The behavioral consequences of exposure to antiepileptic drugs in utero.

The aim of the study was to examine the behavior of 242 children, aged between 6 and 16 years, born to mothers with epilepsy. Exposure to sodium valproate (VPA) in utero was associated with high levels of parental stress induced by the child's maladaptive behavior. These children were also poorer for daily living skills and skills relating to socialization. The outcomes on both measures were strongly affected by the Full Scale IQ (FSIQ) of the child; however, no significant differences were found between the groups and therefore this pattern of results cannot simply be attributed to a lower FSIQ. The results of this study suggest that exposure to VPA in utero and the presence of a lowered FSIQ are risk factors for the development of poorer adaptive behavior and a higher rate of maladaptive behaviors.

Dysmorphic features: an important clue to the diagnosis and severity of fetal anticonvulsant syndromes.

BACKGROUND: In utero exposure to antiepileptic drugs (AEDs) can result in several different teratogenic effects including major malformations, dysmorphic facial features, and learning and behavioural problems. It is estimated that there is a 2-3-fold increase in the risk of malformations compared with the general population. The risk of cognitive impairment and behavioural problems is less clear. OBJECTIVE: To report the frequency and specificity of individual dysmorphic features and to relate the dysmorphic facial phenotype to developmental outcome. METHODS: A retrospective study of 375 children born to 219 mothers with epilepsy. The age of the study group ranged from 6 months to 16 years. Each child underwent a physical examination and a battery of neuropsychological tests. Dysmorphic features were scored from photographs on a blind basis by a panel of dysmorphologists. RESULTS: A total of 274 children were exposed to AEDs (63 to valproate, 94 to carbamazepine, 26 to phenytoin, 15 to other monotherapies, and 76 to polytherapy). Major malformations were identified in 14% of children exposed to valproate in utero, 5% exposed to carbamazepine, and 4% in the non-exposed group. Overall, 47% of exposed children were correctly identified as having been exposed to AEDs in utero. There was a significant correlation between verbal intelligence quotient and dysmorphic facial features in the valproate exposed children only. CONCLUSION: Children exposed to valproate have more distinctive facial features, but a subtle and distinctive facial phenotype is also seen in children exposed to carbamazepine. Nearly half (45%) of unexposed children had some of the facial features associated with AED exposure, showing that many of these features may be seen as part of normal variation and that the diagnosis of the fetal anticonvulsant syndrome is difficult to make on the basis of facial gestalt alone. Developmental surveillance should be offered to children with prenatal exposure to AEDs, particularly those with exposure to high doses of valproate.

Neuropsychological effects of exposure to anticonvulsant medication in utero.

OBJECTIVE: To investigate the long-term differential drug effects on cognitive functioning in school-aged children exposed to antiepileptic drugs (AEDs) in utero. METHODS: Mothers with epilepsy were recruited from specialist epilepsy clinics and obstetric clinics from the Liverpool and Manchester region. The mothers and their children were recruited without prior knowledge of their AED treatment during pregnancy or the health of the offspring. A battery of neuropsychological tests was applied to each mother-child pair in order to obtain a neuropsychological profile for each child. RESULTS: Neuropsychological investigation was performed on 249 children between the ages of 6 and 16. Children exposed to sodium valproate had a significantly lower verbal IQ when compared to children exposed to other antiepileptic drugs or not exposed at all. The same children were more likely to have an IQ below 69 and more likely to have memory impairment when compared to the other groups. The mothers' IQ, exposure to sodium valproate, and the number of tonic-clonic seizures during pregnancy were significant predictors of verbal IQ in this population. CONCLUSIONS: This retrospective study highlights the potential harmful effects of sodium valproate exposure in utero on neuropsychological development.

The longer term outcome of children born to mothers with epilepsy.

OBJECTIVES: To determine the prevalence of cognitive delay and possible associated dysmorphic features in children exposed to antiepileptic drugs (AEDs) in utero. DESIGN: Retrospective study of children born to mothers with epilepsy. SETTING: Regional epilepsy clinics in Liverpool and Manchester, UK. PARTICIPANTS: Children aged between 6 months and 16 years born to mothers with epilepsy. MAIN OUTCOME MEASURES: Structured interviews, hospital records, clinical examination, and psychometric tests (Wechsler) were used to assess exposure and intelligence quotient (IQ). Blinded assessment of photographs was used to score children with characteristic dysmorphic features. RESULTS: A total of 249 children aged 6 and over were studied: 41 were exposed to sodium valproate, 52 to carbamazepine, 21 to phenytoin, 49 to polytherapy, and 80 were unexposed. Mean verbal IQ was significantly lower in the valproate group compared to unexposed and other monotherapy groups. Multiple regression analysis showed that both valproate exposure and frequent tonic-clonic seizures in pregnancy were significantly associated with a lower verbal IQ despite adjusting for other confounding factors. There was a significant negative correlation between dysmorphic features and verbal IQ in children exposed to valproate. CONCLUSIONS: This study identifies valproate as a drug carrying potential risks for developmental delay and cognitive impairment and is the first to suggest that frequent tonic-clonic seizures have a similar effect. Our results need to be interpreted with caution given their retrospective nature. Women with epilepsy need careful counselling about individual risk benefit of AED treatment before pregnancy.

