Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth

Dean, John; Hailey, H.; Moore, Sue; Lloyd, D. J.; Turnpenny, Peter D.; Little, Julian

doi:10.1136/jmg.39.4.251

Cited by 220 publications

(167 citation statements)

References 53 publications

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“…[235][236][237] These physical manifestations are predictive of greater symptom severity and neuroanatomical abnormalities. 235,238,239 Exposure to teratogens during gestation has also been shown to be a risk factor for autism, with higher disease incidence associated with maternal use of valproic acid, [226][227][228]240 thalidomide 241 and misoprostol. 242 The detrimental neurodevelopmental effects of maternal infection have been attributed, in part, to the induction of inflammatory cytokines.…”

Section: Mouse Models Of Environmental Contributions To Autism Etiologymentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism.

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Section: Mouse Models Of Environmental Contributions To Autism Etiologymentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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“…Polytherapy exposure in utero carries an increased risk of malformations and lower cognitive functioning [56,72,73]. Although attempts should be made to avoid polytherapy in pregnancy, there are women whose seizures, pain, or psychiatric disorders cannot be controlled with monotherapy.…”

Section: Polytherapymentioning

confidence: 99%

Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Meador

Baker

Cohen

et al. 2007

Epilepsy & Behavior

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The majority of children of mothers with epilepsy are normal, but they are at increased risk for developmental delay. Antiepileptic drugs (AEDs) appear to play a role. Our current knowledge is reviewed, including research design issues and recommendations for future research. In animals, exposure of the immature brain to some AEDs can produce widespread neuronal apoptosis and behavioral deficits. The risks of AEDs in humans are less clear, but recent studies raise concerns, especially for valproate. There is a critical need for well-designed systematic research to improve our understanding of AED effects on the fetal brain. KeywordsAntiepileptic drugs; Anticonvulsant drugs; Pregnancy; Teratogenesis; Development; Cognition; Behavior Animal studies on behavioral effects of in utero AED exposureAnimal studies have demonstrated that in utero antiepileptic drug (AED) exposure can produce behavioral as well as anatomical defects, which can occur at dosages lower than those required to produce somatic malformations [1,2]. Gestational or neonatal exposure to benzodiazepines can affect brain chemistry and behavior causing hyperactivity or learning deficits [3,4]. Despite the common use of carbamazepine in humans, very few neurobehavioral studies in animals have been conducted with this AED. In utero carbamazepine exposure did not produce hyperexcitability in primates [5]. Perinatal phenobarbital exposure in rats reduces brain weight [6]. Mice exposed prenatally to phenobarbital have neuronal deficits, reduced brain weight, and impaired development of reflexes, open-field activity, schedule-controlled behavior, spatial learning, and cate-cholamine brain levels [7][8][9][10][11][12]. Gestational or neonatal exposure to phenytoin reduces brain weight [13,14], alters neuronal membranes in the hippocampus [15], delays neurodevelopment [16], and impairs spatial learning and motor coordination [17][18][19][20][21][22][23][24][25]. Hyperactivity has been observed in rats and primates following prenatal exposure to phenytoin [5,23,25]. Gestational primidone in rats produces learning deficits and reduces open-field activity [26]. In utero valproate exposure can alter neuronal membranes [27], decrease brain weight in mice [28], and result in adverse neurobehavioral effects [29,30].

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“…Exposure to valproic acid (VPA) in pregnancy is associated with a higher incidence of autism spectrum disorder (ASD) by case reports and population studies [1][2][3][4][5][6][7][8][9]. Rodents exposed to VPA prenatally simulate a number of behavioural traits found in ASD [10,11]; eg.…”

Section: Introductionmentioning

confidence: 99%

A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse

Wei

Lam

et al. 2016

Behavioural Brain Research

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Rationale Rodents exposed to valproic acid (VPA) in prenatal life exhibit post-natal characteristics analogous to autism spectrum disorder (ASD). Many previous studies used relatively high doses of VPA during early pregnancy, potentially confounding interpretation because the offspring are the "survivors" of a toxic insult. Low dose or late gestation exposure has not been widely studied. Objectives We examined the behavioral sequelae of late gestation exposure to low dose VPA in the mouse. We also examined postnatal levels of glutamic acid decarboxylase (GAD65 and GAD67) as markers for GABA neurons, because GABA pathology and subsequent excitatory/inhibitory imbalance is strongly implicated in ASD. Methods Pregnant C57BL/6N mice received a single subcutaneous injection of 100 or 200 mg/kg on gestation day 17. The control group received a saline injection on the same day. The offspring were tested in a battery of behavioral tests in adolescence and adulthood. Six brain regions were harvested and GAD65 and GAD67 were measured by western blotting. Results Compared to saline-exposed controls, adult mice exposed to prenatal VPA had impaired novel object exploration and fear conditioning anomalies. GAD67 was decreased in midbrain, olfactory bulb, prefrontal cortex and increased in cerebellum, hippocampus and striatum; GAD65 was decreased in all 6 regions. ConclusionsOur results suggest that a low dose of VPA in late pregnancy has persistent effects on brain development, and in particular the GABA system, which 3 may be relevant to ASD. Further attention to the impact of gestation time and dose of exposure in VPA-induced ASD models is encouraged.

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Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth

Cited by 220 publications

References 53 publications

Advances in behavioral genetics: mouse models of autism

Advances in behavioral genetics: mouse models of autism

Cognitive/behavioral teratogenetic effects of antiepileptic drugs

A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse

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