Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Abstract

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].

Risks and benefits of psychotropic medication in pregnancy: cohort studies based on UK electronic primary care health records

“…14,15,19,48,[53][54][55]70,71 These included maternal outcomes such as pre-eclampsia, gestational diabetes, caesarean section, and perinatal death; child outcomes such as major congenital malformations and adverse birth outcomes such as low Apgar scores, preterm birth, low birthweight, tremor, agitation, any breathing problems; and problems with the infants' muscle tone, which we divide into 'poor birth outcomes' and 'transient poor birth outcomes'. We also conducted exploratory analyses to evaluate potential associations between psychotropic medication treatment in pregnancy and developmental and behavioural outcomes.…”

The Australian Brain and Cognition and Antiepileptic Drugs Study: IQ in School-Aged Children Exposed to Sodium Valproate and Polytherapy

“…Retrospective ascertainment of drug and medical data in many studies was a further source of potential error. It is, however, becoming increasingly evident that prenatal AED exposure has the potential to affect neurodevelopmental outcomes even in the absence of congenital malformations (Meador, Baker, Cohen, Gaily, & Westerveld, 2007).…”

Intellectual functioning in pediatric patients with epilepsy: a comparison of medically controlled, medically uncontrolled and surgically controlled children

“…Além disso, o grupo não controlado com medicação e o grupo controlado com cirurgia apresentaram maior número de pacientes em politerapia e uso de benzodiazepínicos, quando comparados ao grupo controlado com medicação. Meador et al 24 relataram que algumas drogas antiepilépticas, como o fenobarbital e os benzodiazepínicos, apresentam maior probabilidade de levar ao desenvolvimento de déficits cognitivos do que a carbamazepina, o ácido valproico e os novos medicamentos antiepilépticos. Segundo esses autores, os pacientes em monoterapia com fenitoína, carbamazepina e ácido valproico na faixa terapêutica não apresentaram efeitos cognitivos adversos na concentração, atenção e habilidades psicomotoras quando comparados a voluntários saudáveis.…”