Article

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

Department of Molecular and Clinical Pharmacology, University of Liverpool, , Liverpool, UK.
Journal of neurology, neurosurgery, and psychiatry (Impact Factor: 6.81). 01/2013; 84(6). DOI: 10.1136/jnnp-2012-304270
Source: PubMed

ABSTRACT

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.

Full-text

Available from: Rebecca Bromley
RESEARCH PAPER
The prevalence of neurodevelopmental disorders
in children prenatally exposed to antiepileptic drugs
Rebecca Louise Bromley,
1
George E Mawer,
2
Maria Briggs,
2
Christopher Cheyne,
3
Jill Clayton-Smith,
2
Marta García-Fiñana,
3
Rachel Kneen,
4,5
Sam B Lucas,
2
Rebekah Shallcross,
6
Gus A Baker,
1
On Behalf of the Liverpool and Manchester
Neurodevelopment Group
1
Department of Molecular and
Clinical Pharmacology,
University of Liverpool,
Liverpool, UK
2
Genetic Medicine, Manchester
Academic Health Sciences
Centre, University of
Manchester, Manchester, UK
3
Department of Biostatistics,
University of Liverpool,
Liverpool, UK
4
Department of Neurology,
Alder Hey Childrens NHS
Foundation Trust, Liverpool, UK
5
Institute of Infection and
Global Health, University of
Liverpool, Liverpool, UK
6
Department of Clinical
Psychology, University of
Liverpool, Liverpool, UK
Correspondence to
Dr Rebecca Louise Bromley,
Department of Molecular and
Clinical Pharmacology, Clinical
Sciences Centre for Research
and Education, Lower Lane,
Liverpool L9 7LJ, UK;
r.l.bromley@liv.ac.uk
Received 4 October 2012
Revised 18 December 2012
Accepted 21 December 2012
To cite: Bromley RL,
Mawer GE, Briggs M, et al.
J Neurol Neurosurg
Psychiatry Published Online
First: [please include Day
Month Year] doi:10.1136/
jnnp-2012-304270
ABSTRACT
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 signicant
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.
INTRODUCTION
Prenatal exposure is associated for the majority of
antiepileptic drugs (AEDs), with an increased risk
of major congenital malformations in a dose
dependent manner.
1
There is also evidence demon-
strating that prenatal exposure to sodium valproate
(VPA) is associated with reduced cognitive func-
tioning in the exposed child.
24
This has increased
concern about the longer term inuences of pre-
natal exposure to AEDs.
Neurodevelopmental disorders, such as autistic
spectrum disorders (ASD), attention decit hyper-
activity disorder (ADHD) and dyspraxia, are report-
edly more prevalent following prenatal exposure to a
number of teratogenic substances.
510
The question
remains as to whether prenatal exposure to AEDs is
associated with an increased likelihood of
neurodevelopmental disorders. Altered neuronal
development is regarded as a pathological cause of
ASD
11
and AEDs have been shown to alter neuronal
development,
12 13
in a manner that is consistent with
autistic behaviours in rats and mice.
12 1416
Additionally, there is evidence from case series
1720
and retrospective human studies
22123
that neurode-
velopmental disorders are more prevalent in children
exposed to VPA. Adab et al
2
observed ve cases of
neurodevelopmental disorder in children exposed to
VPA monotherapy (5/41; 12.1%) in a retrospective
cohort. This increase was not found in the groups
exposed to carbamazepine (CBZ) or phenytoin
(PHT). A systematic review of children with a history
of prenatal exposure to AEDs revealed that 8.9% of
children exposed to VPA and 2.5% of children
exposed to CBZ met the diagnostic criteria for
ASD,
23
although no adjustment for potential con-
founding variables was undertaken. High rates of
neurodevelopmental disorders have also been
reported in children diagnosed with Fetal Valproate
Syndr ome.
21
This is a condition characterised by a
pattern of major and minor congenital malforma-
tions, dysmorphic features and cognitive decits,
24 25
and is likely to represent the severely effected end of
aspectrumofdifculties associated with prenatal
exposure to VPA. Preliminary ndings regarding the
prevalence of ASD within this cohort have previously
been published,
26
and highlight an increased risk of
neurodevelopmental disorders following VPA expos-
ure. Further, Cohen et al
27
documented signicantly
higher maternal ratings of inattention, hyperactivity
and reduced social skills in children prenatally
exposed to VPA at 3 years of age.
An association between prenatal CBZ exposure
and ASD has been reported in one study,
23
which is
not consistent with another.
2
There have been no
reports of a signicant association between other
AEDs and neurodevelopmental disorders to date.
