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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. Rebecca.bromley@manchester.ac.uk.

Title Character Count: 90, Abstract Word Count: 225, Word Count: 2988, Tables 5, Web Tables

2, Figures 0.

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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

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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.

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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

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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

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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).

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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)

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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

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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).

Table 3 and 4

AED comparisons by dose

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At half the median dose of valproate (400mg/d) no significant differences were found in

comparison to children exposed to half the median doses for levetiracetam (750mg/d) or

topiramate (100mg/d) or in comparison to no medication controls for FSIQ, verbal or non-verbal

reasoning (Web Table e-2). Comparison at the median doses suggests differences in verbal

reasoning between exposures to valproate (800mg/d) in comparison to no medication controls

and topiramate (200mg/d). However, as dose increased valproate was associated with

reductions in FSIQ, verbal and non-verbal reasoning. For example, at two times the median

dose of valproate (1600mg/d) when compared to the no medication group and exposure to two

times the median doses of topiramate (400mg/d) and levetiracetam (3000mg/d) the reduction in

FSIQ ranged from 11 to 16 IQ points, reduction in verbal reasoning ranged from 17 to 21

points, and reduction in non-verbal reasoning ranged from 6 to 14 (Web Table e-2). Despite

not adjusting for multiple testing when comparisons at different dose levels are made, the

results show consistently that as valproate dose increases the reductions in FSIQ, verbal and

non-verbal components are more pronounced.

Table 5

Influence of non-exposure variables

In terms of confounders, maternal epilepsy type was extensively investigated both as a

covariate and as an interaction term with treatment type and no association with child IQ or

specific cognitive abilities was demonstrated (data not shown, but available on request).

Exposure to seizures was also not associated with outcome. Consistent with the child

developmental literature, higher maternal IQ was associated with improved child performance

on FSIQ, verbal abilities and non-verbal abilities as well as language and memory abilities and

aspects of attention and executive skills (Tables 4 and 5). Socioeconomic status was also

associated with child performance with those with parents in professional employment scoring

6.1 points higher in terms of FSIQ with similar associations for verbal abilities and aspects of

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attention and executive functioning (Table 4). Tables 4, 5 and Web Table e-1 include further

information pertaining to the influence of covariates on specific outcome variables.

Discussion

This cross sectional study indicated that there was no association between child cognitive

functioning during middle childhood and exposure to levetiracetam in utero. This group was

adequately powered to detect a medium effect size (.15) with 89% power (GPower 3.1.3) (20) and

therefore smaller levels of discrepancy cannot be ruled out. A lack of an association is

consistent with our group’s earlier finding in infants under 24 months of age (10) and in later

infancy(9); although there was group overlap with this later cohort. Dose is a key concept in

terms of teratogenicity, and increasing doses of levetiracetam were not found to be associated

with poorer outcomes in comparison to control children and were documented to have superior

outcomes to the children exposed to higher doses of valproate. The lack of significant dose

effect for levetiracetam also supports preclinical studies where it is reported that, even at high

doses, to be exempt from the increased neuronal apoptosis seen following administration of

other AEDs in rodents(21). Levetiracetam is reportedly becoming an encouraging alternative to

valproate in the treatment of generalised epilepsy (22) due to its lack of association with major

congenital malformations(2, 23).

Topiramate has been associated with an increased rate of major congenital malformation

(4.2%)2, with a specific association to orofacial clefts24 and therefore should be considered

teratogenic. The group of children included exposed to topiramate was small and therefore only

large differences in neurodevelopment would have reliably been detected and the results must

be interpreted with caution. No significant level of difference between the children exposed to

topiramate or control children were documented in the adjusted model and increasing doses of

topiramate were not associated with poorer outcomes. Further, higher doses of topiramate

were associated with more favourable cognitive outcomes than children exposed to higher

levels of valproate. The reported findings here are in conflict with the small group (n=9)

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reported previously(11). However, the cohort in this present study was larger, comprised of

children from a narrower age range, utilised blinded assessments and undertook statistical

control for a wider number of likely confounding factors which may account for the difference in

findings. A lack of an association between topiramate exposure and impaired

neuropsychological function would support preclinical data which suggests that, at therapeutic

ranges, administration of topiramate in isolation is not associated with increased levels of

apoptosis in rodent models25,26 .

