Behavioural Teratogenicity

Vorhees, Charles V.; Butcher, Richard E.

doi:10.1007/978-1-4615-9790-2_9

Cited by 21 publications

(10 citation statements)

References 142 publications

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“…As of the 1980s,following descriptions of Fetal Anticonvulsant Syndrome (FACS) and Fetal Valproate Syndrome (FVS), characterized by prominent deficits in social communication and other ASD features [21,22], a consensus emerged that psychotropic drugs could produce behavioral teratological effects even if they did not show clear anatomical abnormalities such as cardiac or neural tube abnormalities after use during pregnancy [23].…”

Section: Biological Plausibilitymentioning

confidence: 99%

“…In the early 1970s the first reports linking serotonin reuptake inhibiting antidepressants to birth defects appeared [19]. In 1990, the first independent study linking SSRI intake to teratogenic potential in animal studies was published [20].As of the 1980s,following descriptions of Fetal Anticonvulsant Syndrome (FACS) and Fetal Valproate Syndrome (FVS), characterized by prominent deficits in social communication and other ASD features [21,22], a consensus emerged that psychotropic drugs could produce behavioral teratological effects even if they did not show clear anatomical abnormalities such as cardiac or neural tube abnormalities after use during pregnancy [23].These developments led companies producing novel centrally acting drugs in the 1980s, including SSRIs, to undertake animal studies. In the case of the SSRIs, the animal studies looked at embryo-…”

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confidence: 99%

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Links between serotonin reuptake inhibition during pregnancy and neurodevelopmental delay/spectrum disorders: A systematic review of epidemiological and physiological evidence

Healy

Noury

Mangin

2016

JRS

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Abstract. OBJECTIVE:To investigate possible linkages between neurodevelopmental delay and neurodevelopmental spectrum disorders and exposure to medication with effects on serotonin reuptake inhibition during pregnancy. METHODS: We systematically reviewed the epidemiological literature for studies bearing on this relationship in children born with neurodevelopmental spectrum disorder and related conditions, as well as animal studies giving serotonin reuptake inhibitors to pregnant animals and in addition reviewed the literature for proposals as to possible mechanisms that might link effects on serotonin reuptake with cognitive changes post-partum.The epidemiological studies were analysed to produce Forest plots to illustrate possible relations. RESULTS: The odds ratio of Autistic Spectrum or related Disorders in children born to women taking serotonin reuptake inhibiting antidepressants during pregnancy in case control studies was 1.95 (95% C.I. 1.63, 2.34) and in prospective cohort studies was 1.96 (95% C.I. 1.33, 2.90).CONCLUSIONS: There appears to be a link between serotonin reuptake inhibition in pregnancy and developmental delay and spectrum disorders in infancy leading to cognitive difficulties in childhood. More work needs to be done to establish more precisely the nature of the difficulties and possible mechanisms through which this link might be mediated.Keywords: Autism spectrum disorder, neurodevelopmental delay, neurodevelopmental spectrum disorders, antidepressants, serotonin reuptake inhibitors, pregnancy BackgroundThe clinical syndrome later called autism was first reported in 1943 [1]. The first studies of the prevalence of autism or autistic disorder (AD) in the 1960s pointed to a rate of 4 per 10,000 [2,3]. Later studies indicated the existence of a spectrum of disorders, and brought the term autistic spectrum disorder (ASD) into being in the mid-1990s 126 D. Healy et al. / Link between SSRIs in pregnancy and autistic spectrum disordersand ASD also now includes other syndromes such as Pervasive Developmental Disorder and Aspergers Disorder so that it is difficult to know how closely current clinical usage of an ASD diagnosis maps onto AD and ASD as first conceived. Current estimates are that ASD in research studies occurs at a rate of more than 1 in 70 children [5,6].Kanner autism was recognized before the emergence of modern psychotropic drugs, and given its submergence in ASD, it may not now be possible to establish whether it is linked to commonly used psychotropic medications. A number of clinical pictures linked to psychotropic drug use, fetal anticonvulsant syndrome (FACS), fetal valproate syndrome (FVS), and fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorder (FASD) have been described since 1970. Aside from the link to treatment, the clinical features of these disorders are consistent with a diagnosis of ASD but not Kanner autism. A growing number of epidemiological studies point to an increase in rates of ASD. This translates popularly into concerns about a change in the p...

