School Aged Cognition in Children Exposed to Levetiracetam, Topiramate Or Sodium Valproate

1

Bromley 2015

School aged cognition in children exposed to levetiracetam, topiramate or sodium valproate

Rebecca L Bromley, PhD1,2*., Rebecca Calderbank, BSc3., Christopher P Cheyne, PhD4, Claire Rooney, BSc5., Penny Trayner, ClinPsyD6., Jill Clayton-Smith, MD1,7., Marta García-Fiñana, PhD4., Beth Irwin, RGN8., James Irvine Morrow, MD8., Rebekah Shallcross, PhD9., & Gus A Baker, PhD10. On behalf of the UK Epilepsy and Pregnancy Register.

1 Institute of Human Development, University of Manchester, Manchester, UK.

2Royal Manchester Children’s Hospital, Manchester, UK.

3Department of Clinical Psychology, University of Lancaster, Lancaster, UK.

4Department of Biostatistics, University of Liverpool, UK.

5 Neuropsychology Trauma Pathway, Merseycare NHS Trust, Liverpool, UK.

6Department of Clinical Psychology, University of Manchester, UK.

7 Manchester Centre For Genomic Medicine, St Mary’s Hospital, Manchester, UK.

8 Department of Neurology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.

9Centre for Women’s Mental Health, The University of Manchester, Manchester, UK.

10Department of Molecular and Clinical Pharmacology, University of Liverpool, UK.

* Correspondence to Dr Rebecca Bromley, Institute of Human Development, University of Manchester, Manchester, UK. +44 161 701 4514. .

Title Character Count: 90, Abstract Word Count: 225, Word Count: 2988, Tables 5, Web Tables 2, Figures 0.

Key Words: [61] antiepileptic drugs, [199] neuropsychology/behaviour, [60] epilepsy/seizures, pregnancy, teratogenicity.

Author Contributions

Dr Bromley contributed to the acquisition of funding, the conception and design of the study, data collection, study coordination, analysis and interpretation of data, drafting the article, and final approval. Dr Bromley accepts full responsibility for the finished article, had access to any data, and controlled the decision to publish. Ms Calderbank contributed to data collection, interpretation of data, drafting of the article, and final approval. Dr Cheyne conducted the analysis and contributed to the interpretation of data, drafting the article and final approval. Ms Rooney contributed to data collection, interpretation of data, drafting of the article, and final approval. Dr Trayner contributed to data collection, interpretation of data, drafting of the article, and final approval. Professor Clayton-Smith contributed to the conception and design of the study, analysis and interpretation of data, drafting the article, and final approval. Dr García-Fiñana supervised the data analysis and contributed to the interpretation of results, drafting of the article and final approval. Ms Irwin contributed to data collection, interpretation of data, drafting of the article, and final approval. Dr Morrow contributed to the acquisition of funding, conception and design of the study, analysis and interpretation of data, drafting the article, and final approval. Dr Shallcross contributed to data collection, interpretation of data, drafting of the article, and final approval. Professor Baker contributed to acquisition of funding, conception and design of the study, analysis and interpretation of data, drafting the article, and final approval.

Study Funding

The study was soley funded by Epilepsy Research UK (P0902). During the write up period of this work Dr Bromley was funded by the National Institute for Health Research (NIHR) (PDF-2013-06-041).

Disclosure

R. Bromley has received lecture fees from Sanofi Aventis (two occasions); received conference travel support from UCB Pharma and provided expert testimony pertaining to fetal anticonvulsant syndrome.

R. Calderbank reports no disclosures relevant to the manuscript.

C. Cheyne reports no disclosures relevant to the manuscript.

C. Rooney reports no disclosures relevant to the manuscript.

P. Trayner reports no disclosures relevant to the manuscript.

J. Clayton-Smith has given expert testimony pertaining to fetal anticonvulsant syndrome.

M. García-Fiñana reports no disclosures relevant to the manuscript.

B. Irwin received sponsorship to attend meetings and honoraria for presentations from Eisai, UCB and Sanofi-Aventis.

J. Morrow has received unrestricted educational grants from Eisai, Glaxo Smith Kline, Novartis, Sanofi-Aventis, Pfizer and UCB for the running of the UK Epilepsy and Pregnancy Register.

R. Shallcross has attended conferences with the support of UCB Pharma and has received honorarium for lectures.

G. Baker has received educational grants from Sanofi Aventis to support this research directly; he has received educational grants from UCB Pharma and lecture speaker fees from Sanofi Aventis, UCB Pharma and GSK. Professor Baker has given expert testimony on fetal anticonvulsant Syndrome.

Objective: To investigate the effects of prenatal exposure to monotherapy levetiracetam, topiramate and valproate on child cognitive functioning.