In relation to valproate, the findings of this study are consistent with that of other cohorts in

demonstrating that prenatal exposure to valproate was associated with significant risks to child

cognitive ability in a dose dependent manner (6-8,27-30). The mean IQ point reduction ranged from

10 to 11 points, which is consisted with the associated decreases reported in a recent meta-

analysis(8). Reduction in group means leads to increased numbers of children falling below the

average range; which is demonstrated for the valproate group with 19% falling over one

standard deviation from the mean for FSIQ in comparison to 6% of control children. Having a

FSIQ below the average range has implications for educational outcomes in the teenage

years(31).

The median dose in this valproate-exposed group was relatively low in regards to the treatment

of seizures (800mg daily) but consistent with the reported mean dose from other cohorts (7, 27).

The data here highlighted the substantial impact higher doses of valproate have on cognitive

functioning in comparison to higher doses of topiramate and levetiracetam.

No significant influence of maternal epilepsy type or exposure to seizures was found to be

associated with child cognitive functioning, supporting previous results (6,7,30). However, as

discussed below, limited information was available on seizure exposure.

A major strength of this study is its utilisation of a national register to reduce the latency

between AED monotherapy licence and teratology risk information. Valproate for example was

licensed for monotherapy use in the 1970s but the associated risks of prenatal exposure to

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later child cognition were only delineated within the last decade. Such a delay in information

undermines clinical risk-benefit decision-making and the utilisation of participants collected in

malformation registers may reduce the time taken to provide the first evidence. Further

methodological strengths of this study included its prospective collection of pregnancy details

which reduces recall bias, the utilisation of blinded standardised neuropsychological

assessment, the collection and control for a number of influential covariates, assessment of

school age child IQ and adequate power to detect large effect sizes. Finally, the consideration

of AED dose is important considering the principles of teratology (32) .

There are a number of limitations to the present study. Pregnancy registers represent only a

small proportion of women with epilepsy in the community and therefore sampling bias is

possible. The low rate of recruitment highlights the challenges of using malformation registers

to collect neurodevelopmental outcomes; but is consistent with the challenges experienced by

others using this model of recruitment(29). The higher rate of participation in the levetiracetam

group is felt to be linked to 60% of this group being assessed as part of an earlier study (9).

Higher recruitment/retention rates are reported for longitudinal studies with multiple follow ups

across the early childhood years(6, 7) but such methodologies are costly, and may not facilitate

collection of data for less frequently prescribed AEDs. Retrospective recruitment and collection

of certain data (i.e. maternal alcohol use) may lead biased results. The four groups however,

were recruited and assessed identically and therefore it was not felt that the differential

outcomes were due to recruitment bias. Of relevance, a recent Cochrane review found

comparable outcomes from prospective longitudinal studies and retrospectively recruited

cohorts from prospective pregnancy registers(8). The use of data pertaining to seizure exposure

and AED dose at time of enrolment onto UK-EPR means that no information was available on

seizure exposure or AED dose alterations towards the end of the pregnancy and the results

should be viewed in light of this. From a statistical viewpoint, although multiple comparisons

were considered to interpret the results of the primary analysis for the IQ outcome, the

secondary analyses (which involved 23 different statistical models) are merely exploratory, as

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well as the comparisons across AEDs that were made at different dose levels. Finally,

consideration regarding the age of these children at assessment is required. In middle

childhood, cognitive development is still dynamic and as age appropriate cognitive skills

become more complex, differential results might be seen.

In conclusion, the potential risks to neurodevelopment posed by prenatal exposure to valproate

at higher doses can be substantial and should be a central aspect of preconceptual

counselling. The documentation that the IQ of school aged children exposed to levetiracetam

and topiramate is similar to non-exposed control children is reassuring but replication and

extension are required.

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role in dealing with these complex clinical problems caused by a multiplicity of environmental

and genetic factors. Pediatrics. 2004;113(4 Suppl):957-68.

Acknowledgements

The authors would also like to thank all of the participants who contributed to the study.