Prospective observational studies using a control
group provide the most reliable evidence to test
this possible association as randomised controlled
trials to establish teratogenic risk are thought to be
unethical. The nal results of this 11-year prospect-
ive study are reported here.
METHODOLOGY
A prospective study of the children born to women
with epilepsy (WWE) was initiated in 2000, aiming
to document physical health and cognitive
Bromley RL, et al. J Neurol Neurosurg Psychiatry 2013;0:17. doi:10.1136/jnnp-2012-304270 1
Epilepsy
Page 1
development. Between 2000 and 2004, 628 pregnant women
were recruited from antenatal clinics in the northwest of
England. Over 99% of the cohort was Caucasian. Twenty preg-
nancies were excluded due to fetal or child death, or on the
basis that the children or mothers had conditions likely to inu-
ence neurodevelopmental outcome (including chromosomal dis-
orders and hydrocephalus). Eighty women (29 WWE and 51
controls) were never accessible to the research team, even by
telephone and were excluded. Therefore the total number of eli-
gible pregnancies between 2000 and 2004 was 528 (243 WWE
and 285 controls). Of those exposed to AEDs in utero 59 were
exposed to CBZ, 59 to VPA, 36 to lamotrigine (LTG), 14 to
other monotherapy treatments and 41 to polytherapy.
Thirty-four children were born to WWE who were not taking
medication during their pregnancy.
At recruitment each woman provided information relating to
education, occupation and lifestyle issues such as smoking and
alcohol use during pregnancy. Maternal health and pregnancy
information was recorded from maternal interview and checked
against medical records. An epilepsy specialist (GEM) conrmed
seizure type, syndrome diagnosis (symptomatic/cryptogenic
focal, idiopathic generalised epilepsy (IGE) or not classiable),
current seizure frequency as well as AED type and dose.
Treatment was classed as polytherapy if a second AED (includ-
ing a benzodiazepine) had been prescribed even for a short
period. Seizure frequency was ascertained from the patient and,
where possible a family member. The study methodology has
been detailed in the earlier paper describing the immediate
pregnancy outcomes.
28
Children from this cohort were assessed at 1year, 3 years and
6 years of age to monitor their physical and cognitive develop-
ment.
428
Thirty-nine per cent of children born to WWE were
also enrolled into a US/UK study.
3272930
This collaborative
study has reported on behaviour in infants at 3 years of age
27
which included earlier age data on 21% (n=86) of children
reported here. Structured interviews with the parents were con-
ducted by a trained research assistant or authors MB, RLB, RS
or JC-S, blinded as to whether the mother had epilepsy and
whether the child had been exposed to medication during preg-
nancy. It was recorded whether the child had been ill, attended
hospital or whether a professional had been consulted regarding
the health, development, behaviour or educational progress of
the child. Information was specically collected on ASD,
ADHD and dyspraxia due to their increased prevalence in an
earlier retrospective cohort.
2
Indication that a child had seen a
specialist pertaining to a developmental difculty or neurodeve-
lopmental disorder was documented and followed up with the
diagnosing health professional, family doctor or school nurse.
The researchers played no clinical role in the treatment of the
WWE or in the diagnosis of the child. Children were referred
to specialist services following contact with the research team if
there were signicant concerns about development. In one case
a referral was made following concerns regarding speech
quality, which led to a diagnosis of ASD. The referring
researcher in this case was blind to the exposure type. Outcome
at 6 years of age was the end point of this longitudinal study
and the presence of a conrmed diagnosis of a neurodevelop-
mental disorder (ASD, ADHD or dyspraxia) at the time of the
6-year assessment is reported here.
Data analyses were conducted in two stages, by author SBL
using SPSS V. 17.0, and by author CC under the supervision of
MG-F using R V.2.12.1. Multiple logistic regression analysis was
applied to explore the likelihood of neurodevelopmental dis-
order of the offspring of WWE exposed to AED treatments
(CBZ, LTG, VPA, other monotherapy and polytherapy) com-
pared with controls and to identify the demographic and clinical
variables associated with the diagnosis of a neurodevelopmental
disorder. Due to the relatively low frequency of diagnosis this
was only possible for the overall category of neurodevelopmen-
tal disorder category and not for the individual types (ASD,
ADHD or dyspraxia). A similar analysis was applied to compare
the likelihood of neurodevelopmental disorder across maternal
epilepsy types. A preliminary exploratory data analysis was used
to identify candidate variables for consideration in the logistic
model by individually exploring their association with the
occurrence of neurodevelopmental disorder. The variables
included seizures during pregnancy, maternal IQ, maternal age,
socioeconomic status, alcohol or nicotine exposure, gender and
gestational age at birth. Paternal date of birth was missing in
over 25% of cases and was therefore not included.
