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Topiramate in pregnancyPreliminary experience from the UK Epilepsy and Pregnancy Register
Topiramate (Topamax®) is licensed to be used, either in monotherapy or as adjunctive
treatment, for generalized tonic clonic seizures or partial seizures with or without secondary
generalization and for prevention of migraine. The safety of topiramate in human pregnancy is
largely unknown. Here we report on our experience of pregnancies exposed to topiramate.
This study is part of a prospective, observational, registration and follow-up study.
Suitable cases are women with epilepsy who become pregnant while taking topiramate either
singly or along with other antiepileptic drugs (AEDs), and who are referred before outcome of the
pregnancy is known. The main outcome measure is the major congenital malformation (MCM) rate.
Secondary outcomes include risk of specific MCM, minor malformation rate, birthweight, andgestational age at delivery.
Full outcome data are available on 203 pregnancies. Of these, 178 resulted in live birth;
reprint requests to Dr. JohnCraig, Department of Neurology,
16 had an MCM (9.0%; 95% CI 5.6% to 14.1%). Three MCMs were observed in 70 mono-
therapy exposures (4.8%; 95% CI 1.7% to 13.3%) and 13 in cases exposed to topiramate as
part of a polytherapy regimen (11.2%; 95% CI 6.7% to 18.2%). Four of the MCMs were oral
clefts (2.2%; 95% CI 0.9% to 5.6%). Four cases of hypospadias were reported (5.1%; 95% CI0.2% to 10.1%) among 78 known live male births of which two were classified as major malfor-mations.
The number of outcomes of human pregnancies exposed to topiramate is low, but
the major congenital malformation rate for topiramate polytherapy raises some concerns. Overall,
the rate of oral clefts observed was 11 times the background rate. Although the present data
provide new information, they should be interpreted with caution due to the sample size and wide
confidence intervals. Neurology
ϭ antiepileptic drug; MCM
ϭ major congenital malformation; SGA
ϭ small for gestational age.
It is widely accepted that prenatal exposure to antiepileptic drugs (AEDs) increases the risk ofmajor congenital malformations (MCM) from the background risk of 1% to 2%1-3 to between4% and 9%.3-5 However, except for lamotrigine,5,6 levetiracetam,7 and oxcarbazepine,8 infor-mation is limited on the other newly available AEDs (vigabatrin, gabapentin, topiramate,tiagabine, pregabalin, and zonisamide).
Topiramate is licensed for use both in monotherapy and as adjunctive treatment for gener-
alized tonic clonic seizures or partial seizures with or without secondary generalization. During2004 it was also licensed by the Food and Drug Administration for prophylaxis of migraine.
From the Department of Neurology (S.H., J.M., J.C.) and Bostock House (R.W., B.I.), Royal Group of Hospitals, Belfast; Department of ClinicalNeurophysiology (A.R.), Southern General Hospital, Glasgow; The Surgery (W.H.S.), Escrick, York; Department of Neurology (L.P.), St Albans CityHospital, Herts; Obstetrics and Gynaecology Department (I.R.), Lancashire Teaching Hospitals NHS Trust, Preston; and Department of MedicalGenetics (P.J.M.), Belfast City Hospital Trust, and School of Biological Sciences, University of Ulster, Coleraine, UK.
The study was made possible by a research grant from the Epilepsy Research Foundation and a number of unrestricted educational grantsfrom pharmaceutical companies (Glaxo-Smith-Kline, Sanofi-Aventis, UCB-Pharma, Janssen-Cilag, Pfizer, Eisai). An Internet-based Web site detailingthe aims of the UK Epilepsy and Pregnancy Register was made possible by a grant from Glaxo-Smith-Kline. Over the lifetime of the register, thesegrants have exceeded $10,000 from each company/grant awarding body. S.H., J.C., A.R., W.H.S., L.P., P.M., R.W., B.I., and J.M. have attendedmeetings with the support of various pharmaceutical companies, including Janssen-Cilag. J.C., L.P., P.M., and J.M. have given lectures at the bequestof pharmaceutical companies, including Janssen-Cilag, for which they have received honoraria. No individual has received personal compensation inexcess of $10,000. I.R. reports no conflicts of interest.
