenyl)propan-2-ylamino)ethyl)phenol) as a tocolytic agent was a matter of concern. Moreover, neuronal nitric oxide momentous role in various behavioral and cognitive functions was reported. In this context, a correlation between prenatal exposures to ritodrine, neuronal nitric oxide level and autism occurrence must be investigated. For this reason, we proposed possible inhibition of neuronal nitric oxide synthase (nNOS) by ritodrine. An insight toward our hypothesis approval was done through docking ritodrine into the catalytic pocket of nNOS. Apparently, ritodrine shared at least five critical binding interactions with a potent nNOS inhibitor (PDB code: JI7). Subsequent in vitro experiment pointed out that ritodrine indeed inhibited the enzymatic activity of nNOS at low micromolar level. As a conclusion, ritodrine should not be used as a tocolytic agent but as a novel non peptidomimetic nNOS inhibitor lead scaffold for future optimization. Graphical Abstract (A) Ritodrine chemical structure (B) Docked pose of ritodrine into nNOS-binding pocket (PDB code: 3B3P, resolution 2.6 Ǻ) (C) Docked pose of inhibitor JI7 (green) as produced by docking simulation and the crystallographic structure of this inhibitor within nNOS
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    • "It is unlikely that a single exposure or insult is responsible for all cases of biologically complex and clinically heterogeneous neurodevelopmental disorders such as those included in the autism spectrum. Yet, it is possible that downstream cellular signaling abnormalities, such as dysregulated cAMP generation, could act as a common pathway in the development of these disorders in some individuals (Connors 2008; Witter et al. 2009). With this in mind, we investigated terbutaline and other B2AR agonists since animal studies have shown that these drugs produced functional changes in developing tissues and behaviors comparable to those noted in autism. "
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    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 (OR(adj) = 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.
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