Ethical approval for this cohort study was awarded by the
Northwest Regional Ethics Committee and research approval
was obtained from individual participating hospitals. All families
provided informed consent to participate in the study.
Preliminary ndings regarding the prevalence of ASD within
this cohort have previously been reported.
26
RESULTS
Of the 528 children who actively participated in the longitudinal
follow-up, 415 (214 controls and 201 children born to WWE)
were assessed at the main outcome age of 6 years (78.6%). The
majority of missing cases were lost to follow-up with less than
5% formally withdrawing or indicating that they were emigrat-
ing. Signicant differences were found between the demograph-
ics of those assessed and those not, with lower maternal IQ
(p=0.01), socioeconomic status ( p=0.01) and maternal age
(p=0.02) associated with non-completion. Further, mothers
whose child participated in the 6-year assessments were less
likely to have smoked during the pregnancy ( p=0.04).
The demographics of the cohort completing assessment at
6 years of age are displayed in table 1. WWE were marginally
younger than the control women (28 vs 29 years, p=0.002) and
had a lower full scale IQ as measured by the National Adult
Reading Test ( p<0.001). Signicantly more control women
reported drinking alcohol during the pregnancy (30.8% vs
17.9%, p=0.004), but signicantly more WWE reported
smoking (27.9% vs 15.9, p=0.008). There was no signicant
difference in the gestational age of the child at birth (p=0.5) or
in the distribution of gender between the groups of children
born to WWE and controls (p=0.3).
Nineteen children had a diagnosis of a neurodevelopmental
disorder at the 6-year assessment (table 2). Twelve were diag-
nosed with ASD; one of which was also diagnosed with ADHD.
Three children had ADHD in isolation. The four remaining
children had a diagnosis of dyspraxia. Of the 19 with a diagno-
sis of neurodevelopmental disorders, physical malformations
were noted in three cases (16%) all of whom were prenatally
exposed to AEDs (table 2).
Diagnosis by group
Neurodevelopmental disorders were more frequently reported in
the children of WWE (15/201; 7.46%) than in the contr ol gr oup
(4/214; 1.87%). Prevalence of neurodevelopmental disorders dif-
fered across the AED groups (gure 1). Children exposed to VPA
showed a high prevalence of neurodevelopmental disorders (6/50:
12.0% for VPA monotherapy and 3/20: 15.0% for VPA polyther-
apy). Prevalence of neurodevelopmental disorder differed for the
other exposures. The small other monother apy group,which
2 Bromley RL, et al. J Neurol Neurosurg Psychiatry 2013;0:17. doi:10.1136/jnnp-2012-304270
Epilepsy
Page 2
Table 1 Cohort demographics in the Liverpool and Manchester neurodevelopment group prospective study
Seizures during
pregnancy (%)
Maternal epilepsy
type
Numbers enrolled
20002004 (n)*
Outcome
known (n)
%
retained Convulsive Non-convulsive
IGE
(%)
F
(%)
UC
(%)
Mean
maternal
age
(years)
Alcohol
(%)
Nicotine
(%)
Socioeconomic
status (%
professional)
Gender
(%
male)
Mean
child
age
(mths)
Mean
gestational
age at birth
(weeks)
Controls 285 214 75 –– 29 30.8 16.4 40.7 51.9 74 40
WWE 243 201 83 33.5 14.3 32.0 54.2 13.8 28 17.9 27.9 31.0 57.1 74 39
CBZ 59 50 85 19.6 19.6 9.8 80.4 9.8 30 17.6 23.5 41.2 49.0 74 39
LTG 36 30 83 40.0 10.0 23.3 56.7 20.0 28 10.0 16.7 40.0 56.7 74 40
Other 14 14 100 35.7 21.4 28.6 71.4 0.0 30 28.6 50.0 28.6 57.1 74 40
VPA 59 50 85 41.2 11.8 66.7 21.6 11.8 27 17.6 29.4 23.5 68.6 74 39
Poly VPA 30 20 67 50.0 10 35.0 55.0 10.0 26 10.5 26.3 25.0 50.0 75 39
Poly Other 11 11 100 81.8 9.1 0 81.8 18.2 29 27.3 18.2 18.2 54.5 74 39
No Med 34 26 76* 4.0 12.0 32.0 40.0 28.0 26 25.0 37.5 32.0 72.0 75 39
*Figures are inclusive of children recruited between 2000 and 2004 who attended at least one appointment or completed one phone visit with investigators (actively enrolled).
Two sets of dizygotic twins included.
Five sets of twinsthree exposed to monotherapy VPA (one dizygotic pair and one unconfirmed) and two exposed to monotherapy CBZ (one dizygotic pair). Alcoholany level of consumption during pregnancy (including prior to conception).
Nicotineincluding prior to knowledge of conception.