Copyright 2008 by AAN Enterprises, Inc.
Outcomes of pregnancies exposed to topiramate
Topiramate as part
Safety data for topiramate in human preg-
of a polytherapy
nancy are limited. A company sponsored ab-
No. of exposures
stract reported outcomes for 75 pregnancies
exposed to topiramate.10 Of 29 monotherapy
exposures two malformations (micrognathia,
phimosis) were noted. Of the remaining 46
pregnancies that had also been exposed to at
least one other AED seven infants had a mal-
Mean dose TPM (range), mg
formation (cleft palate, cleft lip, tetralogy of
Mean gestational age
Fallot, hand malformation, ureteral stenosis,
at enrollment (range), wk
pyloric stenosis, and one infant with cleft lip
Mean gestational age at delivery, wk
and palate, fixed extension of upper limb, bi-
Mean birthweight, g
lateral radial deviation of hands, brachydac-
The UK Epilepsy and Pregnancy Register is a
prospective pregnancy register set up to determine the relative
Mode of delivery
safety of all AEDs taken in pregnancy. Here we report our resultsfor first-trimester exposures to topiramate, through August 31,
Spontaneous vaginal deliveries
Suitable cases are women with epilepsy who became preg-
nant while taking topiramate, either singly or along with other
AEDs, and who were referred before the outcome of the preg-nancy was known. The main outcome measure was the MCM
rate. Cases where any prenatal test (fetal ultrasound, blood test)
had shown an abnormality and cases resulting in a pregnancy
Seizures in pregnancy
loss (induced abortion, spontaneous abortion, stillbirth) in
which an abnormality had been identified before referral to theregister had been made were excluded.
A major seizure is defined as a tonic-clonic seizure. A minor
or other seizure denotes seizures without convulsive activity.
Outcome data were collected at 3 months after the expected
Major malformations [rate (95% CI)]
date of delivery by sending the patient’s general practitioner astandardized questionnaire for completion.
Any malformation [rate (95% CI)]
An MCM was defined as an abnormality of an essential em-
bryonic structure requiring significant treatment and present atbirth or discovered during the first 6 weeks of life. Disorders notconforming to this definition were assigned as minor malforma-
tions based on the definitions and lists of disorders in the EU-
genic in mice, rats, and rabbits.9 In mice doses
The MCM rate was calculated as [total number of live births
with an MCM] ϩ [total number of pregnancy losses with an
MCM] Ϭ [total number of live births] ϩ [total number of preg-
Major congenital malformations with topiramate monotherapy
TPM ϭ topiramate; GTC ϭ generalized tonic– clonic seizure; NR ϭ not recorded.
Minor congenital malformations with topiramate monotherapy
TPM ϭ topiramate; GTC ϭ generalized tonic– clonic seizure; NR ϭ not recorded.
nancy losses with an MCM]. Spontaneous pregnancy losses and
mate, 178 (87.7%) resulted in a live birth. Of these, 31
induced abortions where no abnormalities were reported were
pregnancies had an abnormality of some kind (17.4%;
not included for analysis as we do not know if they were exam-
95% CI 12.5% to 23.7%) with 16 of these being an
ined in detail and therefore cannot know the outcome. The total
MCM (9.0%; 95% CI 5.6% to 14.1%). Four MCMs
numbers presented for each group are therefore either the totalnumber of outcomes or the total number of informative out-
were oral clefts (2.2%; 95% CI 0.9% to 5.6%) with
comes—that is, excluding pregnancy losses with no abnormali-
three infants having both cleft lip and cleft palate. Four
ties reported. Full details on study methodology have been
cases of hypospadias were reported (5.1%; 95% CI
0.2% to 10.1%) among 78 known live male births of
Through August 31, 2007, complete
which two were classified as major malformations. Full
outcome data were available on 203 prospectively re-
details on major and minor malformations are shown in
ported pregnancies that had had first trimester expo-
sure to topiramate, of which 70 had been exposed to
For the three infants who had an MCM and who
were exposed to topiramate in monotherapy the av-
Pregnancy outcome details for all exposures are
erage total daily dose was 400 mg of topiramate com-
shown in table 1. Of all pregnancies exposed to topira-
pared to 238 mg in those without an MCM (p
Major congenital malformations with topiramate polytherapy
GTC seizure in
TPM ϭ topiramate; AED ϭ antiepileptic drug; GTC ϭ generalized tonic– clonic seizure; NR ϭ not recorded; JME ϭ juvenile myoclonic epilepsy.