18

Bromley 2015

Table 1: Group demographic information by antiepileptic exposure groups

No Medication Gabapentin Topiramate Levetiracetam Valproate Significance

Sample size 55 14 27 42 47

Maternal Demographics

AED Dose (mg/d)

mean, (range min-max)-

1828.6

(800-3200)

271.3

(50-800)

1725.0

(200-4000)

1000.0

(400-2400)

Maternal Age (years)

Mean (SD)29.5 (6.5) 27.9 (4.0) 29.3 (5.0) 30.3 (5.5) 32.9 (4.3)

0.004

Maternal IQ

Mean (SD)90.7 (12.0) 93.3 (14.1) 87.1 (16.6) 94.3 (14.9) 98.3 (15.5)

0.009

Maternal Education+

% higher education34, 68% 8, 62% 18,79% 23, 58% 27, 66%

0.668

University Degree

N, % yes10, 20% 3, 23% 13, 50% 12, 30% 17, 37%

<0.001

Maternal Employment*

N,% yes31, 62% 8, 66% 10, 38% 63, 25% 30,65%

0.391

Socioeconomic Status^,~

% professional16, 29% 8, 57% 12, 44% 20, 48% 23, 49%

0.213

Folate Supplementation£

N, % yes40, 83% 13, 100% 25, 96% 27,75% 46, 100%

0.001

Alcohol Exposure~

N, % yes10, 18% 2, 14% 2, 7% 8, 19% 9, 19%

0.691

Nicotine Exposure~

N, % yes14, 26% 2, 14% 3, 11% 6, 14% 10, 21%

0.448

Maternal Epilepsy Type

IGE (n,%) 26, 48% 7, 54% 18, 69% 28,67% 34,74% 0.096

FC (n,%) 22, 41% 5, 38% 6, 23% 14, 33% 10,22%

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Bromley 2015

UC (n,%) 6, 11% 1, 8% 2, 8% 0,0% 2, 4%

Seizure Exposure

N, % yes21, 40% 7, 54% 14, 54% 18, 43% 11, 24%

0.083

Convulsive Seizures

N, % yes14, 26% 3, 33% 9, 35% 12, 29% 6, 13%

0.192

Paternal Demographics

Paternal Age

Mean (SD)32.6 (5.7) 31.5 (5.2) 32.2 (7.2) 30.5 (4.7) 33.9 (7.2)

0.158

Paternal Education+

N, % higher education24, 51% 9, 69% 13, 52% 19, 49% 26, 59%

0.772

Paternal Employment~

N,% yes41, 86% 12, 92% 20, 83% 34, 89% 41, 91%

0.820

Child Demographics

Age at Assessment (months)

Mean (SD)84.2 (16.3) 90.6 (17.5) 76.7 (13.0) 71.9 (6.5) 85.8 (12.6)

<0.001

Gestational Age (weeks)

Mean,(SD)39.0 (2.4) 38.7 (3.0) 39.1 (3.6) 39.5 (1.8) 38.9 (2.6)

0.631

Child Gender

N, % female22, 40% 9, 64% 15, 56% 15, 36% 23, 49%

0.230

Sibling

N,% yes1, 1.9% 2, 14.3% 1, 3.7% 3, 7.1% 6, 12.8%

0.134

+ education in addition to compulsory.* full or part time employment combined. ^ based on parental employment type. £ preconceptual only. ~ greater than 5% missing data. # test of significance: †chi square or ‡Fisher’s exact for dichotomous data, and for continuous data either ᵃANOVA when the normality assumption of the residuals and variance homogeneity is passed or ᵏKruskal-Wallis otherwise.

Key: N = number; SD = standard deviation; mg/d = milligrams daily; IGE = idiopathic generalised epilepsy; FC = focal epilepsy; UC= unclassified epilepsy; IEP = individual educational plan.

20

Bromley 2015

Table 2: Unadjusted means, standard errors and rates below average performance by group for primary cognitive outcomes.

No Medication

N=55

Gabapentin

N=14

Topiramate

N=27

Levetiracetam

N=42

Valproate

N=47

Mean

(SD)

n, % <85

Mean

(SD)

n, % <85

Mean

(SD)

n, % <85

Mean

(SD)

n % <85

Mean

(SD)

WIS

C/W

PPSI

+

Full Scale IQ99.7

(13.6)

3,6% 103.6

(12.9)1,8%

100.5

(13.2)3,12%

99.0

(13.6)5,12%

95.9

(14.1)

Verbal Abilities101.7

(13.0)

4,7% 105.0

(12.6)1,7%

99.2

(11.2)3,11%

101.0

(11.2)1,2%

93.7

(14.6)

Non-Verbal Abilities

100.8

(14.6)

6, 11% 104.3

(14.2)1, 7%

102.4

(14.7)3,11%

99.6

(13.8)7,17%

101.5

(14.7)

Processing Speed97.1

(12.5)

8,15% 103.6

(9.7)0,0%

100.0

(13.3)3,11%

94.7

(12.6)7, 17%

94.6

(11.9)

Means are unadjusted for covariates but adjusted for test instrument used. The WISC normative sample mean is 100 with SD of 15 points, which would be classed as a below average performance.

