Dose-dependent risk of malformation with antiepileptic drugs: An analysis of data from the EURAP epilepsy and pregnancy registry

Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
The Lancet Neurology (Impact Factor: 21.9). 07/2011; 10(7):609-17. DOI: 10.1016/S1474-4422(11)70107-7
Source: PubMed


Prenatal exposure to antiepileptic drugs is associated with a greater risk of major congenital malformations, but there is inadequate information on the comparative teratogenicity of individual antiepileptic drugs and the association with dose. We aimed to establish the risks of major congenital malformations after monotherapy exposure to four major antiepileptic drugs at different doses.
The EURAP epilepsy and pregnancy registry is an observational cohort study representing a collaboration of physicians from 42 countries. We prospectively monitored pregnancies exposed to monotherapy with different doses of four common drugs: carbamazepine, lamotrigine, valproic acid, or phenobarbital. Our primary endpoint was the rate of major congenital malformations detected up to 12 months after birth. We assessed pregnancy outcomes according to dose at the time of conception irrespective of subsequent dose changes.
After excluding pregnancies that ended in spontaneous abortions or chromosomal or genetic abnormalities, those in which the women had treatment changes in the first trimester, and those involving other diseases or treatments that could affect fetal outcome, we assessed rates of major congenital malformations in 1402 pregnancies exposed to carbamazepine, 1280 on lamotrigine, 1010 on valproic acid, and 217 on phenobarbital. An increase in malformation rates with increasing dose at the time of conception was recorded for all drugs. Multivariable analysis including ten covariates in addition to treatment with antiepileptic drugs showed that the risk of malformations was greater with a parental history of major congenital malformations (odds ratio 4·4, 95% CI 2·06-9·23). We noted the lowest rates of malformation with less than 300 mg per day lamotrigine (2·0% [17 events], 95% CI 1·19-3·24) and less than 400 mg per day carbamazepine (3·4% [5 events], 95% CI 1·11-7·71). Compared with lamotrigine monotherapy at doses less than 300 mg per day, risks of malformation were significantly higher with valproic acid and phenobarbital at all investigated doses, and with carbamazepine at doses greater than 400 mg per day.
The risk of major congenital malformations is influenced not only by type of antiepileptic drug, but also by dose and other variables, which should be taken into account in the management of epilepsy in women of childbearing potential.
Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, Netherlands Epilepsy Foundation, Stockholm County Council, and ALF.

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Available from: Dick Lindhout, May 22, 2014
    • "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). There is also evidence, from a number of studies, that timed prenatal exposure to VPA (in rodents) produces consistent anatomical, functional and behavioral abnormalities (Vorhees, 1987; Binkerd et al., 1988; Ingram et al., 2000; Koren et al., 2006; Rinaldi et al., 2007; Snow et al., 2008; Gandal et al., 2010; Tashiro et al., 2011; Mychasiuk et al., 2012; Reynolds et al., 2012; Banerjee et al., 2014; Engineer et al., 2014b). "
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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.
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    • "However, the lower incidence of birth defects in the non-epileptic group could be due to the lower mean daily doses of drugs used by non epileptic women compared to the epileptic group. Tomson and his coworkers [12] pointed out a correlation between AEDs doses and the risk of MCMs. Nonetheless, while malformed children of epileptic women were actually exposed to higher doses compared to those of non-epileptic women, we did not find such a difference with regard to valproic acid in our study. "

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    • "Lamotrigine and levetiracetam are commonly recommended alternatives largely because they are considered to have fewer and less severe adverse side-effects, including foetal teratogenicity . These treatment guidelines are principally informed by observational studies including data from pregnancy registers that show higher rates of major somatic malformations in pregnancies exposed to VPA, for example the EURAP registry [6] showed a rate of 5.6% with <700 mg valproate and 24.2% with >1500 mg valproate per day, 2.0% with <300 mg lamotrigine per day and 4.5% with >300 mg per day. Valproate is also associated with impaired cognitive development [7] in the absence of any foetal malformations. "
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    ABSTRACT: Purpose Although sodium valproate (VPA) remains the most effective antiepileptic for generalised and unclassified epilepsies, clinicians may be failing to discuss this treatment option because of guideline misinterpretation. Current guidelines recommend caution regarding teratogenic risks but do not advocate absolute avoidance. Methods We assessed VPA prescribing in young people attending a transition epilepsy clinic. We present six patients with idiopathic generalised epilepsy (IGE) in whom VPA had been initially avoided. Results Overall, the results were consistent with VPA's superior antiepileptic efficacy and ability to reduce harmful seizure-related complications. Young people denied of VPA showed prolonged periods of poor seizure control with medical, social and psychological complications. Following contraceptive counselling and VPA introduction, all six patients showed improved seizure control including seizure-freedom during follow-up of up to twenty-four months. There was also evidence of reduced seizure-related morbidity and improved educational and occupational functioning. Prior to referral, documentation revealed no discussion of VPA treatment options. Conclusion Failure to prescribe valproate for IGE, particularly when another first-line treatment has failed, may not be in a young woman's best interests particularly when they are most vulnerable to sequelae from uncontrolled seizures. Indiscriminate avoidance of valproate needs to be recognised as a misinterpretation of current epilepsy guidelines as it may harm young people. Although the use of valproate demands careful consideration, there remains a strong case to always discuss this medication because of its efficacy and potential to reduce seizure-related harm. Patients must be allowed to make their own informed decisions about effective epilepsy treatments.
    Full-text · Article · Aug 2014 · Seizure
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