Comment

Abstract

It has long been known that pregnancies in women with epilepsy are associated with a higher risk of congenital malformations than pregnancies in nonepileptic women [ [1] Janz D. Dam M. Bossi L. Helge H. Richens A. Schmidt D. Epilepsy, pregnancy, and the child. Raven Press, New York1982: 317-323 Google Scholar ]. Several factors have been identified in the last two decades to account for the increased risk, including the direct teratogenic effects of antiepileptic drug (AED) therapy [ 2 Battino D. Kaneko S. Andermann E. et al. Intrauterine growth in the offspring of epileptic women: a prospective multicenter study. Epilepsy Res. 1999; 36: 53-60 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar , 3 Holmes L.B. Harvey E.A. Coull B.A. et al. The teratogenicity of anticonvulsant drugs. N. Engl. J. Med. 2001; 344: 1132-1138 Crossref PubMed Scopus (564) Google Scholar ], indirect effects of these drugs on folate metabolism, genetic abnormalities in drug or folate metabolism, and possibly an arrhythmogenic effect of maternal drug therapy on the embryonic heart, leading to ischemia in developing tissues [ 4 Danielsson B.R. Sköld A.C. Azarbayjani F. Class III antiarrhythmics and phenytoin: teratogenicity due to embryonic cardiac dysrhythmia and reoxygenation damage. Curr. Pharm. Des. 2001; 7: 787-802 Crossref PubMed Scopus (61) Google Scholar , 5 Barrett C. Richens A. Conference report. Epilepsy and pregnancy: report of an Epilepsy Research Foundation Workshop. Epilepsy Res. 2003; 52: 147-187 Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar ]. We do not know conclusively if newer AEDs cause fewer malformations than standard drugs such as carbamazepine and valproate. However, the preliminary results of prospective pregnancy registries have already raised a number of important issues and are starting to produce statistics that could be useful to clinicians. In their recent review, Barrett and Richens [ [5] Barrett C. Richens A. Conference report. Epilepsy and pregnancy: report of an Epilepsy Research Foundation Workshop. Epilepsy Res. 2003; 52: 147-187 Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar ] summarized the preliminary results of the prospective UK pregnancy registry. The UK registry study has shown that the crude major congenital malformation (MCM) rate for monotherapy is around 4% (3.2–5.3%) and around 6.3% (4.3–9.1%) for polytherapy. In this study, carbamazepine monotherapy was associated with a 2.3% (1.4–4.0%) risk of an MCM, lamotrigine monotherapy a 3.0% (1.5–5.7%) risk, and phenytoin monotherapy a 3.4% (1.0–11.7%) risk. The relatively low risk associated with phenytoin is surprising considering its reputation as a particularly harmful drug to the fetus. One explanation could be the difference in current prescribing practices compared with those in use when many of the initial studies were done. Sodium valproate had the highest risk at 7.2% (5.2–10%), although there did not seem to be a dose–response effect. One result that could be of particular clinical importance, although the number of cases looked at so far is very small (N=64), is the risk associated with valproate and lamotrigine in combination. The risk of an MCM in this group appears to be around 11.9% (5.9–22.5%). This is noteworthy as this combination is widely used in the United Kingdom due to its perceived efficacy. If this MCM risk is confirmed, Barrett and Richens note that we may need to think again about prescribing these AEDs together in women with epilepsy of childbearing potential [ [5] Barrett C. Richens A. Conference report. Epilepsy and pregnancy: report of an Epilepsy Research Foundation Workshop. Epilepsy Res. 2003; 52: 147-187 Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar ].