JohnCraig, MRCP, Royal Group of Hospitals, Belfast,, Grosvenor Road, Belfast, BT12 6BA, UKjohn.craig@belfasttrust.hscni.net
S. Hunt, MRCP, A. Russell, MRCP (Glasgow), J. Morrow, MD
Submitted November 07, 2008
We agree with Dr. Martínez-Frías that our results need to be replicated and information from more pregnancies is required to affirm the safety of topiramate in pregnancy. However, we would caution against over-interpreting the findings from preclinical models, especially those which concentrate on a particular teratogenic mechanism as a means of predicting adverse outcomes in human pregnancies exposed to any agent.
For example, the major metabolite of levetiracetam (LEV), 2-pyrrolidinone N-butyric acid (PBA) has been considered a valproate analogue and has been shown to inhibit histone deacetylase in human cells. In a mouse model where fetuses were exposed to LEV and PBA, none of those exposed to PBA had gross malformations, although there were significant reductions in fetal weights and an increased rate of skeletal abnormalities in all groups. This included those exposed to PBA. However, 2 out of 107 live fetuses exposed in utero to 1200 mg/kg of LEV had cleft palate. [6]
Due to the varying mechanisms and outcomes of anti-epileptic drugs, we believe that one molecular mechanism is not likely to fit all. Furthermore, human data do not yet provide evidence that LEV is associated with a significantly increased risk for major malformations. Greater numbers of outcomes are required to confirm this hypothesis. [7]
References
6. Isoherranen N, Spiegelstein O, Bialer M, et al. Developmental outcome of levetiracetam, its major metabolite in humans, 2-pyrrolidinone N-butyric acid, and its enantiomer (R)-alpha-ethyl-oxo-pyrrolidine acetamide in a mouse model of teratogenicity. Epilepsia 2003;44:1280-1288.
7. Hunt S, Craig, J, Russell A, et al. Levetiracetam in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 2006;67:1876-1879.
We agree with Dr. Martínez-Frías that our results need to be replicated and information from more pregnancies is required to affirm the safety of topiramate in pregnancy. However, we would caution against over-interpreting the findings from preclinical models, especially those which concentrate on a particular teratogenic mechanism as a means of predicting adverse outcomes in human pregnancies exposed to any agent.
For example, the major metabolite of levetiracetam (LEV), 2-pyrrolidinone N-butyric acid (PBA) has been considered a valproate analogue and has been shown to inhibit histone deacetylase in human cells. In a mouse model where fetuses were exposed to LEV and PBA, none of those exposed to PBA had gross malformations, although there were significant reductions in fetal weights and an increased rate of skeletal abnormalities in all groups. This included those exposed to PBA. However, 2 out of 107 live fetuses exposed in utero to 1200 mg/kg of LEV had cleft palate. [6]
Due to the varying mechanisms and outcomes of anti-epileptic drugs, we believe that one molecular mechanism is not likely to fit all. Furthermore, human data do not yet provide evidence that LEV is associated with a significantly increased risk for major malformations. Greater numbers of outcomes are required to confirm this hypothesis. [7]
References
6. Isoherranen N, Spiegelstein O, Bialer M, et al. Developmental outcome of levetiracetam, its major metabolite in humans, 2-pyrrolidinone N-butyric acid, and its enantiomer (R)-alpha-ethyl-oxo-pyrrolidine acetamide in a mouse model of teratogenicity. Epilepsia 2003;44:1280-1288.
7. Hunt S, Craig, J, Russell A, et al. Levetiracetam in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 2006;67:1876-1879.
Disclosure: The authors report no disclosures.