Original article
Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2015-308278 on 25 September 2015. Downloaded from http://fn.bmj.com/ on December 15, 2023 at Bodleian
▸ Additional material is
published online only. To view
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archdischild-2015-308278).
1 lip and palate (CLP) and isolated cleft palate (ICP). This
Blackpool Victoria Hospital,
Blackpool, Lancashire, UK
2
Institute of Human
Development, The University of
Manchester, Manchester, UK
3
Neurology Department,
Belfast Health and Social Care
Trust, Royal Victoria Hospital,
Belfast, Co Antrim, Northern
Ireland
4
Manchester Centre for
Genomic Medicine, Central
Manchester University
Hospitals, Manchester, UK
Correspondence to
Dr Adam Jackson, Blackpool
Victoria Hospital, Whinney
Heys Road, Blackpool FY3
8NR, UK; Adam.jackson@
doctors.org.uk
Received 20 January 2015
Revised 4 September 2015
Accepted 7 September 2015
Published Online First
25 September 2015
To cite: Jackson A,
Bromley R, Morrow J, et al.
Arch Dis Child Fetal
Neonatal Ed 2016;101:
F207–F211.
Jackson A, et al. Arch Dis Child Fetal Neonatal Ed 2016;101:F207–F211. doi:10.1136/archdischild-2015-308278
In utero exposure to valproate increases the risk
of isolated cleft palate
Adam Jackson,1 Rebecca Bromley,2 James Morrow,3 Beth Irwin,3 Jill Clayton-Smith4
ABSTRACT
Introduction Orofacial clefting (OFC) has been
described in infants exposed to valproic acid (VPA)
prenatally, but often no distinction is made between cleft
distinction is important as these conditions have different
management implications and the distinction has
implications too for understanding the teratogenic
mechanisms.
Methods We searched EMBASE, Medline and Web of
Science for observational studies describing OFC in
association with VPA exposure. Searches for similarly
exposed patients referred to a regional genetic centre
and those recorded in the UK Epilepsy and Pregnancy
Register (UKEPR) were undertaken. Cleft type and,
where available, VPA doses prescribed were recorded.
Results A total of 4459 cases of VPA exposure were
reported in the literature in nine separate studies with
50 cases of OFC, the majority of which did not
differentiate the cleft type. Eight patients ascertained
through the regional genetic centre had ICP. Thirteen
cases of OFC occurred in 1282 VPA monotherapy-
exposed pregnancies in the UKEPR; nine had ICP and
four had CLP, representing an 11.3-fold and 3.5-fold
increase risk in ICP and CLP, respectively, over general
population risk. Doses ranged from 200 to 2500 mg
VPA daily with 73% of monotherapy ICP cases from the
local cohort and UKEPR occurring at doses over
1000 mg.
Conclusion ICP is the predominant cleft type seen in
prenatal VPA exposure. Parents should be counselled
appropriately and infants should undergo review after
delivery for ICP. Pregnancy registers collecting
information on congenital anomalies should make the
distinction between CLP and ICP as the risk differs
across the two conditions.
INTRODUCTION
Fetal valproate syndrome (FVS) describes a constel-
lation of features that has been recognised in a
number of children exposed to valproic acid (VPA)
in utero. First delineated in 1984 by DiLiberti
et al,1 FVS is characterised by a pattern of major
and minor malformations and neurodevelopmental
problems together with a distinctive facial pheno-
type. The latter includes medial deficiency of the
eyebrows which tend to be neat and arched, a
prominent infraorbital groove, a broad and flat
nasal bridge, a smooth philtrum with a thin vermil-
lion border to the upper lip and a small, down-
turned mouth with an everted lower lip.
Congenital abnormalities which occur at greater
frequency in FVS include neural tube defects, radial
ray defects, trigonocephaly and heart defects.
A dose-dependent effect of VPA has been
What is already known on this topic
▸ Orofacial clefting, which includes cleft lip and
palate and isolated cleft palate, occurs more
commonly in children exposed to valproate
in utero.
▸ Previous studies have not assessed the type of
cleft that is most common in this population.
What this study adds
Libraries of the University of Oxford. Protected by copyright.
▸ Orofacial clefting is associated with fetal
valproate exposure in both monotherapy and
polytherapy during pregnancy.
▸ In fetal valproate exposure, isolated cleft palate
is the predominant cleft type.
▸ As isolated cleft palate is more prevalent that
cleft lip and palate in fetal valproate exposure,
separate teratogenicity risk estimates need to
reflect these two distinct conditions.
established,2 with doses above 1000 mg daily being
associated with a greater risk of congenital malfor-
mations. The risk of cognitive impairment is
increased with increasing dose.3
Orofacial clefting (OFC) has been associated
with exposure to VPA in utero4 and has been
described as a feature of FVS.5 However, the spec-
trum of OFC includes cleft lip and/or palate (CLP)
and isolated cleft palate (ICP). The causes and
developmental pathogeneses of these two condi-
tions are different as are the management interven-
tions required and outcomes expected after surgical
correction. Children who have CLP are managed
on a different care pathway from those who have
ICP. The number and types of surgical interventions
will differ, for example, and children with an iso-
lated cleft lip (CL) are not likely to need the same
speech and language interventions or to have the
middle ear complications that are so frequent in
patients with cleft palate. The implications for the
two conditions are thus different, and to provide
correct information to parents about cause, man-
agement, complications and prognosis, it is import-
ant to make the distinction between CLP and ICP.
In the case of FVS, many patient information leaf-
lets, websites, published papers and textbooks link
VPA exposure in pregnancy with an increased inci-
dence of OFC but do not go into details as to
whether this association is more likely to be with
F207
 Original article
CLP or ICP.6–8 Further, research registries which investigate risk
estimates of malformation following VPA exposure in utero
tend not to differentiate cleft type at an analysis and conclusion
