Topiramate in pregnancy

It is widely accepted that prenatal exposure to antiepileptic drugs (AEDs) increases the risk of major congenital malformations (MCM) from the background risk of 1% to 2%^1–3 to between 4% and 9%.^3–5 However, except for lamotrigine,^5,6 levetiracetam,⁷ and oxcarbazepine,⁸ information 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 generalized tonic clonic seizures or partial seizures with or without secondary generalization. During 2004 it was also licensed by the Food and Drug Administration for prophylaxis of migraine.

Topiramate has been shown to be teratogenic in mice, rats, and rabbits.⁹ In mice doses as low as 0.2 times the maximum recommended human dose (400 mg/m²) were associated with an increased frequency of (primarily) craniofacial defects.

Safety data for topiramate in human pregnancy are limited. A company sponsored abstract 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 malformation (cleft palate, cleft lip, tetralogy of Fallot, hand malformation, ureteral stenosis, pyloric stenosis, and one infant with cleft lip and palate, fixed extension of upper limb, bilateral radial deviation of hands, brachydactyly, and hydrocephalus).

METHODS

The UK Epilepsy and Pregnancy Register is a prospective pregnancy register set up to determine the relative safety of all AEDs taken in pregnancy. Here we report our results for first-trimester exposures to topiramate, through August 31, 2007.

Suitable cases are women with epilepsy who became pregnant while taking topiramate, either singly or along with other AEDs, and who were referred before the outcome of the pregnancy 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 loss (induced abortion, spontaneous abortion, stillbirth) in which an abnormality had been identified before referral to the register 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 date of delivery by sending the patient’s general practitioner a standardized questionnaire for completion.

An MCM was defined as an abnormality of an essential embryonic structure requiring significant treatment and present at birth or discovered during the first 6 weeks of life. Disorders not conforming to this definition were assigned as minor malformations based on the definitions and lists of disorders in the EUROCAT registry.¹¹

The MCM rate was calculated as [total number of live births with an MCM] + [total number of pregnancy losses with an MCM] ÷ [total number of live births] + [total number of pregnancy losses with an MCM]. Spontaneous pregnancy losses and induced abortions where no abnormalities were reported were not included for analysis as we do not know if they were examined in detail and therefore cannot know the outcome. The total numbers presented for each group are therefore either the total number of outcomes or the total number of informative outcomes—that is, excluding pregnancy losses with no abnormalities reported. Full details on study methodology have been previously reported.⁵

RESULTS

Through August 31, 2007, complete outcome data were available on 203 prospectively reported pregnancies that had had first trimester exposure to topiramate, of which 70 had been exposed to topiramate in monotherapy.

Pregnancy outcome details for all exposures are shown in table 1. Of all pregnancies exposed to topiramate, 178 (87.7%) resulted in a live birth. Of these, 31 pregnancies had an abnormality of some kind (17.4%; 95% CI 12.5% to 23.7%) with 16 of these being an MCM (9.0%; 95% CI 5.6% to 14.1%). Four MCMs were oral clefts (2.2%; 95% CI 0.9% to 5.6%) with three infants having both cleft lip and cleft palate. Four cases of hypospadias were reported (5.1%; 95% CI 0.2% to 10.1%) among 78 known live male births of which two were classified as major malformations. Full details on major and minor malformations are shown in tables 2 through 5.

For the three infants who had an MCM and who were exposed to topiramate in monotherapy the average total daily dose was 400 mg of topiramate compared to 238 mg in those without an MCM (p = 0.123). Of the 61 cases exposed to topiramate in monotherapy for which there was information about gestational age, six infants (9.8%) were born at 37 weeks gestation or less. The average total daily dose for those born prematurely (250 mg) was not significantly different from those born after 37 weeks (246 mg (p = 0.934). Of the 56 monotherapy outcomes for which there were full data on gestational age and birthweight, 8 (14.3%) were small for gestational age (SGA). The mean total daily dose for those who were SGA (346 mg) was not significantly different from those who were not SGA (239 mg, p = 0.084).