Minor congenital malformations with topiramate polytherapy
retard 1,400;clobazam 10;levetiracetam 2,500
TPM ϭ topiramate; AED ϭ antiepileptic drug; GTC ϭ generalized tonic– clonic seizure; NR ϭ not recorded.
0.123). Of the 61 cases exposed to topiramate in
(260 mg, p
ϭ 0.019). We have no data on maternal
monotherapy for which there was information about
gestational age, six infants (9.8%) were born at 37
Co-administration of valproate with topiramate
weeks gestation or less. The average total daily dose
either as part of a duotherapy regimen (n ϭ 12,
for those born prematurely (250 mg) was not signifi-
MCM rate 36.4%; 95% CI 15.2 to 64.6%) or as part
cantly different from those born after 37 weeks (246
of a regimen of three or more AEDs (n ϭ 23, MCM
ϭ 0.934). Of the 56 monotherapy outcomes
rate 23.8%; 95% CI 10.6 to 45.1%) was associated
for which there were full data on gestational age and
with the highest rates of MCM. This compared with
birthweight, 8 (14.3%) were small for gestational age
a lower rate of MCM for exposures not including
(SGA). The mean total daily dose for those who were
valproate (n ϭ 110, MCM rate 8.4%; 95% CI 4.3%
SGA (346 mg) was not significantly different from
those who were not SGA (239 mg, p
For polytherapy outcomes 32 combinations of at
The MCM rate for monotherapy ex-
least one AED in addition to topiramate were re-
posures to topiramate was well within the range
corded. Thirteen infants born with a major malfor-
quoted for other AEDs.5 For polytherapy exposures
mation were exposed on average to 342 mg per day
the MCM rate was higher, consistent with previous
of topiramate compared with 294 mg per day for live
reports comparing monotherapy and polytherapy ex-
births without an MCM (p
ϭ 0.539). Of the 111
posures to all AEDs.3-5 The MCM rates for combina-
cases exposed to topiramate as part of a polytherapyregimen, for which there was information on gesta-
tions containing valproate in addition to topiramate
tional age, 17 infants (15.3%) were born at 37 weeks
were higher than for combinations not containing
or less gestation. The mean total daily dose for those
valproate. While it is not clear if this is a consequence
born prematurely (347 mg) was not significantly dif-
of an interaction between these drugs, is a reflection
ferent from those born after 37 weeks (288 mg, p
of unidentified patient characteristics, or is due to
0.891). Of 103 live births exposed to topiramate as
valproate, which has increasingly been shown to be
part of a polytherapy regimen and for which there
associated with a high risk of MCMs, either in
were data regarding birthweight and gestational age,
monotherapy or as part of a polytherapy regimen,5,12
20 infants (19.4%) were SGA. The mean total daily
is unclear. Clearly these results need to be replicated
dose for those infants who were SGA (405 mg) was
in larger numbers and from different registers before
significantly different from those who were not SGA
we might counsel women of child-bearing age
against using combinations including topiramate
Received November 19, 2007. Accepted in final form April 2,
All of the MCMs observed have already been de-
scribed in pregnancies exposed to AEDs other than
EUROCAT Annual Report to WHO 2004-5. Available
topiramate and no apparent dose response was evi-
dent either for monotherapy or polytherapy expo-
Annual-Report-2005-for-WHO.pdf. Accessed January
sures. We found the rates of oral clefts (2.2%) and
hypospadias (5.1%) much higher than that reported
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in the United Kingdom. For oral clefts, which occur
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approximately 14 times the background rate.
Samren EB, van Duijn CM, Christiaens GC, Hofman A,
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While our results are preliminary, they are rele-
vant not only in dealing with women with epilepsy of
Kwarta RF, Hulihan JF, Schmider J, Nye JS. Pregnancy
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condition which also occurs frequently in women of
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between patient groups exposed to the same drug but
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used for different indications, the teratogenic poten-
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This is also likely to be the case for topiramate. Mon-
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