level.
From a teratological point of view, it is also important to dis-
tinguish between the two types of OFC as there are different
causal mechanisms.9 Further, current practice in most malforma-
tion registries is to report a single incidence figure for OFC,
combining both CLP and ICP;2 4 10 however, if there are mech-
anistic differences, the risks associated with each type of OFC
may differ and combining them may lead to unreliable risk
estimates.
Palatogenesis begins with the first pair of pharyngeal arches in
the fourth week of gestation. By the sixth week, the medial
nasal prominences fuse forming the philtrum, upper jaw and the
triangular primary palate. It is in the seventh week that the pal-
atine shelves, derived from the maxillary prominences, turn
horizontally and fuse creating the secondary palate with the
incisive foramen marking the division of the secondary and
primary palates.11
Clefts anterior to the incisive foramen cause CL and some-
times clefts of the primary palate, which arise from incomplete
fusion of the maxillary prominence with the medial nasal prom-
inence. Clefts posterior to the incisive foramen cause ICP,
arising from incomplete fusion of the palatine shelves. ICP can
lead to velopharyngeal insufficiency and carries significant risk
of chronic otitis media, hearing loss and abnormal speech,
unlike CL.12
Antenatal ultrasound scans (USS) are helpful in identifying
congenital malformations and allow both parents and clinicians
to make preparations for the management of these conditions
after birth. In the UK, every pregnant mother is offered a
detailed fetal anomaly scan at around 20 weeks of pregnancy.
Offerdal et al13 studied 49 314 pregnancies in Norway and
found a pickup rate of 43% (35 out of 77 cases) for CLP and
0% (0 out of 24 cases) for ICP. A novel three-dimensional (3D)
sonographic technique proposed by Campbell et al14 allowed
for improved antenatal detection of ICP. Overall, however, in a
routine antenatal setting, a scan which is negative for CLP does
not exclude ICP.
Martínez-Frías15 stated that OFC only occurred in children
exposed to VPA in utero as polytherapy. However, two large
epidemiological studies16 17 have since found an increased OR
for ICP in children of mothers taking VPA monotherapy. The
authors’ anecdotal experience of children exposed to VPA in
utero who have attended both a cleft clinic and the regional
genetic clinic in Manchester, UK, together with the results of
cohort studies of children exposed to antiepileptic drugs (AEDs)
in utero carried out within the North West of England have sug-
gested that CLP is, in fact, unusual after VPA exposure in utero
and that ICP is in fact much more likely. Such observations led
to this review of the available literature and of other known
patients with OFC following VPA exposure.
METHODS
A literature search was undertaken to identify any studies that
described OFC occurring in association with FVS. Searches
were conducted in EMBASE, Medline (via PubMed) and Web
of Science for any studies published from 1 January 1995 to 4
June 2015 (the past 20 years) restricted to the English language
and human studies. The search terms were combined in the fol-
lowing manner for each database:
▸ (antiepileptic OR valproate OR epilepsy) AND ( pregnancy)
AND (cleft lip OR cleft palate)
F208 Jackson A, et al. Arch Dis Child Fetal Neonatal Ed 2016;101:F207–F211. doi:10.1136/archdischild-2015-308278
Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2015-308278 on 25 September 2015. Downloaded from http://fn.bmj.com/ on December 15, 2023 at Bodleian
Results were then filtered by title and deduplicated to include
relevant studies. These relevant studies then underwent a full-
text review by one author (AJ) and those fulfilling inclusion cri-
teria were accepted for our study.
Our inclusion criteria were as follows:
▸ case–control or cohort studies describing OFC in VPA expos-
ure during pregnancy;
▸ primary research studies only and
▸ over 100 exposures reported.
Data were then extracted from each included study by one
author (AJ) to include total number of VPA exposures (whether
monotherapy or polytherapy) and the total number of OFC
cases occurring in each study. When reported in the study (or its
online supplementary material), the cleft type was also
extracted, along with information pertaining to dose of VPA,
where available.
For papers reporting updates of pregnancy registers, the most
recent update was included and previous papers were excluded
to avoid duplicate results. Systematic reviews and meta-analyses
were also excluded but their references were reviewed to
include the primary studies quoted in the paper. A manual lit-
Libraries of the University of Oxford. Protected by copyright.
erature search was also undertaken to identify any additional
reports and meeting abstracts in the investigators’ personal
collections.
Moreover, additional cases known to the authors through
attendance at a regional genetic clinic were reviewed and details
regarding cleft subtype and dose of VPA exposure obtained.
Finally, data was obtained from the UK Epilepsy and Pregnancy
Register (UKEPR) about cases with a history of VPA exposure
and OFC. All patient data were anonymised for analysis but
cleft status remained linked to AED type and dose.
RESULTS
Our search strategy identified a total of nine studies that fulfilled
our inclusion criteria (figure 1). Studies excluded and reasons
for exclusion are presented in online supplementary appendix 1.
Nine observational studies meeting inclusion criteria were
identified using the search strategy described (table 1).
Jentink et al16 reviewed the literature on malformations in
FVS and included eight studies in a meta-analysis of 1565
patients. The 14 most common malformations found in this
meta-analysis were then assessed for association with VPA
monotherapy exposure in the first trimester by a case–control
study using the European Surveillance of Congenital
Abnormalities (EUROCAT) database. There were 122
VPA-exposed pregnancies registered with the EUROCAT data-
base that also had one of the 14 malformations mentioned
Figure 1 Returns using our search strategy.
 Original article

Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2015-308278 on 25 September 2015. Downloaded from http://fn.bmj.com/ on December 15, 2023 at Bodleian
Table 1 Cohort and case–control studies reporting OFC in VPA exposure in utero
Reference Study type Total VPA exposures OFC CL±P ICP Dosage

Campbell et al10 UKEPR 1290 monotherapy 13 Not Not Mean daily doses for MCM=1031.2 mg
Prospective observational study stated stated compared with 897.9 mg in those without
MCM
Vajda et al18 Australian Register of AEDs in 447 (monotherapy and 5 Not Not Mean dose (±SD)=880±476 mg/day
pregnancy polytherapy) stated stated
Population-based case–control
study
Hernández-Díaz et al (see North American AED Pregnancy 323 monotherapy 3 2 1 Unclear
online supplementary data)4 Registry
Prospective case–control study
Tomson et al2 EURAP registry 1010 monotherapy 4 Not Not <700 mg/day=3
Prospective cohort study stated stated >700 to <1500 mg/day=1
Jentink et al16 EUROCAT database 122 monotherapy 13 0 13 Unclear
Population-based case–control
study
Artama et al19 Finnish Social Insurance 263 monotherapy 5 Not Not Unclear
(see online supplementary data) Institution 98 polytherapy 2 stated stated
Retrospective cohort study
Wide et al20 Swedish Medical Birth Registry 268 monotherapy 4 Not Not Unclear
Population-based register study 42 polytherapy 0 stated stated

Libraries of the University of Oxford. Protected by copyright.