Methods: This was a cross sectional observational study. Children exposed to monotherapy levetiracetam (n=42), topiramate (n=27) or valproate (n=47) and a group of children born to women who had untreated epilepsy (n=55) were enrolled retrospectively from the UK Epilepsy and Pregnancy Register. Assessor blinded neuropsychological assessments were conducted between five and nine years of age. Information was collected on demographic and health variables and adjusted for in multiple regression analyses.

Results: In the adjusted analyses prenatal exposure to levetiracetam and topiramate were not found to be associated with reductions in child cognitive abilities and adverse outcomes were not associated with increasing dose. Increasing dose of valproate however was associated with poorer FSIQ (-10.6, 95% CI -16.3 to -5.0, p<0.001), verbal abilities (-11.2, 95% CI -16.8 to -5.5, p<0.001), non-verbal abilities (-11.1, 95% CI -17.3 to -4.9, p<0.001) and expressive language ability (-2.3, 95% CI -3.4 to -1.6, p<0.001). Comparisons across medications revealed poorer performance for children exposed to higher doses of valproate in comparison to children exposed to higher doses of levetiracetam or topiramate.

Conclusions: Preconception counselling should include discussion of neurodevelopmental outcomes for specific treatments and their doses and women should be made aware of the limited nature of the evidence base for newer antiepileptic drugs.

Introduction

Concern about the use of valproate in women of childbearing age has led to a shift in prescribing practices towards newer antiepileptic drugs (AEDs), especially levetiracetam, lamotrigine and topiramate(1-3). Prenatal exposure to lamotrigine has been demonstrated to be associated with significantly higher neuropsychological functioning than children exposed to valproate; both in infancy(4, 5) and at school age(6, 7). However, there is extremely limited evidence regarding the risks that may be associated with exposure to levetiracetam or topiramate(8). For infants exposed to levetiracetam, consistent neurodevelopment with control infants and superior development in comparison to infants exposed to valproate at one and three years of age has been reported (9,10). Only a single study has reported on the neurodevelopment of children exposed to topiramate and although this documents an association between prenatal exposure and reduced neurodevelopmental outcome, its findings are substantially limited due to the topiramate cohort size (n=9)(11).

This study aimed to delineate the cognitive abilities of school-aged children exposed prenatally to monotherapy levetiracetam or topiramate in comparison to children born to women with untreated epilepsy and children exposed to valproate. This study had a directional hypothesis, which stated that children exposed to levetiracetam or topiramate would not differ from control children in their cognitive abilities but would have performed significantly higher than the children exposed to valproate on measures of cognitive ability. Child IQ was the primary outcome variable with other, more specific cognitive abilities, investigated as secondary outcome variables.

Procedure

The study was a cross-sectional observational study. Mother-infant pairs were identified from the UK Epilepsy and Pregnancy Register (UK-EPR), a national pregnancy register which investigates the prevalence of major congenital malformations following exposure to AEDs. Detailed information about the register and its methodology have been reported previously(12). Women with epilepsy were enrolled onto UK-EPR through self-referral or referral by their health professional. Recruitment occurs within the first or second trimester facilitating prospective documentation about health and well being during the pregnancy. Within three months of birth, details about the birth and health of the child are reported to the register by local health care services. Mother-infant pairs were eligible for inclusion in this neurodevelopment follow up study if: the infant had been a live birth between September 2004 and May 2007 and mothers were taking either levetiracetam, topiramate or valproate monotherapy or they were untreated during their pregnancy. Recruitment was national across the UK. Families were not invited to participate if their child had a genetic condition associated with neurodevelopmental impairment. Initially, this study also aimed to investigate the neurodevelopment of children exposed to gabapentin in utero; however the numbers enrolled in the UK-EPR were low. Means and SDs for the gabapentin data (n=14) are reported in table format for information.

Enrolment into this follow up study was retrospective. There were approximately three times more eligible participants for the valproate exposed group and the no medication group, than for the other exposure groups and therefore each third mother identified was included in the recruitment list for these two groups. Recruitment letters and information sheets were posted out to those identified. A follow-up letter was issued if no response had been received. Mother-infant pairs who returned a positive response were formally enrolled into the study and informed consent taken.

Pregnancy details and details about the mother’s epilepsy, including AED dose and seizure information, were collected from the prospectively collected records of the UK-EPR. No seizure diaries or frequent monitoring of seizure activity had been taken and therefore seizure exposure was dichotomised as present or absent. Details of the mother and father’s educational history and employment were collected through a semi-structured interview at the time of the assessment. Alcohol, nicotine and concomitant medication use for the second and third trimesters, which is not routinely collected by the UK-EPR, were collected through maternal report retrospectively. Maternal intellectual functioning was measured with the Test of Non-verbal Intelligence (TONI)(13).

Sixty percent of children exposed to levetiracetam and 20% of children exposed to valproate enrolled into this study were previously assessed at three years of age as part of an ongoing study(9), but were not part of the infant cohort reported by this study group(10).