Common antiepileptic drugs in pregnancy in women with epilepsy.

BACKGROUND: The potential adverse effects of antiepileptic drug (AED) exposure in pregnancy have been well recognised but the relative risks of specific antiepileptic drug exposures remain poorly understood. OBJECTIVES: To assess the adverse effects of commonly used antiepileptic drugs on maternal and fetal outcomes in pregnancy in women with epilepsy. Comparison of outcomes following specific antiepileptic drug exposures in utero to unexposed pregnancies in the general population or women with epilepsy are described. The current manuscript reports the first phase of this review which focuses upon neurodevelopmental outcomes in children exposed to antiepileptic drugs in utero. SEARCH STRATEGY: We searched MEDLINE, Pharmline, EMBASE, Reprotox and TERIS from 1966 to December 2003. Review articles and conference abstracts were also hand searched. SELECTION CRITERIA: All randomized controlled trials, prospective cohorts of children of pregnant women with and without epilepsy and case control studies (cases: developmental delay or impaired cognitive outcome, control: normal development) were included. DATA COLLECTION AND ANALYSIS: Methodological quality was assessed using an adapted version of the Newcastle-Ottawa Scale. The wide variety of outcome measures and methodological approaches made meta-analysis difficult and a descriptive analysis of the results is presented. MAIN RESULTS: PART A 1b - DEVELOPMENTAL OUTCOMES: The majority of studies were of limited quality. There was little evidence about which specific drugs carry more risk than others to the development of children exposed in utero. The results between studies are conflicting and while most failed to find a significant detrimental outcome with in utero exposure to monotherapy with carbamazepine, phenytoin or phenobarbitone, this should be interpreted cautiously. There were very few studies of exposure to sodium valproate. Polytherapy exposure in utero was more commonly associated with poorer outcomes, as was exposure to any AEDs when analysis did not take into account type of AED. The latter may reflect the large proportion of children included in these studies who were in fact exposed to polytherapy. REVIEWERS' CONCLUSIONS: PART A 1b - DEVELOPMENTAL OUTCOMES: Based on the best current available evidence it would seem advisable for women to continue medication during pregnancy using monotherapy at the lowest dose required to achieve seizure control. Polytherapy would seem best avoided where possible. More population based studies adequately powered to examine the effects of in utero exposure to specific monotherapies which are used in everyday practice are required.

Additional educational needs in children born to mothers with epilepsy.

OBJECTIVES: To examine the relative risks of additional educational needs (AENs) in children exposed to antiepileptic drug (AED) monotherapy and polytherapy regimes in utero. METHODS: A retrospective survey of women between the ages of 16 to 40 registered at the Mersey Regional Epilepsy Clinic, who received a postal questionnaire concerning their experience of pregnancy and the subsequent schooling of live-born children. RESULTS: 721 (57%) women of the 1267 approached returned an adequately completed questionnaire; 330 (46%) had given birth to at least one live-born child. Information was collected on 594 children, 400 of whom were of school age (4-18). 150 (37.5%) had been exposed to monotherapy in utero, 74 (18.5%) were exposed to polytherapy, and 176 were not exposed to any AEDs. The odds ratio of AENs for all children exposed to AEDs in utero compared with those unexposed was 1.49 (95% confidence interval (95% CI) 0.83 -2.67). Odds ratios for AENs for each therapy subgroup compared with those unexposed were also calculated for all children. Those exposed to valproate monotherapy had an odds ratio of 3.4 (95% CI 1.63-7.10) by contrast with an odds ratio of 0.26 (95% CI 0.06- 1.15) for carbamazepine. Polytherapy including valproate had similarly high odds ratios for AENs compared with those unexposed of 2.51 ( 95% CI 1.04-6.07) versus the odds ratio of 1.51 ( 95% CI 0.56-4.07) for polytherapy excluding valproate. CONCLUSIONS: Although the findings should be treated with caution, they suggest that monotherapy or polytherapy with valproate during pregnancy carries particular risks for the development of children exposed in utero.

Hepatic sarcoidosis complicated by hepatocellular carcinoma.

A case of a 63-year-old man with a long-standing history of portal hypertension secondary to hepatic sarcoidosis who developed hepatocellular carcinoma is reported.