Samrén et al21 Netherlands 158 monotherapy 0 0 0 Unclear
Retrospective cohort study 136 polytherapy 0 0 0
Samrén et al22 Pooled data from five 184 monotherapy 0 Not Not Unclear
prospective European studies 118 polytherapy 1 stated stated
AED, antiepileptic drug; CL, cleft lip; EURAP, European Registry of Antiepileptic Drugs and Pregnancy; EUROCAT, European Surveillance of Congenital Abnormalities; ICP, isolated cleft
palate; MCM, major congenital malformations; OFC, orofacial clefting; UKEPR, UK Epilepsy and Pregnancy Register; VPA, valproic acid.

above. There were 13 ICP in this group; however, no CL and pregnancy for major congenital malformations (MCM). The
CLP were reported. The preselection of malformation cases in most recent update was published in February 201410 and
this study may be a source of ascertainment bias and is likely to found the MCM rate to be highest (6.7%) for VPA monother-
inflate the incidence of malformations in VPA exposure. apy exposure in utero. This is in comparison to 2.6% and 2.3%
A total of 33 OFC cases occurred in 3208 VPA-exposed preg- for carbamazepine and lamotrigine, respectively. Campbell et al
nancies including both monotherapy and polytherapy.2 10 18–21 described 13 cases of OFC occurring in 1282 VPA
However, cleft type was not distinguished in any of these monotherapy-exposed pregnancies; however, no distinction was
papers. OFC was identified in 3/323 by Hernández-Díaz et al4 made between CLP and ICP in that report. Through personal
with two ICP and one CLP; however, this was only to be found correspondence and the contribution of coauthors JM and BI,
in online supplementary data. There were no cases of OFC further details of the cleft phenotypes from these patients are
reported by Samrén et al21 in a total of 294 VPA-exposed preg- presented in table 3, along with an additional four cases of OFC
nancies (monotherapy and polytherapy). from the register where VPA was used as polytherapy. A break-
In summary, a total of 4459 VPA exposures are reported in down of each case is shown in table 4.
the literature with a total of 50 cases of OFC. This gives a crude
prevalence of OFC in VPA exposure of 112 per 10 000. There Effect of dose of VPA on cleft occurrence and type
were 3618 VPA monotherapy exposures and 394 polytherapy Of the patients identified from the local cohort and those seen
exposures. A total of 447 cases reported by Vajda et al18 were a in the UKEPR where the dose was known, 11/15 (73%) of ICP
mixture of monotherapy and polytherapy. There were 14
reported cases of ICP (all occurring in monotherapy), 2 cases of
CLP and the remaining 34 clefts were not distinguished.
Table 2 Case of FVS and OFC known to Manchester Regional
Genetic Service
Cases ascertained through the Regional Genetic Service
The case notes of all individuals known to the Regional Genetic Patient Sex Type of cleft Dose of VPA (mg)
Service in Manchester, who had been exposed to VPA in preg- 1 F ICP 1200*
nancy and who had been noted to have a clefting disorder were 2 M ICP 1800*
reviewed. A summary of these cases is presented in table 2. All 3 M ICP 1500†
of the eight cases had ICP and no cases were found reporting 4 F ICP Unknown
CLP. The dose of VPA taken during pregnancy ranged from 5 F ICP 1200
1200 to 2000 mg daily (mean=1533 mg). One of these cases 6 F Submucous ICP 2000
had been included in the study by Meador et al5 and was not, 7 M Bifid uvula 1500
therefore, a new case. 8 F ICP Unknown
*These cases were referred to in a review of FVS by Clayton-Smith and Donnai.23
Cases ascertained through the UKEPR †Patient 3 as reported by Jackson et al.24
The UKEPR was set up in 1996 with the aim of establishing the FVS, Fetal valproate syndrome; ICP, isolated cleft palate; OFC, orofacial clefting; VPA,
valproic acid.
risks conferred by intrauterine exposure to single AEDs during
Jackson A, et al. Arch Dis Child Fetal Neonatal Ed 2016;101:F207–F211. doi:10.1136/archdischild-2015-308278 F209
 Original article

Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/archdischild-2015-308278 on 25 September 2015. Downloaded from http://fn.bmj.com/ on December 15, 2023 at Bodleian
Many studies and reports have until now described OFC as a
Table 3 Summary statistics from the UKEPR on OFC and exposure
single entity when discussing risks of prenatal VPA expos-
to VPA
ure,2 10 15 18–20 27 resulting in patient information which
CLP suggest that patients with FVS are at risk of CLP as well as ICP.
Outcomes OFC ICP CL CLP To some extent this may be true but the risk for ICP is much
greater, and ICP is associated with many more complications
Monotherapy 1282 13 9 1 3 which require ongoing management such as velopharyngeal
Polytherapy 527 4 4 0 0 insufficiency and hearing loss. Antenatal USS have a much
CL, cleft lip; CLP, cleft lip and palate; ICP, isolated cleft palate; OFC, orofacial clefting; higher pickup rate for CLP than ICP as isolated palatal clefts are
UKEPR, UK Epilepsy and Pregnancy Register; VPA, valproic acid. rarely detected. Newer diagnostic techniques, such as 3D USS,
may increase the pickup rate of ICP and could, therefore, be
beneficial to expectant mothers who are taking VPA. Making
monotherapy cases occurred in children exposed to over
clinicians aware that ICP is a much more common outcome
1000 mg VPA daily. If the four polytherapy cases are included,
than CLP in VPA-exposed babies allows for appropriate prenatal
13/19 (68%) occurred in pregnancies exposed to over 1000 mg
counselling for parents.
daily. This is in contrast to CLP where 75% of cases were
It has previously been suggested that the mechanism behind
exposed to <1000 mg daily.
VPA teratogenicity is folate antagonism, which interrupts DNA
synthesis leading to congenital malformations.28 Studies in the
DISCUSSION
general population have not reached consensus regarding pre-
This review has demonstrated that based on the published litera-
conceptual folic acid (PCFA) supplementation and the risk of
ture and on cases known to the authors the increased prevalence
OFC. A meta-analysis in 2008 found that maternal multivitamin
of clefting in children exposed to VPA is not due to an increase in

Libraries of the University of Oxford. Protected by copyright.

use was inversely proportionate to risk of CLP (OR 0.75) and
both CLP and ICP or to CLP alone but just to an increase in ICP.
to a lesser extent ICP (0.88); however, the evidence regarding
This pattern was found to hold true across both monotherapy
folate intake was much less convincing and studies were heter-
and polytherapy exposures. The International Perinatal Database
ogenous.29 Interestingly, Morrow et al27 studied the effect of
of Typical Oral Clefts25 and EUROCAT working groups26 found
PCFA supplementation on MCM in pregnant women with epi-
the prevalence of CL, CLP and ICP in the European population
lepsy using the UKEPR. In women taking VPA monotherapy,
to be 3.28, 6.64 and 6.20 per 10 000. Based on the UKEPR, the
they found MCM (including OFC) rates of 5.3% in the
prevalence of CL, CLP and ICP in VPA monotherapy exposure is
PFCA group and 4.3% in the group without PCFA.
7.80, 23.40 and 70.20 per 10 000 live births, respectively. This
Folate-independent mechanisms for VPA teratogenicity may be
represents an 11.3-fold increase in ICP, 3.5-fold increase in CLP
important for further study.
and a 2.4-fold increase in CL.

