Topiramate (TPM) was first marketed in 1996 in the United States as Topamax.  While initially approved for use as an antiepileptic medication, topiramate is now also used for migraine prophylaxis, weight loss, and, less commonly, as a mood stabilizer.  We do not see many women for whom topiramate is used to treat psychiatric symptoms; however, we do see a fair number of reproductive-aged women who are using topiramate for migraine prophylaxis and appetite suppression.  In addition, one of the newer weight reduction medications, Qsymia, contains topiramate and phentermine.

Overall Risk of Major Malformations

Beginning in 2008, we started to see studies suggesting that first trimester exposure to topiramate was associated with an increase in the overall risk for major malformations; however, these studies included very small sample sizes. 

  • In a population-based cohort study in Denmark, a major birth defect was diagnosed in 5 of 108 infants (4.6%) exposed to topiramate (adjusted odds ratio of 1.44).

Other studies reported no increase in the frequency of major malformations in topiramate-exposed infants.  

Topiramate and Increased Risk for Oral Clefts

Other studies demonstrated a significant increase in risk for oral clefts among infants with first trimester exposure to topiramate.    In prospective data gathered by the UK Epilepsy and Pregnancy Register, 16 out of 178 (or 9.0%) of topiramate-exposed children had a major malformation.  Three of the major malformations were observed in 70 infants exposed to topiramate monotherapy (4.8%) and 13 in cases exposed to topiramate as part of a polytherapy regimen (11.2%). Four of the major malformations observed were oral clefts.  Overall, the rate of oral clefts in topiramate-exposed infants was 11 times higher than the background rate.

Data from the North American Antiepileptic Drug (AED) Pregnancy Registry estimated that the prevalence of major malformations in women exposed to topiramate monotherapy during the first trimester was 3.8% (11/289), compared to the prevalence of 1.3% (5/372) in an unexposed reference group. Four infants exposed to topiramate had oral clefts.

Based on these preliminary findings and concerns regarding the safety of topiramate during pregnancy, the FDA strengthened the label warning for topiramate by changing its pregnancy classification to category D.

In a meta-analysis from 2015, Alsaad and colleagues analyzed data from six studies including a total of 3420 infants with TPM exposure and 1,204,981 controls. Compared to non-exposed controls, the odds ratio (OR) for oral cleft associated with first trimester exposure to TPM was 6.26 (95% confidence interval: 3.13-12.51; P = 0.00001). 

What About Topiramate and Risk for Other Malformations?

In a retrospective cohort study using data from four insurance claims databases, Tennis and colleagues compared the prevalence of major malformations in three different groups of infants:

  • Infants of women exposed to TPM in the first trimester (cohort 1)
  • Infants of women previously exposed to TPM or other antiepileptic drugs (cohort 2)
  • Infants of women matched to the TPM cohort by indication (i.e., epilepsy, migraine headaches) but with no TPM exposure (cohort 3)

Of the ten most common major malformations evaluated in this study, the researchers observed an increase in the prevalence of conotruncal heart defects in TPM-exposed infants compared to the other two cohorts (odds ratios of 2.80 and 2.55 for comparisons with cohorts 2 and 3, respectively).

In addition, they observed four other malformations were more common among TPM-exposed infants: ventricular septal defects, atrial septal defects, hypospadias, and coarctation of the aorta.  In all cases the odds ratios were greater than 1.5 but differences in prevalence were only observed for comparisons with the similar medical profile group (cohort 3).  

While this study shows an association between TPM exposure and several different types of malformations, the authors remind the reader that the word “association” does not necessarily mean “causation.” TPM use in the mother may be associated with other characteristics or behaviors, such as smoking or being overweight, that also modulate risk. Given these limitations, these  studies may be more useful in identifying potential associations but may be less reliable in quantifying the relative risk.

Nonetheless, the findings of this study, combined with the data suggesting an association between topiramate exposure and increased risk of oral clefts, raises concerns regarding the use of topiramate in women who are either pregnant or planning to conceive.  

Impact of Topiramate Dose on Risk for Malformations

Using data from the US 2000–2010 Medicaid Analytic eXtract, Hernandez-Diaz and colleagues examined outcomes in a cohort of 1,360,101 pregnant women.    Among the 2,425 infants born to women who used topiramate during the first trimester, the risk of oral clefts was 4.1 per 1,000, as compared to 1.1 per 1,000 in the unexposed group (risk ratio or RR 2.90, 95% confidence interval [CI] 1.56–5.40).

