Topiramate in pregnancy: Preliminary experience from the UK Epilepsy and Pregnancy Register
María-LuisaMartínez-Frías, Professor of the Faculty of Medicine, Director of the Research Center of Congenital Anomalies (CIAC), Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Madrid, Spainmlmartinez.frias@isciii.es
Submitted November 07, 2008
I read with great interest the recent article by Hunt et al. on the risk of prenatal exposure to topiramate (TPM). [1] I would like to add information that may provide further rationale to Hunt et al.’s results. [1]
It has been shown that valproic acid (VPA) at therapeutic levels inhibits histone deacetylases (HDACs) and that the teratogenic effects of VPA would likely be mediated by inhibition of HDACs. [2-4] It was demonstrated that VPA and trichostatin induced hyperacetylation in mice embryos at the level of the caudal neural tube and somites [4], and that the defects related to the prenatal exposure to VPA were mimicked by conventional HDACs inhibitors. [3] Therefore, the inhibition of HDACs by VPA likely represents the molecular starting point of its teratogenic effects.
Moreover, the activity of both traditional and newer antiepileptic drugs (AEDs) such as HDACs inhibitors were also analyzed in human cells. [2] The results showed that only VPA, TPM, and the major metabolite of leviteracetam (LEV) inhibited HDACs giving rise to hyperacetylation, although VPA had the highest potency.
Consequently, Hunt et al’s preliminary study—despite the lack of controlling confounders—is compelling because TPM is already recognized as an HDACs inhibitor and its teratogenic risk is highly probable.
An epidemiological study analyzed the outcome of pregnancies exposed to TPM and concluded that this drug does not increase the risk for structural defects, although it reduces the birth weight but not the gestational age. [5] However, either the size of the sample or the biases in collecting and analyzing the data does not permit any positive/negative conclusion. In addition, the exposed cases have significantly lower birth weight which is one of the effects expected after prenatal exposure to any HDACs inhibitors such as TPM. This effect on fetal growth was found in this study because its detection is much easier even with small samples. [5]
The data on the molecular activity of TPM provide a rationale to Hunt et al.’s results. [1] Further investigation is necessary and women planning pregnancy or already pregnant should be informed and ultrasound screening should be recommended.
References
1. Hunt S, Russell A, Smithson WH, et al. Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology. 2008;71:272-276.
2. Eyal S, Yagen B, Sobol E, Altschuler Y, Shmuel M, Bialer M. The activity of antiepileptic drugs as histone deacetylase inhibitors. Epilepsia. 2004;45:737-744.
3. Gurvich N, Berman MG, Wittner BS, Gentleman RC, Klein PS, Green JB. Association of valproate-induced teratogenesis with histone deacetylase inhibition in vivo. FASEB J. 2005;19:1166-1168.
4. Menegola E, Di Renzo F, Broccia ML, Giavini E. Inhibition of histone deacetylase as a new mechanism of teratogenesis. Birth Defects Res C Embryo Today. 2006;78:345-353. Review.
5. Ornoy A, Zvi N, Arnon J, Wajnberg R, Shechtman S, Diav-Citrin O. The outcome of pregnancy following topiramate treatment: a study on 52 pregnancies. Reprod Toxicol. 2008;25:388-389.
Acknowledgements: CIBERER is an initiative of the Instituto de Salud Carlos III, Madrid. Spain.
I read with great interest the recent article by Hunt et al. on the risk of prenatal exposure to topiramate (TPM). [1] I would like to add information that may provide further rationale to Hunt et al.’s results. [1]
It has been shown that valproic acid (VPA) at therapeutic levels inhibits histone deacetylases (HDACs) and that the teratogenic effects of VPA would likely be mediated by inhibition of HDACs. [2-4] It was demonstrated that VPA and trichostatin induced hyperacetylation in mice embryos at the level of the caudal neural tube and somites [4], and that the defects related to the prenatal exposure to VPA were mimicked by conventional HDACs inhibitors. [3] Therefore, the inhibition of HDACs by VPA likely represents the molecular starting point of its teratogenic effects.
Moreover, the activity of both traditional and newer antiepileptic drugs (AEDs) such as HDACs inhibitors were also analyzed in human cells. [2] The results showed that only VPA, TPM, and the major metabolite of leviteracetam (LEV) inhibited HDACs giving rise to hyperacetylation, although VPA had the highest potency.
Consequently, Hunt et al’s preliminary study—despite the lack of controlling confounders—is compelling because TPM is already recognized as an HDACs inhibitor and its teratogenic risk is highly probable.
An epidemiological study analyzed the outcome of pregnancies exposed to TPM and concluded that this drug does not increase the risk for structural defects, although it reduces the birth weight but not the gestational age. [5] However, either the size of the sample or the biases in collecting and analyzing the data does not permit any positive/negative conclusion. In addition, the exposed cases have significantly lower birth weight which is one of the effects expected after prenatal exposure to any HDACs inhibitors such as TPM. This effect on fetal growth was found in this study because its detection is much easier even with small samples. [5]
The data on the molecular activity of TPM provide a rationale to Hunt et al.’s results. [1] Further investigation is necessary and women planning pregnancy or already pregnant should be informed and ultrasound screening should be recommended.
References
1. Hunt S, Russell A, Smithson WH, et al. Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology. 2008;71:272-276.
2. Eyal S, Yagen B, Sobol E, Altschuler Y, Shmuel M, Bialer M. The activity of antiepileptic drugs as histone deacetylase inhibitors. Epilepsia. 2004;45:737-744.
3. Gurvich N, Berman MG, Wittner BS, Gentleman RC, Klein PS, Green JB. Association of valproate-induced teratogenesis with histone deacetylase inhibition in vivo. FASEB J. 2005;19:1166-1168.
4. Menegola E, Di Renzo F, Broccia ML, Giavini E. Inhibition of histone deacetylase as a new mechanism of teratogenesis. Birth Defects Res C Embryo Today. 2006;78:345-353. Review.
5. Ornoy A, Zvi N, Arnon J, Wajnberg R, Shechtman S, Diav-Citrin O. The outcome of pregnancy following topiramate treatment: a study on 52 pregnancies. Reprod Toxicol. 2008;25:388-389.
Acknowledgements: CIBERER is an initiative of the Instituto de Salud Carlos III, Madrid. Spain.
Disclosure: The author reports no disclosures.