Table 4 Breakdown of OFC cases exposed to VPA in either monotherapy or polytherapy from the UKEPR
Case Daily dose VPA (mg) Cleft type Other features

Monotherapy
1 400 ICP (bilateral) Micrognathia
2 600 CLP –
3 1200 ICP Micrognathia
4 1600 ICP –
5 2000 CLP Dysmorphism ‘Hyperketonism’
6 200 ICP –
7 800 CLP –
8 1500 ICP –
9 800 ICP Congenital hypotonia
10 1500 (conception) ICP –
1000 (pregnancy)
11 900 ICP Autistic spectrum disorder
12 2500 ICP Motor delay
Hip problem
13 800 CL (involving gum) –
Polytherapy
1 2000 VPA ICP (bilateral) Absent palmar creases
1800 Gabapentin
(CBZ stopped around conception)
2 400 VPA ICP Intracerebral haemorrhage
1000 CBZ Delivered at 31 weeks
3 500 VPA ICP Fetal valproate syndrome
500 Topiramate Crossed toes
4 1500 VPA ICP –
1.5 Clonazepam
CBZ, carbemazepine; CL, cleft lip; CLP, cleft lip and palate; ICP, isolated cleft palate; OFC, orofacial clefting; UKEPR, UK Epilepsy and Pregnancy Register; VPA, valproic acid.

F210 Jackson A, et al. Arch Dis Child Fetal Neonatal Ed 2016;101:F207–F211. doi:10.1136/archdischild-2015-308278

VPA is a broad class I and class II histone deacetylase inhibi-
tor, which brings about changes in gene expression.30 VPA has
recently been shown to bring about a state of hypervitaminosis
A by reducing expression of retinoic acid-binding protein.31
Lammer et al32 described 21 infants who had been exposed to
isotretinoin (a vitamin A analogue and acne treatment) in utero,
three of which had ICP. The concentration of retinoic acid
appears to be important in palatogenesis and future research
will help to understand the teratogenic action of VPA in relation
to ICP.
There also appears to be a dose-dependent relationship as the
risks of ICP for the offspring of women taking over 1000 mg
daily are much greater than those who are taking <1000 mg.
Observation of a dose-dependent effect is one of the hallmarks
of teratogenicity.33 In our study we observed a dose-dependent
effect for ICP but not for CLP. Studies and pregnancy registers
recording outcomes after exposure to VPA in utero should be
encouraged to distinguish between CLP and ICP to study these
effects further and to allow for more precise risk estimates to be
communicated to both prescribers and women for whom VPA is
a treatment option.
CONCLUSION
The published literature, our own clinical observations and evi-
dence from the UKEPR appear to agree that exposure to VPA in
utero increases the risk of ICP and this applies to both mono-
therapy and polytherapy. Further research is needed to identify
a causative mechanism in VPA-induced ICP.
Contributors AJ wrote the article, performed the literature searches and analysed
the data. RB reviewed the article and added data from her collection. JM and BI
provided data from the UKEPR. JC-S had the idea for this study and added the local
Manchester Regional Genetics Service data. All authors reviewed and added
comments to the final manuscript prior to publication.
Funding No direct funding was provided for this study; however, RB is currently
supported by National Institute for Health Research (PDF-2013-06-041). Cleft
research within the University of Manchester is supported by the Healing Foundation
UK Cleft Cooperative. The UK Epilepsy and Pregnancy Register has received a
research grant from the Epilepsy Research Foundation and a number of educational
grants from pharmaceutical companies (Parke Davis, GlaxoSmithKline, Elsai,
Novartis, Sanofi-Aventis, Pfizer, Janssen-Cilag and UCB).
Competing interests JM is the lead for the UK Epilepsy and Pregnancy Register.
The UK Epilepsy and Pregnancy Register has received a research grants from the
Epilepsy Research Foundation and a number of educational grants from
pharmaceutical companies (Parke Davis, GlaxoSmithKline, Eisai, Novartis,
Sanofi-Aventis, Pfizer, Janssen-Cilag and UCB). RB and JC-S have worked in the past
on studies funded by Sanofi Aventis and UCB Pharma.
Ethics approval Ethical approval was not sought specifically for this study as it did
not involve direct interventions in human subjects and all clinical data were
anonymised. Patients recruited previously to the UK Pregnancy and Epilepsy Register
and to the North West England Cohort Studies have consented to use of their data.
Provenance and peer review Not commissioned; externally peer reviewed.
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