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Section: Biological Plausibilitymentioning

confidence: 99%

mentioning

confidence: 99%

Links between serotonin reuptake inhibition during pregnancy and neurodevelopmental delay/spectrum disorders: A systematic review of epidemiological and physiological evidence

Healy

Noury

Mangin

2016

JRS

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“…In developmental psychotoxicity studies, it has been recommended that at least two species should be employed (Vorhees and Butcher 1982). In previous studies in the mouse, using doses of phenobarbitone within the normal ranges of anticonvulsant effectiveness, we have observed dose-dependent retardation of reflex development despite normal growth in animals that had been exposed throughout the period of gestation and lactation (Chapman and Cutler 1983).…”

mentioning

confidence: 95%

Phenobarbitone: adverse effects on reproductive performance and offspring development in the Mongolian gerbil, (Meriones unguiculatus)

Chapman

Cutler

1988

Psychopharmacology

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Phenobarbitone at a concentration of 500 mg/l in drinking fluid of gerbils during pregnancy (60 mg/kg) and lactation (136 mg/kg) markedly reduced the proportion of animals bearing litters, decreased pup weights at birth and during later life and delayed development of the self-righting reflex, auditory startle reaction, eye opening and full fur coverage. It also prolonged the period of suckling. Scars of implantation were evident in uterine horns of 60% of treated and in none of control females that had failed to give birth. Treated offspring after weaning were given phenobarbitone (500 mg/l; 42-124 mg/kg) as their drinking fluid throughout life and a further group of gerbils received this concentration of the drug from the time of weaning. Seizure susceptibility was unaltered by the drug treatment, and the only evidence of behavioural change was seen in offspring gerbils at 6 weeks when the bout length of social investigation during encounters was increased. Drug-treated offspring showed no abnormality in brain weight relative to body weight. Weight gain and brain weight remained normal among the gerbils given phenobarbitone after weaning. The drug treatment reduced scent gland size in breeding males, though not in the offspring, and had no effect on weights of the testes or ovaries and uterus. no effect on weights of the testes or ovaries and uterus. Plasma concentrations of phenobarbitone in females of the postweaning group amounted on average to 4.4 mg/kg. Most of the adverse effects of this dose of phenobarbitone in the gerbil can thus be seen to be associated either with reproductive impairment or with exposure during sensitive periods of early development.

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“…Drug-induced teratogenic defects in intelligence or behaviour may not be immediately apparent in the human infant, and the hazard would not be detected by the customary animal test for teratogens. Tests for behavioural teratogens in animals are time consuming and complex [20], and the development of a rapid in vitro screen for potential behavioural teratogens would be advantageous.…”

Section: Introductionmentioning

confidence: 99%

Effects of anticonvulsant drugs on brain cultures from chick embryos: A comparison with cultures from embryos treated in ovo

Sedowofia

Clayton

1985

Teratog Carcinog Mutagen

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The effects of anticonvulsant drugs phenytoin, phenobarbitone, and sodium valproate on neurons and glia from embryonic chicken brain have been tested. These effects have been compared with those produced in neuronal and glial cultures established from embryos that were injected with the drugs in ovo. Choline acetyl transferase activity and accumulation of gamma-aminobutyric acid were measured in neuronal cultures, and carbonic anhydrase and 2,'3'-cyclic nucleotide 3' phosphohydrolase activities were measured in glial cultures. Similarities have been observed in the morphological and biochemical changes brought about by the in vitro and in vivo treatment with the drugs. The use of in vitro cell culture systems for screening drugs for potential behavioural teratogenic effects is discussed.

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Behavioural Teratogenicity

Cited by 21 publications

References 142 publications

Links between serotonin reuptake inhibition during pregnancy and neurodevelopmental delay/spectrum disorders: A systematic review of epidemiological and physiological evidence

Links between serotonin reuptake inhibition during pregnancy and neurodevelopmental delay/spectrum disorders: A systematic review of epidemiological and physiological evidence

Phenobarbitone: adverse effects on reproductive performance and offspring development in the Mongolian gerbil, (Meriones unguiculatus)

Effects of anticonvulsant drugs on brain cultures from chick embryos: A comparison with cultures from embryos treated in ovo

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