CBZ, carbamazepine; F, focal; IGE, idiopathic generalised epilepsy; LTG, lamotrigine; UC, unclassified; VPA, valproate; WWE, women with epilepsy.
Bromley RL, et al. J Neurol Neurosurg Psychiatry 2013;0:17. doi:10.1136/jnnp-2012-304270 3
Epilepsy
Page 3
comprised of a number of differ ent AEDs had a prevalence of
14.29% (2/14), with one case prenatally exposed to PHT and the
other vigaba trin. A single case of ADHD was found in the group
of children exposed to CBZ (1/50: 2.0%). This child also had
IGE with active seizures. For the LTG exposed group there were
two cases with a diagnosis (2/30: 6.67%), one child with a diag-
nosis of Aspergers syndr ome and another of dyspr axia. Ther e
wer e no r eported cases of neurodevelopmental disorder in the
children born to untreated WWE. A single case of dyspraxia was
found in the group of children exposed to polytherapy without
VPA (1/11: 9.1%). Finally, four control children (4/214: 1.87%)
wer e diagnosed with a neurodev elopmental disorder , which w as
ASD in all cases.
Multiple logistic regression analysis revealed that children
born to WWE exposed to VPA monotherapy and VPA polyther-
apy were, respectively, six times (aOR 6.05, 95% CI 1.65 to
24.53, p=0.007) and 10 times (aOR 9.97, 95% CI 1.82 to
49.40, p=0.005) more likely to be diagnosed with a neurodeve-
lopmental disorder than controls (table 3).
The other mono therapy group also showed a signicantly
higher risk compared with controls (aOR 8.17, 95% CI 1.1 to
49.4, p=0.02) but, similarly to what is obs erved for the VPA
polytherapy group, the low sample sizes in these two groups
are linked to wide CIs and large SE of the corresponding aORs
(table 3). For the other AED groups, the risk of neurodevelop-
mental diso rder was not statistical ly signicant when compared
with the control group (CBZ, LTG and polytherapy w ithout
VPA).
When the VPA exposed groups were split by dose the preva-
lence of neurodevelopmental disorder appeared to increase with
dose (table 4). A logistic regression analysis, unadjusted for
other factors due to the low number of cases per dose and VPA
exposure groups, showed a positive association between the
prevalence of neurodevelopmental disorder and the preconcep-
tual dose of VPA in monotherapy but this failed to attain signi-
cance (p=0.1).
The prevalence of neurodevelopmental disorder was similar
across maternal epilepsy type: focal 8.33%; IGE 6.15% and
Table 2 Individual cases of neurodevelopmental disorder alongside demographic information
Diagnosis Gender AED
Dose (mg
daily)
Maternal
epilepsy
type Seizures
Congenital
malformation
Maternal
age
Paternal
age
Siblings
with
ASD* Alcohol Nicotine
Autistic spectrum disorders
1 Aspergers M VPA 1000 IGE 1TC Multiple minor 33 39 None Yes No
2 Autism M VPA 600 F 1 PS+SG None 27 29 1sibling
(VPA
exposed)
No No
3 Autism M VPA 1500 F 2PS+SG None 22 30 None No Yes
4 Pervasive
Developmental
Disorder
M VPA 2500 IGE 2TC None 23 29 None Yes Yes
5 Autism F VPA+LTG 2000+100 F 2TC None 26 37 None No No
6 Aspergers M LTG 500 F 1PS+SG None 30 31 None No No
7 Aspergers and
ADHD
F VGB 4000 F 2TC None 19 Not
known
None No Yes
8 Autism M PHT 300 F 0 None 35 Not
known
None Yes Not
known
9 Autism M Control N/A N/A N/A None 32 Not
known
None Yes No
10 Aspergers M Control N/A N/A N/A None 31 32 None No No
11 Aspergers F Control N/A N/A N/A None 32 31 1 sibling No No
12 Autism M Control N/A N/A N/A 37 None No Yes
ADHD
13 ADHD M VPA+LTG 2000+50 IGE 0 1 major 27 40 2 Siblings
(VPA
exposed)
No No
14 ADHD F CBZ 1200 F 0 None 24 31 None No No
15 ADHD M VPA+LTG 1500+25 F 2TC None 18 Not
known
None Yes No
Dyspraxia
16 Dyspraxia M LTG 100 F 2 TC None 22 Not
known
None No No
17 Dyspraxia M VPA 600 IGE 0 None 26 30 None No No
18 Dyspraxia M CBZ+LTG 600+50 UC 2TC Isolated minor 24 Not
known
None No No
19 Dyspraxia M VPA 1000 UC 2TC None 40 Not
known
None No No
*ASD was the only reported diagnosed disorder in siblings.