Key: WISC – Wechsler Intelligence for Children –IV: WPPSI = Wechsler Preschool and Primary Scale of Intelligence-III: n = number: SE = standard error.

Table 3: Unadjusted means and standard deviation by group for the specific cognitive and behavioural outcomes.

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Bromley 2015

NM

Mean,

SD

GBP

Mean,

SD

TPM

Mean,

SD

LEV

Mean,

SD

VPA

Mean,

SD

NM

Mean,

SD

GBP

Mean,

SD

TPM

Mean,

SD

LEV

Mean,

SD

VPA

Mean,

SD

Language Behaviour

Concepts and Following Directions 9.5 (3.1) 10.4 (3.0) 9.7 (3.3) 9.7 (3.4) 9.0 (2.9)

Maladaptive Behaviour+

Formulated Sentences 8.6 (3.1) 10.1 (2.6) 9.1 (3.5) 9.0 (2.6) 7.3 (3.2)Hyperactivity

53.8 (11.4) 52.9 (12.0) 51.9 (10.1)50.2

(9.9)49.4 (11.0)

Expressive Naming 10.3 (2.2) 10.5 (2.3) 10.3 (2.8) 9.9 (2.7) 9.6 (2.8) Aggression 50.7 (9.6) 51.2 (10.1) 46.8 (67.0) 48.4 (10.9) 49.4 (11.0)

Memory Anxiety 52.5 (10.5) 53.3 (15.3) 48.9 (11.8) 52.7 (12.9) 52.8 (15.5)

Memory for Designs Total 10.3 (2.6) 10.1 (3.7) 10.2 (2.9) 10.2 (2.7) 10.3 (3.2) Depression 52.5 (11.0) 54.7 (18.0) 47.8 (9.0) 52.6 (13.3) 52.6 (15.1)

Memory for Faces 9.8 (2.3) 10.3 (2.8) 9.3 (2.2) 10.0 (2.5) 10.4 (2.7) Somatisation 47.3 (10.6) 52.5 (15.6) 45.8 (10.5) 48.7 (10.9) 49.0 (12.6)

Narrative Memory (Free and Cued) 10.6 (2.8) 10.1 (3.4) 9.6 (2.7) 10.6 (2.9) 10.6 (2.6)

Withdrawal45.6 (8.4) 51.9 (14.6) 47.8 (11.6) 48.8 (11.0) 47.8 (11.9)

Attention and Executive Attention 52.7 (11.1) 48.6 (10.3) 52.7 (8.7) 51.7 (12.6) 51.9 (12.6)

Auditory Attention 8.9 (3.1) 11.2 (2.1) 11.4 (2.8) 10.4 (2.8) 8.9 (3.3) Adaptive Behaviour>

Design Fluency9.0

(2.7)10.0 (1.9) 8.7 (3.0) 8.7 (2.6) 9.2 (2.4)

Adaptability 51.2 (10.7)

54.2 (11.0) 55.1 (10.2) 53.7 (10.5) 54.9 (11.0)

Inhibition- Naming 8.8 (3.5) 10.8 (3.5) 10.9 (3.2) 8.7 (2.6) 9.2 (2.4) Social Skills 52.1 (9.5) 54.0 55.1 53.8 53.6 (11.4)

22

Bromley 2015

NEPSY^

Combined BASC~

(9.7) (8.7) (8.7)

Inhibition –Inhibition Combined 8.7 (3.4) 10.1 (2.1) 8.7 (3.0) 10.0 (3.0) 9.1 (3.3)

Daily Living

49.8 (10.3)

53.2 (11.7) 53.2 (10.2) 51.6 (10.4) 50.0 (12.0)

^ test mean is 10 with a standard deviation of 3. ~ test mean is 50 with a standard deviation of 10. + higher score means poorer outcome. > higher score means better outcome.

Key: SD = standard deviation: NM= no medication: GBP = gabapentin: TPM = topiramate: LEV = levetiracetam: CELF= Clinical Evaluation of Language Fundamentals-IV: NEPSY= Neuropsychological Assessments-II: BASC= Behavioural Assessment System for Children-II.

23

Bromley 2015

Table 4: Multivariate outcomes for the primary outcome IQ and its indexes

*Only p-values equal to 0.017 or less were considered to be statistically significant after using the Bonferroni correction when considering multiple

Explanatory Variable/Group

Full Scale IQ Verbal Abilities Performance Abilities Processing Speed

Coef.

