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

Cheyne, Christopher P.; Garcı́a-Fiñana, Marta; Baker, Gus A.; Briggs, Michelle; Bromley, Rebecca; Clayton‐Smith, Jill; Dixon, Pete; Fryer, Alan; Gummery, Alison; Kneen, Rachel; Kerr, Lydia; Lucas, S. B.; Mawer, G. E.; Shallcross, Rebekah

doi:10.1136/jnnp-2012-304270

Cited by 318 publications

(250 citation statements)

References 44 publications

(37 reference statements)

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“…The neurodevelopment research group from Liverpool and Manchester also reported that children assessed at 6 years of age who were exposed to VPA in utero had a higher prevalence of neurodevelopmental disorders [22]. Multiple logistic regression analysis revealed that the children born to WWE and exposed to VPA monotherapy and VPA polytherapy were, respectively, 6 times [adjusted OR 6.05; 95 % CI 1.65-24.53 (p = 0.007)] and 10 times [adjusted OR 9.97; 95 % CI 1.82-49.40 (p = 0.005)] more likely to be diagnosed with a neurodevelopmental disorder than controls.…”

Section: Neurodevelopmental Outcomesmentioning

confidence: 99%

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Pennell

2016

Neurotherapeutics

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Although prenatal exposure to antiepileptic drugs (AEDs) is known to impart relatively higher risks of major congenital malformations, prospective studies have provided refined data that allow us to differentiate the risks of different types and doses of AEDs. As the number of AED prescriptions has dramatically increased in reproductive-aged women with a variety of neuropsychiatric indications, the evolving concepts learned from studies in women with epilepsy can be applied to a much larger group of pregnant women to improve child outcomes while maintaining maternal disease control. In addition to careful selection of the type of medication, the amount of fetal exposure at conception and in the first trimester probably matters across all AEDs. Some AED polytherapy regimens are not associated with a higher risk of malformations, although other outcomes have not yet been formally studied. The individual woman's drug target concentration should be established preconception and maintained during pregnancy, to prevent seizure worsening. Substantial pharmacokinetic changes occur with many of the medications during pregnancy and postpartum, and interindividual variability supports the use of therapeutic drug monitoring for most AEDs. During pregnancy, vigilance and close monitoring should also include intrauterine fetal growth, obstetric complications, and neonatal complications. Breastfeeding can provide additional neurodevelopmental benefit and should be an option for women on AEDs. Knowledge of these key principles enhances our ability to make treatment recommendations with resultant improved maternal and child outcomes. Additional prospective studies are needed to further define the risk-benefit ratio across a variety of medications, dosing strategies, and neuropsychiatric disorders.

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Section: Neurodevelopmental Outcomesmentioning

confidence: 99%

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Pennell

2016

Neurotherapeutics

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“…For example, Ͼ40 different mutations and various environmental risk factors have been associated with ASD (Abrahams and Geschwind, 2008;Lichtenstein et al, 2010;Neale et al, 2012). Despite this great diversity of potential causes and complex cognitive symptoms, there is reason to believe that these symptoms originate from a few fundamental abnormalities in nervous system development and function (Pratt and Khakhalin, 2013).…”

Section: Introductionmentioning

confidence: 99%

Valproate-Induced Neurodevelopmental Deficits inXenopus laevisTadpoles

James

Ramirez-Vizcarrondo

et al. 2015

J. Neurosci.

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Autism spectrum disorder (ASD) is increasingly thought to result from low-level deficits in synaptic development and neural circuit formation that cascade into more complex cognitive symptoms. However, the link between synaptic dysfunction and behavior is not well understood. By comparing the effects of abnormal circuit formation and behavioral outcomes across different species, it should be possible to pinpoint the conserved fundamental processes that result in disease. Here we use a novel model for neurodevelopmental disorders in which we expose Xenopus laevis tadpoles to valproic acid (VPA) during a critical time point in brain development at which neurogenesis and neural circuit formation required for sensory processing are occurring. VPA is a commonly prescribed antiepileptic drug with known teratogenic effects. In utero exposure to VPA in humans or rodents results in a higher incidence of ASD or ASD-like behavior later in life. We find that tadpoles exposed to VPA have abnormal sensorimotor and schooling behavior that is accompanied by hyperconnected neural networks in the optic tectum, increased excitatory and inhibitory synaptic drive, elevated levels of spontaneous synaptic activity, and decreased neuronal intrinsic excitability. Consistent with these findings, VPA-treated tadpoles also have increased seizure susceptibility and decreased acoustic startle habituation. These findings indicate that the effects of VPA are remarkably conserved across vertebrate species and that changes in neural circuitry resulting from abnormal developmental pruning can cascade into higher-level behavioral deficits.

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“…Earlier publications from this longitudinal cohort have reported an increased risk of major congenital malformations, 19 significantly lower early cognitive development, 15 and increased rates of autistic spectrum disorder 20 after exposure to VPA.…”

mentioning

confidence: 99%

IQ at 6 years after in utero exposure to antiepileptic drugs

et al. 2015

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Objective: To delineate the risk to child IQ associated with frequently prescribed antiepileptic drugs.Methods: Children born to women with epilepsy (n 5 243) and women without epilepsy (n 5 287) were recruited during pregnancy and followed prospectively. Of these, 408 were blindly assessed at 6 years of age. Maternal and child demographics were collected and entered into statistical models.Results: The adjusted mean IQ was 9.7 points lower (95% confidence interval [CI] 24.9 to 214.6; p , 0.001) for children exposed to high-dose (.800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, and spatial subscales. Children exposed to high-dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8.0, 2.5-19.7; p , 0.001). Valproate at doses ,800 mg daily was not associated with reduced IQ, but was associated with impaired verbal abilities (25.6, 95% CI 211.1 to 20.1; p 5 0.04) and a 6-fold increase in educational intervention (95% CI 1.4-18.0; p 5 0.01). In utero exposure to carbamazepine or lamotrigine did not have a significant effect on IQ, but carbamazepine was associated with reduced verbal abilities (24.2, 95% CI 20.6 to 27.8; p 5 0.02) and increased frequency of IQ ,85.Conclusions: Consistent with data from younger cohorts, school-aged children exposed to valproate at maternal doses more than 800 mg daily continue to experience significantly poorer cognitive development than control children or children exposed to lamotrigine and carbamazepine. Antiepileptic drugs (AEDs) are associated with teratogenic risk to the development of the fetus, with the prevalence of major congenital malformations differing by treatment type and dose. Determining the association between exposure to AEDs and child cognitive functioning represents a challenge, and a number of different methodologies have been utilized in its investigation including case studies, 2-4 retrospective studies, 5,6 and prospective studies. 7-15 Despite limitations, 16 there is growing evidence that exposure to sodium valproate (VPA) in utero is associated with significantly poorer functioning. [10][11][12]15,17 Prospective studies consistently document that VPA is associated with an increase in risk of cognitive impairment in young children, 10,12,15 but any longer-term effects are unlikely to be comprehensively documented until the children studied are of school age, when cognitive development is more stable.10 In a comparison across AED monotherapies, a significantly poorer IQ in school-aged children exposed in utero to

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

Cited by 318 publications

References 44 publications

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Valproate-Induced Neurodevelopmental Deficits inXenopus laevisTadpoles

IQ at 6 years after in utero exposure to antiepileptic drugs

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