The risk was greater in women using topiramate for the treatment of epilepsy.  The RR among women with epilepsy using topiramate was 8.30 (95% CI 2.65–26.07); in contrast, the RR was only 1.45 (95% CI 0.54–3.86) among women using topiramate for  other indications, such as bipolar disorder.

This difference in magnitude of risk was related, in part, to dosage of topiramate.  The median daily dose of topiramate was 200 mg for women with epilepsy and 100 mg for women without epilepsy.  Looking only at women with topiramate monotherapy, the RR for oral clefts was 1.64 (95% CI 0.53–5.07) in women taking doses less than 100 mg and for doses >100 mg the RR was 5.16 (95% CI 1.94–13.73).  Consistent with what has been observed with other teratogens, including valproic acid, there is a dose-effect relationship, where doses of topiramate above 100 mg were associated with greater risk.  

Should We Use Topiramate in Women of Childbearing Age?

These studies provide strong evidence that first trimester exposure to topiramate is associated with an increased risk of oral clefts and preliminary evidence that topiramate may be associated with an increased risk of other malformations as well.  Based on these findings, we would recommend that women who are pregnant or planning to conceive should avoid the use of topiramate and switch to an alternative medication.

But we must be cognizant of the fact that half of all pregnancies are unplanned. Thus, we must discuss the use of effective contraception in all women of childbearing age who are treated with topiramate. While topiramate is not so commonly used to treat psychiatric illness, it is used fairly commonly in women of reproductive age to promote weight loss (alone or as a component of Qsymia) and as a preventative treatment for migraines.

The FDA required a Risk Evaluation and Mitigation Strategy (REMS) for Qsymia so that healthcare providers and patients can be informed about the increased risk of teratogenicity associated with the appetite suppressant Qsymia which contains topiramate and phentermine.  It is puzzling that a similar REMS, or some other type of monitoring program, was not set up for topiramate, which would typically be used at higher doses for treating seizures.  

Ruta Nonacs, MD PhD

 

REFERENCES

Alsaad AM, Chaudhry SA, Koren G.First trimester exposure to topiramate and the risk of oral clefts in the offspring: A systematic review and meta-analysis.  Reprod Toxicol. 2015 Jun;53: 45-50.

Hernandez-Diaz S, Huybrechts KF, Desai RJ, Cohen JM, Mogun H, Pennell PB, Bateman BT, Patorno E.  Topiramate use early in pregnancy and the risk of oral clefts: A pregnancy cohort study.  Neurology. 2018 Jan 23;90(4):e342-e351. Free article.

Hernández-Díaz S, Smith CR, Shen A, Mittendorf R, Hauser WA, Yerby M, Holmes LB; North American AED Pregnancy Registry; North American AED Pregnancy Registry.  Comparative safety of antiepileptic drugs during pregnancy.  Neurology. 2012 May 22;78(21):1692-9. 

Hernandez-Diaz S.  Evidence accumulates on the association between topiramate use early in pregnancy and the risk of oral clefts.  Pharmacoepidemiol Drug Saf. 2014 Aug 12.

Hunt S, Russell A, Smithson WH, Parsons L, Robertson I, Waddell R, Irwin B, Morrison PJ, Morrow J, Craig J; UK Epilepsy and Pregnancy Register.  Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register.  Neurology. 2008 Jul 22;71(4):272-6. 

Margulis AV, Mitchell AA,  Gilboa SM, et al.  Use of topiramate in pregnancy and risk of oral clefts.  Am J Obstet Gynecol 2012.

Mines D, Tennis P, Curkendall SM, et al.  Topiramate use in pregnancy and the birth prevalence of oral clefts.  Pharmacoepidemiol Drug Saf. 2014 Oct;23(10):1017-25.

Mølgaard-Nielsen D, Hviid A.  Newer-generation antiepileptic drugs and the risk of major birth defects.  JAMA. 2011 May 18;305(19):1996-2002. 

Tennis P, Chan KA, Curkendall SM, et al.  Topiramate use during pregnancy and major congenital malformations in multiple populations.  Birth Defects Res A Clin Mol Teratol. 2015 Apr; 103(4): 269-75.

Vajda FJ, Graham J, Roten A, Lander CM, O’Brien TJ, Eadie M.  Teratogenicity of the newer antiepileptic drugs–the Australian experience.  J Clin Neurosci. 2012 Jan;19(1):57-9.

 

 

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