SoniaHernandez-Diaz, Associate Professor, Harvard School of Public Healthshernan@hsph.harvard.edu
Lewis B. Holmes, Boston, MA, USA
Submitted September 07, 2012
We excluded spontaneous abortions because there was not enough information as to whether the embryo had, or was going to develop, a malformation. We would include spontaneous abortions if we had postmortem reports, including the results of chromosome analyses, since 50% of spontaneous abortions are associated with chromosome abnormalities. There is no current information on any of the spontaneous abortions which have occurred among the women enrolled in the North American AED Pregnancy Registry. In general, pregnancy registries are not a good study design to observe the occurrence of spontaneous abortions, as so many occur before the typical gestational age when women enroll. However, spontaneous abortions were excluded from all exposure groups, not only from the lamotrigine group. The proportion of women excluded because of spontaneous abortions, withdrawals, or losses to follow up did not vary significantly with the specific anticonvulsant. Therefore, it is unlikely for this selection bias to explain the lower risks found for lamotrigine.
We took into account dose changes during the first trimester and did not find a dose effect for lamotrigine.[1-5] Maheshwari et al. question whether serum levels would be a better exposure measurement. We are obtaining these on a subset of women whose doctors' records include levels. We will be analyzing the associations of outcomes, like malformations, in the exposed fetuses in those subsets when the sample size is large enough to be informative.
We did not find a positive association between seizures during pregnancy and a higher risk of malformations. Others had found that neither the number of seizures during pregnancy nor having epilepsy itself increase the risk of having children with major malformations. Therefore, we found unlikely that epilepsy itself could explain the risks found for valproic acid. Of note, in our population, even low valproate doses were associated with a two-fold increased risk of malformations. However, we agree that there are risks associated with seizures during pregnancy and that most pregnant women need to maintain their medication. The question is what is the safest drug for a particular patient among those that are effective for her type of epilepsy.
1. M?lgaard-Nielsen D, Hviid A. Newer-Generation Antiepileptic Drugs and the Risk of Major Birth Defects. JAMA 2011;305:1996-2002.
2. Morrow J, Russell A, Guthrie B, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006;77:193-198.
3. Sabers A, Dam M, a-Rogvi-Hansen B, et al. Epilepsy and pregnancy:
lamotrigine as main drug used. Acta Neurol Scand 2004;109:9-13.
4. Vajda F, Hitchcock A, Graham J, O'Brien T, Lander C, Eadie M. The Australian Register of Antiepileptic Drugs in Pregnancy: The first 1002 pregnancies. Aust NZ J Obstet Gynaecol 2007;47:468-474.
5. Cunnington M, Ferber S, Quartey G, and the International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Effect of Dose on the Frequency of Major Birth Defects Following Fetal Exposure to Lamotrigine Monotherapy in an International Observational Study. Epilepsia 2007;48:1207-1210.
For disclosures, contact the editorial office at journal@neurology.org.
We excluded spontaneous abortions because there was not enough information as to whether the embryo had, or was going to develop, a malformation. We would include spontaneous abortions if we had postmortem reports, including the results of chromosome analyses, since 50% of spontaneous abortions are associated with chromosome abnormalities. There is no current information on any of the spontaneous abortions which have occurred among the women enrolled in the North American AED Pregnancy Registry. In general, pregnancy registries are not a good study design to observe the occurrence of spontaneous abortions, as so many occur before the typical gestational age when women enroll. However, spontaneous abortions were excluded from all exposure groups, not only from the lamotrigine group. The proportion of women excluded because of spontaneous abortions, withdrawals, or losses to follow up did not vary significantly with the specific anticonvulsant. Therefore, it is unlikely for this selection bias to explain the lower risks found for lamotrigine.
We took into account dose changes during the first trimester and did not find a dose effect for lamotrigine.[1-5] Maheshwari et al. question whether serum levels would be a better exposure measurement. We are obtaining these on a subset of women whose doctors' records include levels. We will be analyzing the associations of outcomes, like malformations, in the exposed fetuses in those subsets when the sample size is large enough to be informative.
We did not find a positive association between seizures during pregnancy and a higher risk of malformations. Others had found that neither the number of seizures during pregnancy nor having epilepsy itself increase the risk of having children with major malformations. Therefore, we found unlikely that epilepsy itself could explain the risks found for valproic acid. Of note, in our population, even low valproate doses were associated with a two-fold increased risk of malformations. However, we agree that there are risks associated with seizures during pregnancy and that most pregnant women need to maintain their medication. The question is what is the safest drug for a particular patient among those that are effective for her type of epilepsy.
1. M?lgaard-Nielsen D, Hviid A. Newer-Generation Antiepileptic Drugs and the Risk of Major Birth Defects. JAMA 2011;305:1996-2002.
2. Morrow J, Russell A, Guthrie B, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006;77:193-198.
3. Sabers A, Dam M, a-Rogvi-Hansen B, et al. Epilepsy and pregnancy: lamotrigine as main drug used. Acta Neurol Scand 2004;109:9-13.
4. Vajda F, Hitchcock A, Graham J, O'Brien T, Lander C, Eadie M. The Australian Register of Antiepileptic Drugs in Pregnancy: The first 1002 pregnancies. Aust NZ J Obstet Gynaecol 2007;47:468-474.
5. Cunnington M, Ferber S, Quartey G, and the International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Effect of Dose on the Frequency of Major Birth Defects Following Fetal Exposure to Lamotrigine Monotherapy in an International Observational Study. Epilepsia 2007;48:1207-1210.
For disclosures, contact the editorial office at journal@neurology.org.