Normal intelligence in children with prenatal exposure to carbamazepine

Gaily, Eija; Kantola-Sorsa, Elisa; Hiilesmaa, Vilho; Isoaho, M.; Matila, Riitta; Kotila, Mervi; Nylund, T.; Bardy, A.; Kaaja, Erja; Granström, Marja‐Liisa

doi:10.1212/wnl.62.1.28

Cited by 271 publications

(318 citation statements)

References 19 publications

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“…Pooled data from two prospective population-based studies [55,56] showed a 1.9% (2/105) incidence of mental deficiency in carbamazepine monotherapy-exposed children of WWE. One of the two children had West syndrome in infancy as a possible etiology.…”

Section: Carbamazepinementioning

confidence: 99%

“…Carbamazepine monotherapy was the most common AED exposure in two recent prospective, controlled, population-based studies [56,57] with blinded evaluation of outcome. These studies included approximately 50% of the population of children born to WWE in their catchment areas: carbamazepine monotherapy exposures numbered 35 in the former and 86 in the latter study.…”

Section: Carbamazepinementioning

confidence: 99%

“…These studies included approximately 50% of the population of children born to WWE in their catchment areas: carbamazepine monotherapy exposures numbered 35 in the former and 86 in the latter study. Blinded assessment of DQ or IQ was done at ages 2-8 using the Griffiths test [57] or at 5-11 years with the age-appropriate Wechsler scale [56]. No IQ impairment was found in the children exposed to carbamazepine monotherapy compared with nonexposed children of WWE or controls.…”

Section: Carbamazepinementioning

confidence: 99%

“…At present, prospective data on IQ scores in children with prenatal valproate monotherapy exposure are available only for 26 children from two population-based, evaluator-blinded studies [56,68]. In both studies, verbal IQ was 11-13 points lower in the valproate monotherapy-exposed group than in children not exposed to AEDs or exposed to carbamazepine monotherapy.…”

Section: Valproatementioning

confidence: 99%

“…Polytherapy exposure in utero carries an increased risk of malformations and lower cognitive functioning [56,72,73]. Although attempts should be made to avoid polytherapy in pregnancy, there are women whose seizures, pain, or psychiatric disorders cannot be controlled with monotherapy.…”

Section: Polytherapymentioning

confidence: 99%

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Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Meador

Baker

Cohen

et al. 2007

Epilepsy & Behavior

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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].

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Section: Carbamazepinementioning

confidence: 99%

Section: Carbamazepinementioning

confidence: 99%

Section: Carbamazepinementioning

confidence: 99%

Section: Valproatementioning

confidence: 99%

Section: Polytherapymentioning

confidence: 99%

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Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Meador

Baker

Cohen

et al. 2007

Epilepsy & Behavior

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Two-Year-Old Cognitive Outcomes in Children of Pregnant Women With Epilepsy in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study

et al. 2021

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IMPORTANCEThe neurodevelopmental risks of fetal exposure are uncertain for many antiseizure medications (ASMs).OBJECTIVE To compare children at 2 years of age who were born to women with epilepsy (WWE) vs healthy women and assess the association of maximum ASM exposure in the third trimester and subsequent cognitive abilities among children of WWE. DESIGN, SETTING, AND PARTICIPANTSThe Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational, multicenter investigation of pregnancy outcomes that enrolled women from December 19, 2012, to January 13, 2016, at 20 US epilepsy centers. Children are followed up from birth to 6 years of age, with assessment at 2 years of age for this study. Of 1123 pregnant women assessed, 456 were enrolled; 426 did not meet criteria, and 241 chose not to participate. Data were analyzed from February 20 to December 4, 2020.MAIN OUTCOMES AND MEASURES Language domain score according to the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), which incorporates 5 domain scores (language, motor, cognitive, social-emotional, and general adaptive), and association between BSID-III language domain and ASM blood levels in the third trimester in children of WWE. Analyses were adjusted for multiple potential confounding factors, and measures of ASM exposure were assessed. RESULTSThe BSID-III assessments were analyzed in 292 children of WWE (median age, 2.1 [range, 1.9-2.5] years; 155 female [53.1%] and 137 male [46.9%]) and 90 children of healthy women (median age, 2.1 [range, 2.0-2.4] years; 43 female [47.8%] and 47 male [52.2%]). No differences were found between groups on the primary outcome of language domain (−0.5; 95% CI, −4.1 to 3.2). None of the other 4 BSID-III domains differed between children of WWE vs healthy women. Most WWE were taking lamotrigine and/or levetiracetam. Exposure to ASMs in children of WWE showed no association with the language domain. However, secondary analyses revealed that higher maximum observed ASM levels in the third trimester were associated with lower BSID-III scores for the motor domain (−5.6; 95% CI, −10.7 to −0.5), and higher maximum ASM doses in the third trimester were associated with lower scores in the general adaptive domain (−1.4; 95% CI, −2.8 to −0.05). CONCLUSIONS AND RELEVANCEOutcomes of children at 2 years of age did not differ between children of WWE taking ASMs and children of healthy women.