Case was included in the preliminary report from this cohort.
26
Child also has idiopathic generalised epilepsy.
ADHD, attention deficit hyperactivity disorder; ASD, autistic spectrum disorders; CBZ, carbamazepine; F, focal; IGE, Idiopathic generalised epilepsy; PHT, phenytoin; PS, partial seizures;
TC, tonic clonic seizures; UC, unclassified; VGB, vigabatrin. Alcohol includes intake prior to knowledge of conception. Nicotinesmoking even prior to knowledge of conception.
4 Bromley RL, et al. J Neurol Neurosurg Psychiatry 2013;0:17. doi:10.1136/jnnp-2012-304270
Epilepsy
Page 4
unclassied (UC) type 7.14% (table 3). A signicant aOR was
demonstrated for maternal focal epilepsy (aOR 4.76, 95% CI
1.42 to 15.94, p=0.01) in comparison with the control group,
but the aOR remained similar to that for IGE and UC type
(table 3). Differences due to epilepsy type are unavoidably con-
founded with differences due to AED treatment. After exclusion
of all cases exposed to VPA there were ve cases of NDD in the
children of 86 women with focal epilepsy. The corresponding
gures for IGE were 0/25 and for UC epilepsy 1/22. There were
no cases of neurodevelopmental disorder in the children of
women with untreated epilepsy.
In terms of demographic inuences, boys tend to be three
times more likely than girls to be diagnosed with a neurodeve-
lopmental disorder (aOR 3.2, 95% CI 1.0 to 10.1, p=0.05),
but no signicant association was found for maternal age, mater-
nal IQ, gestational age at birth, seizure exposure or any other
demographic variable (data not shown).
DISCUSSION
The prevalence of ASD in the control group (1.87%) was com-
parable with population rates reported for the UK (1%),
31
sug-
gesting that the control group was representative. Furthermore
the association of neurodevelopmental disorder and male
gender is consistent with a large existing body of evidence.
32
No diagnosis of dyspraxia or ADHD was reported in the
control group, which may be related to the relatively young age
of this cohort and the average age of diagnosis for these condi-
tions in the UK, 511 years of age for ASD and 7 years of age
for ADHD.
3335
No cases of neurodevelopmental disorder were
reported in the children of women with untreated epilepsy. This
is likely linked to the small size of the group (n=26), as all
groups displayed similar mean child age.
This is the rst prospective report regarding prevalence, and
replication and extension is required. A 6 or 10 times increased
prevalence of neurodevelopmental disorders is reported here for
children with a history of prenatal VPA exposure respectively
for monotherapy and polytherapy exposure. The most common
neurodevelopmental disorder at 6 years of age for VPA exposed
children was ASD. The increased prevalence of ASD within this
group is consistent with previous retrospective clinical
research
2123
and reports from animal studies.
1416
Consistent with previous research, a dose effect for VPA was
indicated but such an association failed to reach statistical sig-
nicance for monotherapy VPA, possibly due to limited power.
Figure 1 Prevalence of neurodevelopmental disorder by group.
Table 3 Crude and adjusted ORs for antiepileptic drug (AED) type and maternal epilepsy type
Group Total NDDs No NDDs Incidence rate (%) Unadjusted OR Adjusted OR* (95% CI) p Value
Control 214 4 210 1.87 Reference group Reference group
No Medication 26 0 26 0.00 ––
VPA 50 6 44 12.00 7.16 6.05 (1.65 to 24.53) 0.007
CBZ 50 1 49 2.00 1.07 1.09 (0.06 to 7.39) 0.9
LTG 30 2 28 6.67 3.75 4.06 (0.55 to 22.20) 0.1
Other Monotherapy 14 2 12 14.29 8.75 8.17 (1.09 to 49.40) 0.02
Polytherapy with VPA 20 3 17 15.00 9.26 9.97 (1.82 to 49.40) 0.005
Other Polytherapy 11 1 10 9.09 5.25 4.95 (0.25 to 40.45) 0.2
Focal 108 9 99 8.33 4.77 4.76 (1.42 to 15.94) 0.01
Idiopathic Generalised 65 4 61 6.15 3.44 3.15 (0.76 to 13.09) 0.1
Unclassified 28 2 26 7.14 4.04 3.74 (0.65 to 21.67) 0.1
Note: significant results are highlighted in bold.
*Separate regression models were created for AED and maternal epilepsy type regressions due to the limited numbers of cases per drug by maternal epilepsy type.
CBZ, carbamazepine; VPA, valproate.
