George Mawer

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.

AUTISM SPECTRUM DISORDERS FOLLOWING IN UTERO EXPOSURE TO ANTIEPILEPTIC DRUGS

There is evidence that in utero exposure to teratogenic substances such as thalidomide and alcohol may increase the risk of developing autism spectrum disorder (ASD)1 and that prenatal development may be a critical time. Animal model, case study, and retrospective reports have demonstrated that exposure to antiepileptic drugs (AEDs) in utero may also carry an increased risk for the development of ASD.2–5 ### Methods. The Liverpool and Manchester Neurodevelopment group is currently undertaking a prospective study to investigate the effects of exposure to AEDs in utero. Between 2000 and 2006, 620 women were recruited from antenatal clinics in both Liverpool and Manchester. Information has been collected on 632 live births; 296 births were to women with epilepsy (including 6 twin pairs), 249 of whom were exposed to AEDs at the beginning of gestation. Within the exposed group, 64 children were exposed to sodium valproate (VPA), 44 to lamotrigine (LTG), 76 to carbamazepine (CBZ), 14 to other monotherapy treatments, and 51 to polytherapy treatments. The remaining 47 births were to women with epilepsy who were not on medication. In addition, information has been collected on 336 live births (including two twin pairs) born to women without epilepsy who were not …

The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs

The aim of this study was to compare the prevalence of diagnosed neurodevelopmental disorders in children exposed, in utero, to different antiepileptic drug treatments. A prospective cohort of women with epilepsy and a control group of women without epilepsy were recruited from antenatal clinics. The children of this cohort were followed longitudinally until 6 years of age (n=415). Diagnosis of a neurodevelopmental disorder was made independently of the research team. Multiple logistic regression analysis revealed an increase in risk of neurodevelopmental disorders in children exposed to monotherapy sodium valproate (VPA) (6/50, 12.0%; aOR 6.05, 95%CI 1.65 to 24.53, p=0.007) and in those exposed to polytherapy with sodium VPA (3/20, 15.0%; aOR 9.97, 95% CI 1.82 to 49.40, p=0.005) compared with control children (4/214; 1.87%). Autistic spectrum disorder was the most frequent diagnosis. No significant increase was found among children exposed to carbamazepine (1/50) or lamotrigine (2/30). An accumulation of evidence demonstrates that the risks associated with prenatal sodium VPA exposure include an increased prevalence of neurodevelopmental disorders. Whether such disorders are discrete or represent the severe end of a continuum of altered neurodevelopmental functioning requires further investigation. Replication and extension of this research is required to investigate the mechanism(s) underpinning the relationship. Finally, the increased likelihood of neurodevelopmental disorders should be communicated to women for whom sodium VPA is a treatment option.

Factors Influencing the Incidence of Lamotrigine-Related Skin Rash

OBJECTIVE: To determine the incidences of serious and nonserious lamotrigine-related rash, determine the risk factors for lamotrigine-related rash, and evaluate the impact on the incidence of rash of the manufacturers recommendation to reduce the starting dose of lamotrigine. METHODS: This was a retrospective case record survey at five tertiary referral epilepsy centers in the UK. The risk factors for lamotrigine-related rash were identified by logistic regression. The independent factors tested were gender, age, epilepsy type, concurrent medication, and starting dose of lamotrigine. The incidences of rash before and after the recommendation of reduction in starting dose were compared by •2 analysis. RESULTS: A total of 1050 patients were included. The incidences of serious and nonserious rash were 1.1% (95% CI 0.5% to 1.8%) and 7% (95% CI 5.5% to 8.6%), respectively. Females were at higher risk of developing rash than were males, with a relative risk of 1.8 (95% CI 1.2 to 2.8). The starting dose of lamotrigine was reduced in response to the manufacturers recommendation, and there was a significant reduction (p = 0.045) in the incidence of serious rash, from 1.5% (12/805) to 0% (0/245). However, there was no reduction in the overall incidence of lamotrigine-related rash, with 63/805 (8%) before and 23/245 (9%) after the recommendation. CONCLUSIONS: Failure to detect a reduction in the incidence of lamotrigine-related rash since the new (reduced) recommended starting dose of lamotrigine may arise from failure to reduce the starting dose below a critical threshold level, incomplete compliance with current recommendations, or insufficient sample size. The results of this and other studies show that the starting dose of lamotrigine is a significant factor affecting the incidence of rash; furthermore, this study also shows that significant reduction in the incidence of serious rash can be achieved by reducing the starting dose. Therefore, clinicians should not deviate from the recommendations.