(SE)

95%

CIP

Coef

.

(SE)

95%

CIP*

Coef.

(SE)

95%

CIP*

Coef.

(SE)

95%

CIP*

Epile

psy

No Medication Reference Group

Trea

tmen

t Gro

up

TPM

Constant-0.4

(4.7)

(-9.7,

8.9)0.44

-6.4

(4.7)

(-15.6,

2.8)0.17

-0.9

(5.1)

(-10.9,

9.1)0.86

4.8

(3.0)

(-1.0,

10.7)0.10

Dose Effect0.2

(2.5)

(-

4.7, 5.2)0.93

2.0

(2.5)

(-3.0,

6.9)0.44

2.3

(2.7)

(-3.1,

7.6)0.41 - - -

LEV

Constant1.5

(4.5)

(-7.3,

10.3)0.74

-3.0

(4.5)

(-11.8,

5.9)0.51

1.7

(4.9)

(-7.9,

11.4)0.72

-1.6

(2.5)

(-6.5,

3.3)0.51

Dose Effect-3.2

(3.1)

(-9.4,

2.9)0.30

-0.1

(3.1)

(-6.3,

6.0)0.96

-3.1

(3.4)

(-9.9,

3.6)0.36 - - -

VPA

Constant5.1

(4.6)

(-3.9,

14.1)0.26

1.6

(4.6)

(-7.4,

10.6)0.73

11.8

(5.0)

(2.0,

21.7)0.02

-3.4

(2.5)

(-8.3,

1.5)0.17

Dose Effect-10.6

(2.9)

(-16.3, -

5.0)<0.001

-11.2

(2.9)

(-16.8, -

5.5)

<0.00

1

-11.1

(3.2)

(-17.3, -

4.9)<0.001 - - -

Cova

riate

s

Maternal IQ^0.2

(0.08)

(0.09,

0.4)0.002

0.2

(0.08)

(0.08,

0.4)0.003

0.2

(0.08)

(0.05,

0.4)0.01

0.2

(0.07)

(0.02,

0.3)0.02

Professional

Employment

6.1

(2.1)

(2.0,

10.2)0.004

5.4

(2.1)

(1.3,

9.5)0.01

5.4

(2.2)

(1.0,

9.8)0.02 - - -

Gender4.5

(2.0)

(0.6,

8.4)0.02

4.5

(2.0)

(0.6,

8.4)0.03 - - -

7.3

(1.9)

(3.6,

11.0)

<0.00

1

24

Bromley 2015

comparisons (p = 0.05/3 = 0.017). Significant results were consistently observed in the VPA exposed group even with the correction applied.^ measured using the Test of non-verbal attention. Dose refers here to the standardised continuous value (actual dose divided by the median dose for each respective AED type).

Key: coef= coefficient: SE= standard error: CI= confidence interval: TPM= topiramate: LEV= levetiracetam: VPA= valproate.

Table 5: Results of multivariate analyses for the specific cognitive outcomes.

Domain* Language Memory

Explanatory Variable/Group Concepts Formulated Expressive Naming Memory Designs Memory for Faces Memory for Names Narrative Memory

25

Bromley 2015

Following Sentences Total

Coef.

(SE)

95%

CIP

Coef.

(SE)

95%

CIP

Coef

.

(SE)

95%

CIP Coef.

(SE)

95%

CIP

Coef

.

(SE)

95%

CIP Coef.

(SE)

95%

CIP Coef.

(SE)

95%

CIP

Epile

psy

No Medication Reference Group

Trea

tmen

t Gro

up

TPM

Constant0.06

(1.1)

(-2.2,

2.3)

0.9

6

1.5

(0.8)

(-

0.01,

3.0)

0.05-0.09

(0.9)

(-1.8,

1.7)0.92

0.4

(0.7)

(-1.0,

1.7)

0.60 -0.3

(0.8)

(-1.8,

0.7)

0.70 -0.3

(0.7)

(-1.6,

0.9)

0.60 -0.9

(0.7)

(-2.3,

0.5)

0.22

Dose

Effect

0.5

(0.6)

(-0.7,

1.8)

0.4

0- - -

0.2

(0.5)

(-0.7,

1.1)0.69 - - - - - - - - - - - -

LEV

Constant-0.01

(1.1)

(-2.1,

2.1)

0.9

9

0.2

(0.7)

(-1.1,

1.6)0.72

-1.1

(0.8)

(-2.7,

0.5)0.17

-0.3

(0.6)