Bromley RL, et al. J Neurol Neurosurg Psychiatry 2013;0:17. doi:10.1136/jnnp-2012-304270 5
Epilepsy
Page 5
Analysis of monotherapy and polytherapy VPA combined was
not undertaken due to the potential bias. Further research is
required to conrm a VPA dose dependent effect. The demon-
stration of dose dependency strengthens the case against a sus-
pected teratogen
36
and dose effects have been reported for rates
of malformations and impaired cognitive abilities following VPA
exposure.
1437
In earlier publications from this cohort, increased risk of
major congenital malformations and reduced early cognitive
ability were documented.
428
Further investigation is required
into whether an increased prevalence of neurodevelopmental
disorders are discretely diagnosable conditions or whether they
represent the severe end of a continuum of altered neurodeve-
lopmental functioning following VPA exposure. Previous
research has documented that prenatal exposure to VPA is asso-
ciated with verbal, social and attentional difculties,
242730
and
it is proposed here the raised prevalence of neurodevelopmental
disorders is due to severe difculties with language, social and
attentional abilities, which meet a threshold level for diagnosis
of a neurodevelopmental disorder. The majority of children
received a diagnosis between 3 years and 5 years of age. Of
interest, global or specic developmental difculties were noted
under the age of 2 years in six out of seven VPA (monotherapy
or polytherapy) exposed infants previously assessed. Such an
observation demonstrates that the early developmental trajec-
tory of these children is altered and surveillance through the
early childhood years is necessary. Decits in neurodevelopment
of this nature can have a large impact on the child and their
families, and present increased costs to society through
increased health and educational support.
The use of VPA was associated with maternal IGE (66.7%),
an expected association due to its efcacy in this epilepsy syn-
drome.
38
Therefore the effects of one could not be viewed in
isolation of the other in the logistic regression analysis.
However, no signicant aOR was found for IGE. Maternal focal
epilepsy and not IGE, was associated with an increased rate of
neurodevelopmental disorders in the offspring. Of the cases in
offspring born to women with focal epilepsy, four out of nine
were treated with VPA in either monotherapy or polytherapy
form, with the remaining cases exposed to other monotherapy
or polytherapy AEDs.
The suggestion that VPA exposure is associated with an
increased prevalence of neurodevelopmental disorders, which is
independent of the maternal epilepsy type is consistent with the
results of animal work, where there is no maternal epilepsy inu-
ence.
12 1416
Studies are now required into the mechanism by
which VPA is associated with this increased risk of
neurodevelopmental disorders, considering that environmental
(in utero) and genetic inuences may not be mutually
exclusive.
11 16
This study does not replicate the nding of Rasalam et al
23
in
relation to CBZ, as there was only a single case of ADHD
among the CBZ-exposed children. Single cases of neurodevelop-
mental disorder were also noted following exposure to PHT and
vigabatrin, and two cases exposed to LTG. Larger studies includ-
ing wider dose ranges for individual AEDs are called for in
order to provide reliable evidence with regards to AED treat-
ment other than VPA exposure and potential occurrence of neu-
rodevelopmental disorders.
A major strength of this study is its prospective design. The
enrolment of mothers during pregnancy reduces the bias asso-
ciated with knowledge of outcome and selective recall of health
information. The utilisation of a control group representative of
the general population provides risk information relevant to the
effects of AEDs in epilepsy and in other conditions (eg, mood
disorders and pain). Ascertainment of diagnosis independently
of the research team, through routine clinical practice, where
other causes are likely to have been considered and excluded
(eg, chromosomal syndromes) helps to ensure objectivity.
Additional strengths of this study include its: (i) follow-up into
middle childhood; (ii) inclusion of multiple AED groups; (iii)
blinding of researchers to exposure type and epilepsy type and
(iv) control for a number of inuential confounding variables.
A potential weakness was the setting of the nal study
outcome at 6 years of age which, as discussed above, has impli-
cations for prevalence of diagnosis. It is possible that reassess-
ment at an older age would reveal an even higher prevalence of
neurodevelopmental disorder. Furthermore, only 79% of those
actively enrolled, completed the assessment at 6 years. It could
be suggested that families of a child with difculties would be
more likely to bring their child for assessment. This however is
unlikely to account for a selective rise in prevalence for the VPA
exposed only, as the dropout rate did not differ signi cantly
across AED groups.
Although the within data correlation from twin pairs was not
taken into account in the analysis, it is felt to be justied on the
relative infrequency and the lack of association with neurodeve-
lopmental disorder (only a single case of ASD). Further limita-
tions are (i) low sample size of disorder cases (n=19) were
involved in the analysis, (ii) due to the low number of cases, the
individual types of neurodevelopmental disorder (ASD, ADHD
and dyspraxia) were not investigated through regression analysis,
(iii) the limitations imposed by the relationship between maternal
epilepsy and type of prescribed medication (eg, VPA and IGE and
CBZ and focal epilepsy), discussed above. Further a binary
outcome (presence or absence of a disorder) was taken as a
measure of prevalence. Questionnaires completed by parents and
formal systematic clinical observations could provide graded
information on children experiencing mildmoderate levels of
difculty and should be considered in future work.
