In utero beta 2 adrenergic agonist exposure and adverse neurophysiologic and behavioral outcomes
2009; Elsevier BV; Volume: 201; Issue: 6 Linguagem: Inglês
10.1016/j.ajog.2009.07.010
ISSN1097-6868
AutoresFrank R. Witter, Andrew W. Zimmerman, J Reichmann, Susan L. Connors,
Tópico(s)Child and Adolescent Psychosocial and Emotional Development
ResumoBeta 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. 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. Beta 2 adrenergic agonist drugs as a class are used widely in obstetrics as both tocolytics and bronchodilators. This article will correlate the basic science and clinical data to illustrate that, when given prenatally, they can act as functional and behavioral teratogens in that they can alter permanently the balance of sympathetic and parasympathetic tone in the individual after exposure in utero.For Editors' Commentary, see Table of Contents For Editors' Commentary, see Table of Contents Animal studies will be presented to support the concept that, in humans, prenatal exposure to continuous high doses of beta 2 adrenergic agonists can dysregulate signaling from the beta 2 adrenergic receptor (B2AR) permanently. The association between sympathetic overactivity and disease will be illustrated, and the association between in utero exposure to beta 2 adrenergic agonists in humans and the later development of these conditions or their precursors will be demonstrated. Additionally, data to support a genetic predisposition to the teratogenic effect of beta 2 adrenergic agonists will be presented. The implications for safe practice in obstetrics will be discussed in light of the teratogenic risk that is posed by beta 2 adrenergic agonists. Terbutaline and similar drugs stimulate the B2AR, which is part of the catecholamine system of neurotransmitters. Cell signaling that is associated with B2AR stimulation results from the binding of the ligands norepinephrine in the central nervous system (CNS) and norepinephrine and epinephrine in peripheral tissues. The B2AR is expressed on mammalian oocytes and preimplantation embryos. 1Cikos S. Veselá J. Il'ková G. Rehák P. Czikková S. Koppel J. Expression of beta adrenergic receptors in mouse oocytes and preimplantation embryos.Mol Reprod Dev. 2005; 71: 145-153Crossref PubMed Scopus (37) Google Scholar Beta adrenergic receptors are expressed widely in mammalian tissues, which includes the brain during gestation. 2Slotkin T.A. Lau C. Seidler F.J. 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Thyroid hormone-induced morphological differentiation and maturation of astrocytes are mediated through the beta-adrenergic receptor.J Neurochem. 2000; 75: 1962-1969Crossref PubMed Scopus (23) Google Scholar B2AR signaling is regulated during postnatal life by desensitization (decreased signaling) and down-regulation (decreased numbers of receptors on the cell surface). Both processes terminate cell signaling if excessive input occurs and are essential homeostatic mechanisms that protect the cell from overstimulation and metabolic acidosis. Animal studies have shown that these protective regulatory mechanisms for B2AR signaling are not intrinsic properties of cells but are acquired during prenatal development. Fetal and newborn tissues are not only resistant to B2AR desensitization but actually show the opposite: agonist stimulation of the fetal receptor enhances net physiologic responses, instead of producing desensitization, as in adult tissues. 8Slotkin T.A. Auman J.T. Seidler F.J. Ontogenesis of β-adrenoceptor signaling: implications for perinatal physiology and for fetal effects of tocolytic drugs.J Pharmacol Exp Ther. 2003; 306: 1-7Crossref PubMed Scopus (66) Google Scholar, 9Connors S.L. Prenatal beta 2 adrenergic receptor signaling and autism: dysmaturation and retained fetal function.in: Zimmerman A.W. Autism: current theories and evidence. Humana Press, Totowa, NJ2008: 147-182Google Scholar The beta 2 agonist terbutaline crosses the placenta and blood brain barrier and stimulates B2ARs in all tissues of the fetus. 2Slotkin T.A. Lau C. Seidler F.J. Beta-adrenergic receptor overexpression in the fetal rat: distribution, receptor subtypes, and coupling to adenylate cyclase activity via G-proteins.Toxicol Appl Pharmacol. 1994; 129: 223-234Crossref PubMed Scopus (48) Google Scholar, 10Bergman B. Bokstrom H. Borga O. Enk L. Hedner T. Wangberg B. 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Developmental exposure to terbutaline alters cell signaling in mature rat brain regions and augments the effects of subsequent neonatal exposure to the organophosphorus insecticide chlorpyrifos.Toxicol Appl Pharmacol. 2005; 203: 154-166Crossref PubMed Scopus (40) Google Scholar Rodent studies have shown that daily subcutaneous injections of terbutaline during postnatal days 2-5 result in abnormalities in brain development and behavior, compared with control rats. Differences include changes in microarchitecture in the cerebellum, hippocampus, and cortex in juvenile rats (postnatal day 30), functional differences in cell signaling in juvenile and adolescent (postnatal day 45) and adult rats (postnatal day 60), behavioral changes in juvenile rats, and neuroinflammation of the brain in juvenile rats. These findings are similar to those found in autism. 8Slotkin T.A. Auman J.T. Seidler F.J. 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Ontogenesis of β-adrenoceptor signaling: implications for perinatal physiology and for fetal effects of tocolytic drugs.J Pharmacol Exp Ther. 2003; 306: 1-7Crossref PubMed Scopus (66) Google Scholar The dosage of terbutaline in human pregnancy is 0.5-2 mg/kg/d 17Lam F. Elliott J. Jones J.S. et al.Clinical issues surrounding the use of terbutaline sulfate for preterm labor.Obstet Gynecol Surv. 1998; 53: S85-S95Crossref PubMed Scopus (42) Google Scholar, 18Goldenberg R.L. The management of preterm labor.Obstet Gynecol. 2002; 100: 1020-1037Crossref PubMed Scopus (276) Google Scholar; however, because the drug has a much shorter half-life in the rat, 19Tegner K. Nilsson H.T. Persson C.G. Ryrfeldt A. Elimination pathways of terbutaline.Eur J Respir Dis Suppl. 