For polytherapy outcomes 32 combinations of at least one AED in addition to topiramate were recorded. Thirteen infants born with a major malformation were exposed on average to 342 mg per day of topiramate compared with 294 mg per day for live births without an MCM (p = 0.539). Of the 111 cases exposed to topiramate as part of a polytherapy regimen, for which there was information on gestational age, 17 infants (15.3%) were born at 37 weeks or less gestation. The mean total daily dose for those born prematurely (347 mg) was not significantly different from those born after 37 weeks (288 mg, p = 0.891). Of 103 live births exposed to topiramate as part of a polytherapy regimen and for which there were data regarding birthweight and gestational age, 20 infants (19.4%) were SGA. The mean total daily dose for those infants who were SGA (405 mg) was significantly different from those who were not SGA (260 mg, p = 0.019). We have no data on maternal weights in pregnancy.

Co-administration of valproate with topiramate either as part of a duotherapy regimen (n = 12, MCM rate 36.4%; 95% CI 15.2 to 64.6%) or as part of a regimen of three or more AEDs (n = 23, MCM rate 23.8%; 95% CI 10.6 to 45.1%) was associated with the highest rates of MCM. This compared with a lower rate of MCM for exposures not including valproate (n = 110, MCM rate 8.4%; 95% CI 4.3% to 15.8%).

DISCUSSION

The MCM rate for monotherapy exposures to topiramate was well within the range quoted for other AEDs.⁵ For polytherapy exposures the MCM rate was higher, consistent with previous reports comparing monotherapy and polytherapy exposures to all AEDs.^3–5 The MCM rates for combinations containing valproate in addition to topiramate were higher than for combinations not containing valproate. While it is not clear if this is a consequence of an interaction between these drugs, is a reflection of unidentified patient characteristics, or is due to valproate, which has increasingly been shown to be associated with a high risk of MCMs, either in monotherapy or as part of a polytherapy regimen,^5,12 is unclear. Clearly these results need to be replicated in larger numbers and from different registers before we might counsel women of child-bearing age against using combinations including topiramate and valproate.

All of the MCMs observed have already been described in pregnancies exposed to AEDs other than topiramate and no apparent dose response was evident either for monotherapy or polytherapy exposures. We found the rates of oral clefts (2.2%) and hypospadias (5.1%) much higher than that reported in the United Kingdom. For oral clefts, which occur in 1 in 500 live births in the United Kingdom,¹³ the observed rate was 11 times higher than the background rate. For hypospadias, which is estimated to occur in 1 in 300 live births,¹⁴ the observed rate was approximately 14 times the background rate.

The mean birthweights for live infants exposed in utero to topiramate either as monotherapy or as part of combination therapy were within the normal range with a trend to lower birth weight in polytherapy exposures. Infants who were SGA were exposed to a significantly higher daily dose of topiramate but only when exposed to topiramate as part of combination therapy. In animal studies embryotoxicity (including reduced fetal weight gain) was observed at doses as low as 0.5 times the maximum recommended human dose.⁹ Unfortunately we have no data on maternal weights, either before or during pregnancy, and therefore cannot comment on any potential interaction between maternal weights and the outcome of SGA.

While our results are preliminary, they are relevant not only in dealing with women with epilepsy of childbearing years. Topiramate is also licensed for use for migraine prophylaxis, an even more common condition which also occurs frequently in women of childbearing years. While the risks for adverse outcomes, including teratogenic endpoints, may differ between patient groups exposed to the same drug but used for different indications, the teratogenic potential of any agent is also likely determined by factors related to the structure and functional effects of the agent, the dose prescribed, and the timing of use. This is also likely to be the case for topiramate. Monitoring pregnancies in women with migraine exposed to topiramate should therefore be encouraged.