CONCLUSIONS
Consideration of the results here, in the context of already pub-
lished work, suggests that the risks associated with VPA treat-
ment during pregnancy include neurodevelopmental disorders.
The extent to which such conditions are discrete or are part of
the wider neurobehavioural effects of prenatal exposure to VPA
requires further investigation. If VPA is the treatment of choice,
women should be provided with as much information as pos-
sible to enable them to make an informed decision. This should
take place prior to conception as the evidence suggests that the
Table 4 Prevalence of neurodevelopmental disorders by dose of
sodium valproate
Valproate
combined
(n=70)
Valproate
monotherapy
(n=50)
Valproate
polytherapy
(n=20)
Dose of valproate
mg/daily* Yes No % Yes No % Yes No %
20003000 2 2 50 0 1 0 2 1 66.7
10001900 5 28 15.2 4 22 15.4 1 6 14.3
100900 2 31 6.5 2 21 8.7 0 10 0
*Preconception dose.
Monotherapy and polytherapy combined.
6 Bromley RL, et al. J Neurol Neurosurg Psychiatry 2013;0:17. doi:10.1136/jnnp-2012-304270
Epilepsy
Page 6
neuropathology of ASD develops early in gestation.
39 40
Further, these ndings have implications for the care of children
with a history of prenatal exposure to AEDs. Children exposed
to AEDs in utero, particularly VPA, should be monitored closely
during early childhood to allow for early intervention, diagnosis
and support, should it be required.
Acknowledgements The authors would like to acknowledge the families for their
participation in this longitudinal study and also Dr Kimford Meador for his
comments on the manuscript and ongoing collaboration as part of the NEAD study.
Collaborators Members of the Liverpool and Manchester Neurodevelopment
Group: Professor Gus Baker, Maria Briggs, Dr Rebecca Bromley, Professor Jill
Clayton-Smith, Dr Pete Dixon, Dr Alan Fryer, Alison Gummery, Dr Rachel Kneen,
Loretta Kerr, Dr Sam Lucas, Professor George Mawer, Dr Rebekah Shallcross.
Contributors RLB and GEM, GAB and JC-S were involved in the conception,
design, analysis, interpretation and the writing of the manuscript. CC, MG-F and
SBL were involved in the analysis, interpretation and the writing of the manuscript.
RS, RK and MB were involved in data collection and the writing of the manuscript.
Funding Supported by grants from Epilepsy Research UK RB219738 (National
Lottery Charities Board) and through two educational grants from Sano Aventis
pharmaceutical company. The research group was also in receipt of funding from the
National Institute of Health (NIH grant #NS038455) as part of the NEAD study,
these funds were not directly used for the collection of data included in this paper,
however the study group was supported more generally by such funding.
Competing interests Dr Bromley has received honorarium from Sano-Aventis for
presenting to their Advisory Panel on two occasions. Dr Bromley has also provided
expert testimony regarding fetal exposure to antiepileptic drugs. Travel support for
two conferences has also been received from UCB Pharma and she has worked on
projects supported by Educational grants from Sano Aventis and UCB Pharma.
Professor Mawer has provided expert testimony regarding fetal exposure to
antiepileptic drugs. Ms Briggs has no disclosures. Dr Cheyne has no disclosures.
Professor Jill Clayton-Smith has provided expert testimony regarding fetal exposure to
antiepileptic drugs and has received honorarium from GSK. Dr García-Fiñana has no
disclosures. Dr Kneen has no disclosures. Dr Lucas has no disclosures. Dr Shallcross
has received honorarium from UCB pharma for a lecture and also travel support from
UCB pharma for conference attendance. Professor Baker has received educational
grants for this research from Sano-Aventis and has also received an educational
grant from UCB Pharma for work not reported here. Professor Baker has also provided
expert testimony regarding fetal exposure to antiepileptic drugs and has received
honorarium from UCB pharma, GSK and Sano Aventis for lectures given.
Ethics approval NRES Commitee North West.
Provenance and peer review Not commissioned; externally peer reviewed.
