A Clinical Study of 57 Children With Fetal Anticonvulsant Syndromes

Moore, Susan; Turnpenny, Peter D.; Quinn, Andrea; Glover, S.; Lloyd, D. J.; Montgomery, Thaddeus L.; Dean, John

doi:10.1097/00006254-200104000-00011

Cited by 88 publications

(137 citation statements)

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“…These results suggest molecular and synaptic alterations in children prenatally exposed to VPA. It is known that many of these children suffer from what is known as fetal anticonvulsant syndrome, and as many as 60% suffer from two or more of the core symptoms of autism (4). Further investigations are required to determine whether NMDA receptors are up-regulated in these cases.…”

Section: Discussionmentioning

confidence: 99%

“…Its etiology has not yet been clarified, but genetic and environmental contributions to neurodevelopmental alterations either cause or confer vulnerability to this disorder (1). The teratogens that have been most clearly linked to autism include thalidomide (2) and valproic acid (VPA) (3)(4)(5)(6)(7). These drugs can cause diverse birth defects, but over a narrow time window of vulnerability (days 20-24 of human pregnancy), they have a higher likelihood of causing autism (8,9).…”

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confidence: 99%

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Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid

Rinaldi

Kulangara²,

Antoniello³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

266

218

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Valproic acid (VPA) is a powerful teratogen causing birth defects in humans, including autism spectrum disorder (ASD), if exposure occurs during the first trimester of embryogenesis. Learning and memory alterations are common symptoms of ASD, but underlying molecular and synaptic alterations remain unknown. We therefore studied plasticity-related mechanisms in the neocortex of 2-weekold rats prenatally exposed to VPA and tested for changes in glutamate-mediated transmission and plasticity in the neocortex. We found a selective overexpression of NR2A and NR2B subunits of NMDA receptors, as well as the commonly linked kinase calcium/ calmodulin-dependent protein kinase II. Synaptic plasticity experiments between pairs of pyramidal neurons revealed an augmented postsynaptic form of long-term potentiation. These results indicate that VPA significantly enhances NMDA receptor-mediated transmission and causes increased plasticity in the neocortex. Enhanced plasticity introduces a surprising perspective to the potential molecular and synaptic mechanisms involved in children prenatally exposed to VPA.autism ͉ in vitro electrophysiology ͉ plasticity ͉ somatosensory cortex ͉ NMDA receptors A utism is a developmental disorder of neurological origin primarily affecting social cognition. Its etiology has not yet been clarified, but genetic and environmental contributions to neurodevelopmental alterations either cause or confer vulnerability to this disorder (1). The teratogens that have been most clearly linked to autism include thalidomide (2) and valproic acid (VPA) (3-7). These drugs can cause diverse birth defects, but over a narrow time window of vulnerability (days 20-24 of human pregnancy), they have a higher likelihood of causing autism (8, 9). The core symptoms of autism, first identified by Leo Kanner in 1943 (10), are centered around inappropriate social interaction, poor or no language development, enhanced sensory sensitivity, repetitive behaviors, attention abnormalities, and resistance to novel environments (11). Most affected children tend to have a lower IQ than their peers, but the extent to which the communication deficit has clouded these assessments is not clear. A fraction of autistic children are considered high functioning, with unusually powerful memory capabilities, and children who do solve the communication handicap are often found to have unusual learning and memory capabilities (12-17). There are currently no potential molecular and synaptic candidates for the learning and memory alterations found in autistic children.Recent studies are focusing more on animal models of autism, which could provide the only means of rapidly exploring molecular, synaptic, and cellular candidates linked to the disorder. The rat VPA model is one example of an insult-based model that is being increasingly explored (9, 18-21). Offspring of pregnant rats exposed to a single injection of VPA display some of the gross anatomical changes (18,22) and core behavioral symptoms observed in autism, such as impaired social inter...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid

Rinaldi

Kulangara²,

Antoniello³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

266

218

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“…A systematic review of children with a history of prenatal exposure to AEDs revealed that 8.9% of children exposed to VPA and 2.5% of children exposed to CBZ met the diagnostic criteria for ASD,23 although no adjustment for potential confounding variables was undertaken. High rates of neurodevelopmental disorders have also been reported in children diagnosed with Fetal Valproate Syndrome 21. This is a condition characterised by a pattern of major and minor congenital malformations, dysmorphic features and cognitive deficits,24 25 and is likely to represent the severely effected end of a spectrum of difficulties associated with prenatal exposure to VPA.…”

Section: Introductionmentioning

confidence: 99%

The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs

Cheyne

Garcı́a-Fiñana

Baker

et al. 2013

Journal of Neurology, Neurosurgery & Psychiatry

310

229

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The aim of this study was to compare the prevalence of diagnosed neurodevelopmental disorders in children exposed, in utero, to different antiepileptic drug (AED) treatments. A prospective cohort of women with epilepsy and a control group of women without epilepsy were recruited from antenatal clinics. The children of this cohort were followed longitudinally until six years of age (n=415). Diagnosis of a neurodevelopmental disorder was made independently of the research team. Multiple logistic regression analysis revealed an increase in risk of neurodevelopmental disorders in children exposed to monotherapy sodium valproate (6/50, 12.0%; aOR 6.05, 95%CI 1.65–24.53; p=0.007) and in those exposed to polytherapy with sodium valproate (3/20, 15.0%; aOR 9.97, 95%CI 1.82–49.40; p=0.005) compared to control children (4/214; 1.87%). Autistic spectrum disorder was the most frequent diagnosis. No significant increase was found amongst children exposed to carbamazepine (1/50) or lamotrigine (2/30). An accumulation of evidence demonstrates that the risks associated with prenatal sodium valproate exposure include an increased prevalence of neurodevelopmental disorders. Whether such disorders are discrete or represent the severe end of a continuum of altered neurodevelopmental functioning requires further investigation. Replication and extension of this research is required to investigate the mechanism(s) underpinning the relationship. Finally, the increased likelihood of neurodevelopmental disorders should be communicated to women for whom sodium valproate is a treatment option.

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“…In a recent clinical study of 34 children exposed in utero to valproate alone, however, trigonocephaly was not recorded. 11 Gardner and associates 8 found no statistically significant increase in the risk ratios of craniosynostosis associated with prenatal exposure to valproic acid; however, in their article, the diagnosis of craniosynostosis is questionable because there is a probable confusion between craniosynostosis and moulding plagiocephaly confounding their results.…”

Section: Discussionmentioning

confidence: 96%

“…In a series of 34 children with fetal valproate syndrome, 26 displayed learning difficulties, and 29 exhibited behavioral problems. 11 Nevertheless, to date there has been no prospective study of developmental delay following maternal sodium valproate use.…”

Section: Discussionmentioning

confidence: 99%