Neurocognition after prenatal levetiracetam, lamotrigine, carbamazepine or valproate exposure

Abstract

Objective To examine neurocognitive functioning of children exposed prenatally to carbamazepine, lamotrigine, levetiracetam or valproate monotherapy. Methods In a prospective observational study, children aged 6 or 7 years, identified from the European Registry of Antiepileptic Drugs and Pregnancy database in The Netherlands, were assessed using the Wechsler Intelligence Scale for Children and the developmental neuropsychological assessment. Maternal IQ was measured using Wechsler Adult Intelligence Scale. Assessors were blinded to drug exposures. Results One hundred and sixty-one children (one set of twins and 21 sibling pairs) of 139 mothers were included. As a group, children achieved average scores on neurocognitive outcomes. Children exposed to valproate (n = 22) performed lower on all six neurocognitive domains, especially language, than those exposed to carbamazepine (n = 32), lamotrigine (n = 82) or levetiracetam (n = 25). After controlling for maternal IQ and drug dose, the verbal IQ of valproate-exposed children was on average 9.1 points lower than those exposed to carbamazepine (95% confidence interval [CI] 1.3-17.0; p = 0.023), 10.3 lower than lamotrigine-exposed children (CI 3.4-17.3; p = 0.004) and 13.4 lower than levetiracetam-exposed children (CI 5.2-21.6; p = 0.002). No significant dose-effect was found. Virtually no significant differences were found between lamotrigine and levetiracetam or lamotrigine and carbamazepine exposed children. Conclusions Consistent with previous research, valproate-exposed children experienced more problems compared to three other common antiepileptic drugs, while children exposed to lamotrigine, carbamazepine or levetiracetam revealed little to no problems. This illustrates the need for systematic follow-up of prenatally exposed children, to support pre-pregnancy counseling and treatment decisions in women of reproductive age.

Impactos no Desenvolvimento de Crianças com Mães Epilépticas Submetidas ao Tratamento com Antiepilépticos: uma Revisão Literária/ Developmental Impacts of antiepileptic treatment in Children with Epileptic Mothers: a Literature Review

“…Outro medicamento utilizado é a CBZ, uma AEDs de grande utilização e, até o momento, poucos ou nenhum efeito sobre a neurocognição foram encontrados com relação a essa 8 . Entretanto, tal droga demonstra relação com anomalias congênitas, dentre as quais destacam-se defeitos do septo AV, hipoplasia renal, microcefalia, criptorquidia e espinha bífida 1,11 .…”

“…O conhecimento da teratogenicidade dos medicamentos antiepilépticos aumentou na última década, incluindo a preocupação de que o Valproato de Sódio (VPA) esteja associado a desfechos prejudiciais neurocognitivos e comportamentais do bebê. Como esta droga está associada a malformações e efeitos deletérios, não é mais prescrita rotineiramente para mulheres com potencial para engravidar, o que resultou no aumento do uso de novos medicamentos, como Lamotrigina (LTG), Levetiracetam (LEV) e Carbamazepina (CBZ) 8 .…”

Alternatives to valproate in girls and women of childbearing potential with Idiopathic Generalized Epilepsies: state of the art and guidance for the clinician proposed by the Epilepsy and Gender Commission of the Italian League Against Epilepsy (LICE)

“…No significant overall neurodevelopmental delay has been reported in association with intrauterine exposure to CBZ [5][6][7][8]94]. Although mean performance IQ was significantly lower in exposed subjects than in the pooled group of controls, this significance was lost when they were compared with only the epilepsy controls in a meta-analysis of cohort studies [5].…”

“…Several studies failed to demonstrate a detrimental effect on later cognitive assessment in exposed children [6,94,[103][104][105][106]. Intrauterine exposure to LTG was significantly associated with autism/dyspraxia according to a network meta-analysis; however, when results were adjusted for higher quality studies in terms of the adequacy of follow up of cohorts, the association was no longer significant; moreover, the authors pointed out that several known confounders could not be assessed in most of the included studies [8].…”

“…Although preliminary data are reassuring, there is a consistent lack of evidence regarding possible cognitive adverse outcomes after intrauterine exposure to LEV [6,8,94].…”