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    • "Autism spectrum disorder (ASD) is a neurodevelopmentalPurkinje cells are considered neuropathological hallmarks of ASD (Wegiel et al., 2014; Lukose et al., 2015). The recent increase in ASD diagnoses is believed to result, at least in part, from environmental factors (Christianson et al., 1994; Moore et al., 2000; Rasalam et al., 2005).Of particular note is the observation of increased risk of neurodevelopmental disorders (most commonly ASD) in children exposed to the antiepileptic valproic acid (VPA), compared to unexposed children (Bescoby-Chambers et al., 2001; Williams et al., 2001; Rasalam et al., 2005; Koren et al., 2006; Bromley et al., 2013 ). The prevalence of ASD in children exposed prenatally to antiepileptic drugs is estimated to be 8–18 times higher than unexposed children (Rasalam et al., 2005) and VPA produces malformations in a dose-dependent manner (Tomson et al., 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties with communication and social interactions, restricted, repetitive behaviors and sensory abnormalities. Additionally, the vast majority of subjects with ASD suffer some degree of auditory dysfunction and we have previously identified significant hypoplasia and dysmorphology in auditory brainstem centers in individuals with ASD. Prenatal exposure to the antiepileptic drug valproic acid (VPA) is associated with an increased risk of ASD. In rodents, prenatal exposure to VPA is utilized as an animal model of ASD and is associated with a number of anatomical, physiological and behavioral deficits, including hypoplasia and dysmorphology in the auditory brainstem. Based on these observations, we hypothesized that such dysmorphology in VPA-exposed animals would translate into abnormal activity in brainstem circuits and irregular tonotopic maps. Herein, we have subjected control and VPA-exposed animals to 4 or 16kHz tones and examined neuronal activation with immunohistochemistry for c-Fos. After these sound exposures, we found significantly more c-Fos-positive neurons in the auditory brainstem of VPA-exposed animals. Further, we found a larger dispersion of c-Fos-positive neurons and shifted tonotopic bands in VPA-exposed rats. We interpret these findings to suggest hyper-responsiveness to sounds and disrupted mapping of sound frequencies after prenatal VPA exposure. Based on these findings, we suggest that such abnormal patterns of activation may play a role in auditory processing deficits in ASD.
    No preview · Article · Oct 2015 · Neuroscience
  • Source
    • "Characterized by impairments in social interactions, communication, and repetitive behaviors, the etiology of autism is not entirely known, but genetic and environmental components have been hypothesized to be involved [1] [2]. There is an accumulating body of evidence that in utero exposure to valproic acid (VPA), a teratogenic anticonvulsant, leads to an increased risk and incidence of autism [3] [4] [5]. In fact, several retrospective human and case studies have documented difficulties in attentional, social, language, and motor abilities among children prenatally exposed to VPA, leading to the idea that valproate exposure during fetal development greatly alters neurodevelopment, including emotional and cognitive functioning [5] [6] [7] [8] [9] [10] [11] [12]. "
    [Show abstract] [Hide abstract] ABSTRACT: Autism is a severe neurodevelopmental disorder with a population prevalence of 1 in 68, and dramatically increasing. While no single pharmacologic intervention has successfully targeted the core symptoms of autism, emerging evidence suggests that postnatal environmental manipulations may offer greater therapeutic efficacy. Massage therapy, or tactile stimulation (TS), early in life has repeatedly been shown to be an effective, low-cost, therapeutic approach in ameliorating the cognitive, social, and emotional symptoms of autism. While early TS treatment attenuates many of the behavioral aberrations among children with autism, the neuroanatomical correlates driving such changes are unknown. The present study assessed the therapeutic effects of early TS treatment on behavior and neuroanatomy using the valproic acid (VPA) rodent model of autism. Rats were prenatally exposed to VPA on gestational day 12.5 and received TS shortly following birth. Whereas TS reversed almost all the VPA-induced alterations in neuroanatomy, it failed to do so behaviorally. The TS VPA animals, when compared to VPA animals, did not exhibit altered or improved behavior in the delayed non-match-to-sample T-maze, Whishaw tray reaching, activity box, or elevated plus maze tasks. Anatomically, however, there were significant increases in dendritic branching and spine density in the medial prefrontal cortex, orbital frontal cortex, and amygdala in VPA animals following early TS treatment, suggesting a complete reversal or remediation of the VPA-induced effects in these regions. The results suggest that postnatal TS, during a critical period in development, acts as a powerful reorganization tool that can ameliorate the neuroanatomical consequences of prenatal VPA exposure. Copyright © 2014. Published by Elsevier B.V.
    Full-text · Article · Dec 2014 · Behavioural Brain Research
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    • "This can pose difficult risk–benefit decision-making, particularly for young women with idiopathic generalized epilepsy, and especially for those with more refractory disease. In addition, recent evidence is accumulating that children born to mothers receiving sodium valproate are more likely to experience learning difficulties and autistic spectrum disorders compared with children exposed in utero to other AEDs, such as carbamazepine, lamotrigine, and levetiracetam [213,214]. Some very effective AEDs are also limited by idiosyncratic adverse drug reactions. "
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