Dose-dependent risk of malformations 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
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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.
    Seizure 08/2014; 24. DOI:10.1016/j.seizure.2014.08.006 · 1.82 Impact Factor
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    • "In the present study, we used a similar quantitative stereological evaluation for an estimate of the total number of neocortical neurons and we used a rat model that aimed to mimic the human clinical condition by using a long term administration of VPA at doses that were estimated as non-toxic and assumed to be relevant to the human clinic ( [3] [17]. The pups were exposed during maternal pregnancy from prenatal day E12.5-E21- 22 and during the lactating phase via injections of the dams until weaning P23 aiming to mimic the human conditions as much as possible taking into consideration that the time window of rat pups in the postnatal lactation period corresponds more or less to the 3th trimester in human pregnancy. "
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    ABSTRACT: The aim of this study was to test the hypothesis that long-term fetal valproic acid (VPA) exposure at doses relevant to the human clinic interferes with normal brain development. Pregnant rats were given intraperitoneal injections of VPA (20mg/kg or 100mg/kg) continuously during the last 9-12 days of pregnancy and during the lactation period until sacrifice on the 23(rd) postnatal day. Total number of neocortical neurons was estimated using the optical fractionator and frontal cortical thicknesses were sampled in VPA exposed pups compared with an unexposed control group. We found that pups exposed to 20mg/kg and 100mg/kg doses of VPA had statistically significant higher total number of neurons in neocortex by 15.8% and 12.3%, respectively (P< 0.05) compared to controls amounting to 15.5×10(6) neocortical neurons (P<0.01). There was no statistical difference between the two VPA groups. Pups exposed to100mg/kg, but not to 20mg/kg VPA displayed a significant (p<0.05) broader (7.5%) of frontal cortical thickness compared to controls. Our results support the hypothesis that fetal exposure of VPA may interfere with normal brain development by disturbing neocortical organisation, resulting in overgrowth of frontal lobes and increased neuronal cell numbers. The results indirectly suggest that prenatal VPA may contribute as a causative factor in the brain developmental disturbances equivalent to those seen in human autism spectrum disorders. We therefore suggest that this version of the VPA model may provide a translational model of autism.
    Neuroscience Letters 07/2014; 580. DOI:10.1016/j.neulet.2014.07.036 · 2.03 Impact Factor
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