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

Department of Molecular and Clinical Pharmacology, University of Liverpool, , Liverpool, UK.
Journal of neurology, neurosurgery, and psychiatry (Impact Factor: 6.81). 01/2013; 84(6). DOI: 10.1136/jnnp-2012-304270
Source: PubMed


The aim of this study was to compare the prevalence of diagnosed neurodevelopmental disorders in children exposed, in utero, to different antiepileptic drug 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 6 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 (VPA) (6/50, 12.0%; aOR 6.05, 95%CI 1.65 to 24.53, p=0.007) and in those exposed to polytherapy with sodium VPA (3/20, 15.0%; aOR 9.97, 95% CI 1.82 to 49.40, p=0.005) compared with control children (4/214; 1.87%). Autistic spectrum disorder was the most frequent diagnosis. No significant increase was found among children exposed to carbamazepine (1/50) or lamotrigine (2/30). An accumulation of evidence demonstrates that the risks associated with prenatal sodium VPA 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 VPA is a treatment option.

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Available from: Rebecca Bromley
    • "Abbreviations: ASD, autism spectrum disorder; AVCN, anterior ventral cochlear nucleus; CN, cochlear nucleus; CNIC, central nucleus of the inferior colliculus; D, dorsal; DCIC, dorsal cortex of the inferior colliculus; DCN, dorsal cochlear nucleus; E, embryonic; ECIC, external cortex of the inferior colliculus; fn, facial nerve; IC, inferior colliculus; L, lateral; LNTB, lateral nucleus of the trapezoid body; LSO, lateral superior olive; MNTB, medial nucleus of the trapezoid body; MSO, medial superior olive; P, posterior; PAG, periaqueductal gray; PB, phosphate buffer; PVCN, posterior ventral cochlear nucleus; RF, reticular formation; SOC, superior olivary complex; SPON, superior paraolivary nucleus; tz, trapezoid body; VCN, ventral cochlear nucleus; VPA, valproic acid. Neuroscience 311 (2015) 349–361 valproic acid (VPA), compared to unexposed children (Bescoby-Chamber et al., 2001; Williams et al., 2001; Rasalam et al., 2005; Koren et al., 2006; Bromley et al., 2013). The prevalence of ASD in children exposed prenatally to antiepileptic drugs is estimated to be 8–18 times higher than unexposed children (Rasalam et al., 2005) and VPA produces malformations in a dose-dependent manner (Tomson et al., 2011). "
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    ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties with communication and social interactions, restricted, repetitive behaviors and sensory abnormalities. Additionally, the vast majority of subjects with ASD suffer some degree of auditory dysfunction and we have previously identified significant hypoplasia and dysmorphology in auditory brainstem centers in individuals with ASD. Prenatal exposure to the antiepileptic drug valproic acid (VPA) is associated with an increased risk of ASD. In rodents, prenatal exposure to VPA is utilized as an animal model of ASD and is associated with a number of anatomical, physiological and behavioral deficits, including hypoplasia and dysmorphology in the auditory brainstem. Based on these observations, we hypothesized that such dysmorphology in VPA-exposed animals would translate into abnormal activity in brainstem circuits and irregular tonotopic maps. Herein, we have subjected control and VPA-exposed animals to 4 or 16kHz tones and examined neuronal activation with immunohistochemistry for c-Fos. After these sound exposures, we found significantly more c-Fos-positive neurons in the auditory brainstem of VPA-exposed animals. Further, we found a larger dispersion of c-Fos-positive neurons and shifted tonotopic bands in VPA-exposed rats. We interpret these findings to suggest hyper-responsiveness to sounds and disrupted mapping of sound frequencies after prenatal VPA exposure. Based on these findings, we suggest that such abnormal patterns of activation may play a role in auditory processing deficits in ASD.
    No preview · Article · Oct 2015 · Neuroscience
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    • "Characterized by impairments in social interactions, communication, and repetitive behaviors, the etiology of autism is not entirely known, but genetic and environmental components have been hypothesized to be involved [1] [2]. There is an accumulating body of evidence that in utero exposure to valproic acid (VPA), a teratogenic anticonvulsant, leads to an increased risk and incidence of autism [3] [4] [5]. In fact, several retrospective human and case studies have documented difficulties in attentional, social, language, and motor abilities among children prenatally exposed to VPA, leading to the idea that valproate exposure during fetal development greatly alters neurodevelopment, including emotional and cognitive functioning [5] [6] [7] [8] [9] [10] [11] [12]. "
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    ABSTRACT: Autism is a severe neurodevelopmental disorder with a population prevalence of 1 in 68, and dramatically increasing. While no single pharmacologic intervention has successfully targeted the core symptoms of autism, emerging evidence suggests that postnatal environmental manipulations may offer greater therapeutic efficacy. Massage therapy, or tactile stimulation (TS), early in life has repeatedly been shown to be an effective, low-cost, therapeutic approach in ameliorating the cognitive, social, and emotional symptoms of autism. While early TS treatment attenuates many of the behavioral aberrations among children with autism, the neuroanatomical correlates driving such changes are unknown. The present study assessed the therapeutic effects of early TS treatment on behavior and neuroanatomy using the valproic acid (VPA) rodent model of autism. Rats were prenatally exposed to VPA on gestational day 12.5 and received TS shortly following birth. Whereas TS reversed almost all the VPA-induced alterations in neuroanatomy, it failed to do so behaviorally. The TS VPA animals, when compared to VPA animals, did not exhibit altered or improved behavior in the delayed non-match-to-sample T-maze, Whishaw tray reaching, activity box, or elevated plus maze tasks. Anatomically, however, there were significant increases in dendritic branching and spine density in the medial prefrontal cortex, orbital frontal cortex, and amygdala in VPA animals following early TS treatment, suggesting a complete reversal or remediation of the VPA-induced effects in these regions. The results suggest that postnatal TS, during a critical period in development, acts as a powerful reorganization tool that can ameliorate the neuroanatomical consequences of prenatal VPA exposure. Copyright © 2014. Published by Elsevier B.V.
    Full-text · Article · Dec 2014 · Behavioural Brain Research
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    • "The authors of the two recent papers discussed above also noted a need to define the mechanism behind the increased risk of ASD with VPA exposure. Several questions arise as to the relationship between environmental exposure to chemicals such as VPA in the manifestation of ASD [33, 34]. Christensen et al. suggested several mechanisms by which VPA may increase the risk of ASD that need further study, including interference in neurotransmitter function, neuronal apoptosis or plasticity, histone deacetylase inhibition, and disruption of folic acid metabolism [34]. "
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    ABSTRACT: Two recent epidemiological investigations in children exposed to valproic acid (VPA) treatment in utero have reported a significant risk associated with neurodevelopmental disorders and autism spectrum disorder (ASD) in particular. Parallel to this work, there is a growing body of animal research literature using VPA as an animal model of ASD. In this focused review we first summarize the epidemiological evidence linking VPA to ASD and then comment on two important neurobiological findings linking VPA to ASD clinicopathology, namely, accelerated or early brain overgrowth and hyperexcitable networks. Improving our understanding of how the drug VPA can alter early development of neurological systems will ultimately improve our understanding of ASD.
    Full-text · Article · Dec 2013
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