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Breastfeeding in Children of Women Taking Antiepileptic Drugs

et al. 2014

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IMPORTANCE Breastfeeding is known to have beneficial effects, but concern exists that breastfeeding during maternal antiepileptic drug (AED) therapy may be harmful. We previously noted no adverse effects of breastfeeding associated with AED use on IQ at age 3 years, but IQ at age 6 years is more predictive of school performance and adult abilities. OBJECTIVES To examine the effects of AED exposure via breastfeeding on cognitive functions at age 6 years. DESIGN, SETTING, AND PARTICIPANTS Prospective observational multicenter study of long-term neurodevelopmental effects of AED use. Pregnant women with epilepsy receiving monotherapy (ie, carbamazepine, lamotrigine, phenytoin, or valproate) were enrolled from October 14, 1999, through April 14, 2004, in the United States and the United Kingdom. At age 6 years, 181 children were assessed for whom we had both breastfeeding and IQ data. All mothers in this analysis continued taking the drug after delivery. MAIN OUTCOMES AND MEASURES Differential Ability Scales IQ was the primary outcome. Secondary measures included measures of verbal, nonverbal, memory, and executive functions. For our primary analysis, we used a linear regression model with IQ at age 6 years as the dependent variable, comparing children who breastfed with those who did not. Similar secondary analyses were performed for the other cognitive measures. RESULTS In total, 42.9% of children were breastfed a mean of 7.2 months. Breastfeeding rates and duration did not differ across drug groups. The IQ at age 6 years was related to drug group (P italic> .001 [adjusted IQ worse by 7–13 IQ points for valproate compared to other drugs]), drug dosage (regression coefficient, −0.1; 95% CI, −0.2 to 0.0; P = .01 [higher dosage worse]), maternal IQ (regression coefficient, 0.2; 95% CI, 0.0 to 0.4; P = .01 [higher child IQ with higher maternal IQ]), periconception folate use (adjusted IQ 6 [95% CI, 2–10] points higher for folate, P = .005), and breastfeeding (adjusted IQ 4 [95% CI, 0–8] points higher for breastfeeding, P = .045). For the other cognitive domains, only verbal abilities differed between the breastfed and nonbreastfed groups (adjusted verbal index 4 [95% CI, 0–7] points higher for breastfed children, P = .03). CONCLUSIONS AND RELEVANCE No adverse effects of AED exposure via breast milk were observed at age 6 years, consistent with another recent study at age 3 years. In our study, breastfed children exhibited higher IQ and enhanced verbal abilities. Additional studies are needed to fully delineate the effects of all AEDs. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00021866

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Normal intelligence in children with prenatal exposure to carbamazepine

Cited by 271 publications

References 19 publications

Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Two-Year-Old Cognitive Outcomes in Children of Pregnant Women With Epilepsy in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study

Breastfeeding in Children of Women Taking Antiepileptic Drugs

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