Neuropsychological assessments were conducted blinded by authors R.B, R.C, C.R or R.S. either in the child’s home or school. The assessment battery included the Wechsler Intelligence Scale for Children –IV edition (WISC-IV)(14) or the Wechsler Preschool and Primary Intelligence Scale (WPPSI-III)(15) if the child was five years of age. The primary outcome measures were the full-scale intelligence quotient (FSIQ), verbal index, non-verbal index and the processing speed index. Analysis of these outcomes was adjusted for administered assessment test version (WISC-IV or WPPSI-III). Specific cognitive domains were assessed utilising subtests from the NEPSY: A Neuropsychological Assessment (NEPSY), 2nd edition(16) and the Clinical Evaluation of Language Fundamentals, 4th edition (CELF-IV)(17), with parental rating of behaviour collected using the Behavioural Assessment Schedule for Children (BASC), 2nd edition(18). Assessments were double scored and data entry double-checked to minimise errors. Feedback was provided to the family on the outcome of the assessments.

The data were analysed using multiple linear regression. The following covariates were considered: maternal epilepsy type, treatment group, dose, professional employment, maternal IQ, maternal age, gestational age of child at birth, gender, age and exposure to seizures, tobacco or alcohol. Inverse probability weighting(19) was used to account for the influence of missing outcomes. The analysis of AED doses utilised dose recorded in the UK-EPR at enrolment, which represents dose around the time of conception. For the purposes of comparison between the AED types, doses were standardized by dividing dose by the median dose for each respective AED type. The median was used due to the doses having skewed distributions. To take into account that three components of child IQ were investigated, multiple comparisons were considered when interpreting the results of the primary analysis. The secondary analyses, which involve a large number of statistical models (23 different models) have been added for completeness but should be regarded as merely exploratory. In a separate analysis, comparisons across AEDs were made at different dose levels (0.5 times median dose, median dose, 1.5 times median dose and two times median dose) for the primary outcome. Data analysis was performed using the statistical packages MLwiN 2.16 and R i386 3.1.1.

Standard Protocol Approvals, Registrations and Patient Consents

Approval was obtained from the North West Regional Ethics Committee, UK and Belfast Health and Social Care Trust who host the UK-EPR. All participants provided informed written consent.

Results

Four hundred and forty nine participant invitations to participate were sent out with 201 positive responses received (45%). Forty cases declined participation (9%), whilst the majority did not respond (46%). Of the 201 positive responses, 16 cases (8%) required exclusion due to conditions likely to impact on cognitive functioning (e.g. brain injury, meningitis) or were too old (>9 years) by the time of assessment. Therefore 185 of the 449 who were sent letters completed the assessment (41%). The percentage completing the study from the available sample on the UK-EPR varied by treatment group (no medication 35% of those eligible, topiramate 53%, levetiracetam 67%, gabapentin 58% and valproate 31%).

Table 1 and 2

The groups were comparable across the majority of demographic variables (Table 1). However, differences were found in terms of frequency of seizures, with those exposed to levetiracetam being exposed to the highest number of seizures (43%). The mothers of children exposed to valproate were older and they had the highest mean maternal IQ and level of folate supplementation (Table 1).

Children exposed to valproate had the lowest unadjusted mean scores for FSIQ and verbal reasoning (Table 2) and across a number of other cognitive and behavioural domains (Table 3).

In the adjusted analyses exposure to levetiracetam was not found to be associated with reductions in FSIQ, verbal abilities, non-verbal abilities or processing speed (Table 4) and dose of levetiracetam was not predictive of poorer outcome. Consistently, being exposed to levetiracetam was not associated with poorer outcomes on language, memory, attention and executive functioning or behavioural variables when outcomes were adjusted for covariates (Table 5 and Web Table e-1). Similarly for topiramate, no association with prenatal exposure was found for FSIQ, verbal abilities, non-verbal abilities or processing speed and dose of topiramate was not predictive of poorer outcomes (Table 4). In terms of specific cognitive and behavioural outcomes, prenatal exposure to topiramate was not associated with poorer outcomes across the domains but had higher scores (better performance) on one aspect of attention and executive functioning in comparison to the control children (Table 5 and Web Table e-1). A dose effect was observed for valproate, with higher doses of valproate associated with poorer FSIQ, verbal and non-verbal abilities. In particular, an increment of 800mg (median value) of valproate was significantly associated with a 10.6 point reduction in FSIQ, a 11.2 point reduction in verbal abilities and a 11.1 point reduction in non-verbal abilities (Table 4). Secondary analyses suggested that valproate may also be associated with poorer outcomes on the expressive naming index as well as the behavioural variables of withdrawal, adaptability and daily living skills but not other measures of language, memory, attention and executive functioning or behavioural outcomes (Table 5 and Web Table e-1).