(-1.5,

0.9)

0.61 -0.6

(0.6)

(-1.9,

0.7)

0.35 -0.08

(0.6)

(-1.2,

1.0)

0.89 -0.4

(0.6)

(-1.6,

0.8)

0.54

Dose

Effect

-0.03

(0.8)

(-1.5,

1.4)

0.9

6- - -

0.3

(0.6)

(-0.8,

1.4)0.61 - - - - - - - - - - - -

VPA

Constant1.2

(1.1)

(-1.0,

3.4)

0.2

7

-1.4

(0.6)

(-2.7,

-0.2)0.03

1.2

(0.9)

(-0.5,

2.8)0.18

-0.4

(0.6)

(-1.6,

0.8)

0.52 -0.4

(0.7)

(-1.7,

0.9)

0.57 -0.3,

0.6

(-1.4,

0.8)

0.56 -0.6

(0.6)

(-1.7,

0.6)

0.34

Dose

Effect

-1.5

(0.7)

(-2.9,

-

0.07)

0.0

4- - -

-2.3

(0.6)

(-3.4,

-1.6)

<0.00

1- - - - - - - - - - - -

Domain Attention and Executive Functioning Theory of Mind ±

26

Bromley 2015

Explanatory Variable/Group

AA Combined Design Fluency INN Combined INI Combined Theory of Mind

Coef.

(SE)

95%

CIP

Coef.

(SE)

95%

CIP

Coef

.

(SE)

95%

CIP

Coef.

(SE)

95%

CI P

Coef

.

(SE)

95%

CI P

Epile

psy

No medication Reference

Trea

tmen

t Gro

up

TPM

Constant1.9

(0.8)

(0.4,

3.4)

0.0

1

-0.1

(0.7)

(-1.4,

1.2)0.84

2.2

(0.8)

(0.6,

3.7)0.005

0.2

(0.8)

(-1.4,

1.8) 0.80

4.0

(1.6)

(1.2,

7.6)0.01

Dose

Effect- - - - - - - - - - - -

-1.6

(1.1)

(-4.6,

0.05)0.16

LVT

Constant0.5

(0.7)

(-0.9,

1.9)

0.4

9

-0.4

(0.6)

(-1.6,

0.7)0.44

0.8

(0.7)

(-0.5,

2.1)0.21

0.8

(0.7)

(-0.6,

2.1) 0.27

2.3

(1.6)

(-0.9,

5.5)0.16

Dose

Effect- - - - - - - - - - - -

-2.1

(1.7)

(-6.1,

0.7)0.22

VPA

Constant0.4

(0.7)

(-1.0,

1.7)

0.5

8

0.04

(0.6)

(-1.1,

1.1)0.95

0.06

(0.7)

(-1.3,

1.4)0.93

-0.08

(0.7)

(-1.5,

1.3) 0.91

-2.0

(1.2)

(-4.7,

0.3)0.10

Dose

Effect- - - - - - - - - - - -

2.3

(0.8)

(1.0,

4.0)

0.00

2

* Multivariate models constructed separately for each cognitive domain. Where dose outcome is not reported dose was not included in the model due to a lack of association with that specific outcome. ± Theory of mind was fitted using a univariate logistic regression analysis. Note that the results of this table are merely exploratory and no correction for multiple comparisons has been applied. Covariates associated with a specific outcomes: Language – concepts and following directions maternal IQ 0.07 95% CI 0.04-0.1, p<0.001; formulated sentences maternal IQ 0.06 95% CI 0.02-0.09, p=0.001 and child weight -0.1 -0.2-0.04, p<0.001; expressive vocabulary

27

Bromley 2015

maternal IQ 0.06 95% CI 0.04-0.09, p<0.001 and maternal age 0.09 95% CI 0.03-0.2, p=0.005; Memory- memory for designs maternal IQ 0.05 95% CI 0.02-0.08,p=0.002; memory for faces maternal IQ 0.04 95% CI 0.003-0.07,p=0.02; memory for names maternal IQ 0.04 95% CI 0.009 – 0.07, p=0.01; narrative memory maternal IQ 0.04 95% CI 0.003-0.07; Attention – design fluency SES 1.5 95% CI 0.6-2.3,p<0.001; INI Combined maternal IQ 0.06 95% CI 0.02-0.1,p=0.001.

Key: coef= coefficient: SE= standard error: CI= confidence interval: TPM= topiramate: LEV= levetiracetam: VPA= valproate.

28