IQ at 6 years after in utero exposure to antiepileptic drugs A controlled cohort study

Objective: To delineate the risk to child IQ associated with frequently prescribed antiepileptic drugs. Methods: Children born to women with epilepsy (n = 243) and women without epilepsy (n = 287) were recruited during pregnancy and followed prospectively. Of these, 408 were blindly assessed at 6 years of age. Maternal and child demographics were collected and entered into statistical models. Results: The adjusted mean IQ was 9.7 points lower (95% confidence interval [CI] −4.9 to −14.6; p < 0.001) for children exposed to high-dose (>800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, and spatial subscales. Children exposed to high-dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8.0, 2.5–19.7; p < 0.001). Valproate at doses <800 mg daily was not associated with reduced IQ, but was associated with impaired verbal abilities (−5.6, 95% CI −11.1 to −0.1; p = 0.04) and a 6-fold increase in educational intervention (95% CI 1.4–18.0; p = 0.01). In utero exposure to carbamazepine or lamotrigine did not have a significant effect on IQ, but carbamazepine was associated with reduced verbal abilities (−4.2, 95% CI −0.6 to −7.8; p = 0.02) and increased frequency of IQ <85. Conclusions: Consistent with data from younger cohorts, school-aged children exposed to valproate at maternal doses more than 800 mg daily continue to experience significantly poorer cognitive development than control children or children exposed to lamotrigine and carbamazepine.

Outcome of pregnancy in women attending an outpatient epilepsy clinic: adverse features associated with higher doses of sodium valproate

The risk of an adverse outcome to pregnancy is increased in women with epilepsy. This is partly attributable to antiepileptic drugs. Guidelines for the management of pregnancy in women with epilepsy generally advise against polytherapy but make no distinction between the risks of different drugs. Several recent studies have however shown greater risk of adverse outcome in offspring exposed to sodium valproate in utero, particularly at higher doses. The outcome of pregnancy was monitored to identify antiepileptic drug treatment associated with a poor outcome in a mainly prospective study of women attending an outpatient clinic. From January 1990 to December 1999 all 69 pregnancies in women referred to the clinic were monitored. Drug treatments and other risk factors were recorded. In each child dysmorphic features, developmental delay and structural anomalies were assessed and graded. Data were analysed for drug- and dosage-dependent differences in outcome. In each assessment area a positive association between adverse outcome and dose was found for sodium valproate but not for carbamazepine. Severe adverse outcomes were found only in children exposed to sodium valproate at maternal doses above 1000 mg per day.

Early cognitive development in children born to women with epilepsy: A prospective report

Purpose:  In this prospective study the early cognitive development of children born to women with epilepsy (n = 198) was assessed and compared to a group of children representative of the general population (n = 230).

Pregnancy with epilepsy: Obstetric and neonatal outcome of a controlled study

PURPOSE To determine the influence of epilepsy and its treatment on pregnancy and its outcome. DESIGN Controlled, observational study. SETTING National Health Service maternity hospitals in Liverpool and Manchester regions. POPULATION 277 women with epilepsy (WWE) and 315 control women. METHODS WWE were recruited from antenatal clinics. Controls were matched for age and parity but not gestational age. Information was obtained by interview and from clinical records. MAIN OUTCOME MEASURES Obstetric complications, mode of delivery, condition of newborn. RESULTS Distribution of epilepsy syndromes was similar to previous surveys. Most WWE (67%) received monotherapy with carbamazepine, sodium valproate or lamotrigine. Half WWE had no seizures during pregnancy but 34% had tonic clonic seizures. Seizure-related injuries were infrequent. Pregnancies with obstetric complications were increased in women with treated epilepsy (WWTE 45%, controls 33%; p=0.01). Most had normal vaginal delivery (WWTE 63%, controls 61%; p=0.65). Low birth weight was not increased (WWTE 6.2%, controls 5.2%; p=0.69). There were more major congenital malformations (MCM) (WWTE 6.6%, controls 2.1%; p=0.02) and fetal/infant deaths (WWTE 2.2%, controls 0.3%; p=0.09). Amongst monotherapies MCM prevalence was highest with valproate (11.3%; p=0.005). Lamotrigine (5.4%; p=0.23) and carbamazepine (3.0%; p=0.65) were closer to controls (2.1%). There was no association between MCM and dose of folic acid pre-conception. CONCLUSION MCM were more prevalent in the babies of WWTE particularly amongst those receiving sodium valproate.

The Long‐Term Use of Gabapentin, Lamotrigine, and Vigabatrin in Patients with Chronic Epilepsy

Summary: Purpose: To compare the long‐term retention of gabapentin (GBP), lamotrigine (LTG), and vigabatrin (VGB) by patients with chronic epilepsy and the reasons for treatment discontinuation. To assess the likelihood of seizure freedom, seizure‐related injury/hospital admission and mortality after these drugs were commenced.

Seizure Frequency and Major Life Events in Epilepsy

Summary: A group of 18 patients with chronic epilepsy were followed in an outpatient clinic for 1–6 years. Month‐by‐month seizure records were kept and the response to treatment was systematically explored. The present study was prompted when three patients became seizure‐free, apparently in response to major life events (marriage, parenthood, and retirement) rather than to changes in treatment. All the subjects were interviewed in their own homes with a companion, friend, or relative present. The interview was based on a standard instrument (Life Experiences Survey, LES). The home environment was chosen to facilitate recall of events and to enable subjects to confirm dates. The seizure record was then compared with the parallel life events record. Two methods of analysis were adopted. In the first, each life event was assumed to have impact on seizure frequency only during the month in which it occurred; life event months were compared with non‐life‐event months. In the second, a life event was considered a watershed; seizure frequencies before and after the event were compared. Nonparametric statistical methods were used. These approaches revealed associations between life events and seizure frequency in three additional patients (total six). Most of the patients who showed an association experienced partial seizures.