1984; 134: 93-100PubMed Google Scholar the dose that was used by the researchers cited earlier was proportionately higher. 14Rhodes M.C. Seidler F.J. Abdel-Rahman A. et al.Terbutaline is a 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 The 4-day duration for terbutaline administration (postnatal days 2-5) is equivalent to 3-4 weeks in human pregnancy. 20Rice D. Barone S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models.Environ Health Perspect. 2000; 108: 511-513PubMed Google Scholar, 21Clancy B. Kersh B. Hyde J. Darlington R.B. Anand K.J.S. Finlay B.L. Web-based method for translating neurodevelopment from laboratory species to humans.Neuroinformatics. 2007; 5: 79-94Crossref PubMed Scopus (250) Google Scholar This early postnatal period in the rat correlates with the mid-to-late second and early third trimester in human gestation, 20Rice D. Barone S. 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Ontogenesis of β-adrenoceptor signaling: implications for perinatal physiology and for fetal effects of tocolytic drugs.J Pharmacol Exp Ther. 2003; 306: 1-7Crossref PubMed Scopus (66) Google Scholar Overactivity of the sympathetic nervous system has been implicated in the cause of certain disease states and contributes to abnormal function in others. Increased catecholamine levels are part of the disease process in congestive heart failure and cause chronic stimulation of beta adrenergic receptors, which results in tachycardia and increased contractility. 22Feldman D.S. Elton T.S. Sun B. Martin M.M. Ziolo M.T. Mechanisms of disease: detrimental adrenergic signaling in acute decompensated heart failure.Nat Clin Pract Cardiovasc Med. 2008; 5: 208-218Crossref PubMed Scopus (43) Google Scholar, 23El-Armouche A. Eschenhagen T. Beta-adrenergic stimulation and myocardial function in the failing heart.Heart Fail Rev. 2008 Dec 27; (Epub ahead of print)Google Scholar This overstimulation leads to receptor desensitization, abnormal downstream cellular signaling, and maladaptation that eventually results in myocyte hypertrophy, ventricular chamber enlargement, and fibrosis. By decreasing beta adrenergic receptor stimulation, beta blockers have become part of the basic treatment for this condition. Hypertension, like congestive heart failure, often is treated with beta adrenergic receptor antagonists, although overstimulation of beta receptors is not thought to be the basis for this condition. 24Del Colle S. Morello F. Rabbia F. et al.Antihypertensive drugs and the sympathetic nervous system.J Cardiovasc Pharmacol. 2007; 50: 487-496Crossref PubMed Scopus (37) Google Scholar The exact mechanism for beta blockers antihypertensive effects is unknown but is thought to be due to several modes of action, which include antagonism of beta 1 adrenergic receptors in the renal vascular bed. Stimulation of these receptors normally produces renin; blocking these receptors decreases renin levels and conversion of renin to angiotensin II, which is a potent vasoconstrictor. Other mechanisms may involve blocking beta adrenergic receptors that control sympathetic outflow in the CNS and changes in arterial baroceptor sensitivity. Ming et al 25Ming X. Julu P.O.O. Brimacombe M. Connor S. Daniels M.L. Reduced cardiac parasympathetic activity in children with autism.Brain Dev. 2005; 27: 509-516Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar measured baseline cardiovascular autonomic function in children with autism (ages, 4-14) and in age-matched healthy control subjects. They found that measures of parasympathetic activity, cardiac vagal tone, and cardiac sensitivity to baroreflex were significantly lower in children with autism, compared with control subjects, and were associated with significant elevations in indices of sympathetic tone: heart rate, mean arterial blood pressure, and diastolic blood pressure. Low levels of cardiac vagal tone and cardiac sensitivity to baroreflex suggest impaired cardiac parasympathetic activity, with unrestrained and hyperactivity of the sympathetic nervous system. Rodent work has shown that overstimulation of the B2AR by terbutaline during postnatal days 2-5 results in effects that can be related indirectly to sympathetic hyperactivity, as in the study of Ming et al. 25Ming X. Julu P.O.O. Brimacombe M. Connor S. Daniels M.L. Reduced cardiac parasympathetic activity in children with autism.Brain Dev. 2005; 27: 509-516Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar Acetylcholine receptors that are found in the cardiovascular system that normally act to balance the catecholamine system are decreased in number and function in the heart after neonatal terbutaline administration. 8Slotkin T.A. Auman J.T. Seidler F.J. Ontogenesis of β-adrenoceptor signaling: implications for perinatal physiology and for fetal effects of tocolytic drugs.J Pharmacol Exp Ther. 2003; 306: 1-7Crossref PubMed Scopus (66) Google Scholar, 26Garofolo M.C. Seidler F.J. Auman J.T. Slotkin T.A. 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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 (68) Google Scholar found an increase in the more active polymorphisms of the B2AR in twins with autism spectrum disorders, and Cheslack-Postava et al 50Cheslack-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 found an increased prevalence and transmission of these polymorphisms in singleton autism births. Thus, genetic polymorphisms can change the physiologic condition of receptor function and contribute to predispositions for several disease states. Considering the importance of the B2AR in normal brain and organ development, it is likely that polymorphisms that increase or decrease signaling are genetic risk factors for abnormal brain development during gestation, in a similar way as they are linked to disease in other organs. The presence of polymorphisms that are associated with enhanced signaling would then become a susceptibility factor for exposures to sympathomimetic drugs and may be a factor in defining the "population at risk" for later neurodevelopmental disorders in children after exposure to b
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