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Epitomes Important Advances in Clinical Medicine
Neurology The Scientific Board ofthe California Medical Association presents the following inventory of items ofprogress in neurology. Each item, in thejudgment ofa panel of knowledgeable physicians, has recently become reasonablyfirmly established, both as to scientificfact and important clinical significance. The items are presented in simple epitome, and an authoritative reference, both to the item itselfand to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, or scholars to stay abreast of these items ofprogress in neurology that have recently achieved a substantial degree of authoritative acceptance, whether in their own field of special interest or another. The items ofprogress listed below were selected by the Advisory Panel to the Section on Neurology ofthe California Medical Association, and the summaries were prepared under its direction. Reprint requests to Division of Scientific and Educational Activities, California Medical Association, PO Box 7690, San Francisco, CA 94120-7690
Use of Antiepileptic Drugs in Pregnancy THE TREATMENT OF epileptic women of childbearing age is highly controversial. All antiepileptic drugs have the potential for causing birth defects, although genetics and socioeconomic status play roles as well. These birth defects may be caused by direct drug effect, drug interactions, drug metabolites (epoxides), or folate deficiency caused by certain antiepileptic drugs. Congenital malformations (defined as requiring medical or surgical intervention) such as spina bifida, cleft lip-palate, and congenital heart defects are the main concerns when using these drugs. These defects occur in approximately 7.3% of children of epileptic mothersmore than double that for infants not having exposure to the drugs. It is now known that the risk of birth defects increases with the use of multiple drugs and higher drug levels. Trimethadione, although now rarely used, causes a 50% rate of birth defects and is absolutely contraindicated for use in pregnancy. Taking valproic acid causes a 1.5% to 2% risk of spina bifida, 20 times higher than in the general population. Carbamazepine therapy has also been found to cause a 0.5% to 1% risk of spina bifida. In the past, certain drugs were thought to cause specific congenital anomalies, such as the "fetal hydantoin syndrome." Researchers now prefer the term "fetal anticonvulsant syndrome" because all drugs used to treat epilepsy in women may produce dysmorphic features in their children. It should be noted that dysmorphic features were noted in the offspring of epileptic women before the use of anticonvulsant drugs. The significance of these anomalies is unclear, and research is underway to determine the cause of minor anomalies. Prenatal counseling is the most important aspect in the treatment of epileptic women of childbearing age because the teratogenic effects occur during the first trimester. Women should be cautioned regarding the risks of congenital malformations and of the risks of seizures for themselves and their unborn children should they decide to discontinue their medication. Although rare, there have been reports of fetal death after a generalized tonic-clonic seizure. While it might seem reasonable to discontinue all antiepileptic drugs before conceptioii, this is not wise because a third of all women experience atn increased rate of seizures during pregnancy. The
mechanism of this increase is not clear but is not necessarily related to falling drug levels. A decrease of serum anticonvulsant levels in itself does not justify an increased dosage. For example, total concentrations of phenytoin and valproic acid may fall, but free levels-which should be monitored monthly-may remain stable. Patients should be seen frequently during pregnancy and their drug levels monitored regularly. Pregnant women who have seizures have an increased risk for toxemia. Certain steps can be taken before conception to minimize the risk of malformations. Because there is an increased risk of birth defects with the use of multiple drugs and higher drug levels, a switch to single-drug therapy, if possible, should be made, and the lowest effective dose should be used. Multivitamins and folic acid should be given because birth defects may be caused by folate deficiency. If valproic acid, carbamazepine, or both are used, abdominal ultrasonography should be done and a-fetoprotein levels in the amniotic fluid should be measured. Finally, phytonadione vitamin K1 therapy, 20 mg per day, should be begun during the last four weeks of pregnancy to prevent neonatal hemorrhage. Although all antiepileptic drugs except valproic acid are present in breast milk, few problems are linked to breastfeeding. Breast-feeding should be discontinued if sedation is noted in the infant, however. If breast-feeding is discontinued, drug withdrawal may occur in the infant. Although the risk of congenital malformations in children of epileptic women using antiepileptic drugs is twice that of the general population, epileptic women should be informed that the overall outcome is usually good and that more than 90% have normal children. MARIAN V. SOWA, MD
Long Beach, California REFERENCES
Commission on Genetics, Pregnancy and the Child, International League Against Epilepsy: Guidelines for the care of epileptic women of childbearing age. Epilepsia 1989; 30:409-410 Epilepsy Management Report-International Symposium on Pregnancy, Teratogenesis, and Genetics in Epilepsy. Pearl River, NY, William J. Miller Assoc, 1990. pp 1-10
Wladimiroff JW, Stewart PA, Reuss A, van Swaay E, Lindbout D, Sachs ES: The role of ultrasound in the early diagnosis of fetal structural defects following maternal anticonvulsant therapy. Ultrasound Med Biol 1988; 14:657-660 Yerby MS: Pregnancy and epilepsy, In Hauser WA (Ed): Current Trends in Epilepsy: A Self-Study Course for Physicians. Landover, Md, Epilepsy Foundation of America, 1990. pp 48-57
Epitomes Important Advances in Clinical Medicine
Neurology The Scientific Board ofthe California Medical Association presents the following inventory of items ofprogress in neurology. Each item, in thejudgment ofa panel of knowledgeable physicians, has recently become reasonablyfirmly established, both as to scientificfact and important clinical significance. The items are presented in simple epitome, and an authoritative reference, both to the item itselfand to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, or scholars to stay abreast of these items ofprogress in neurology that have recently achieved a substantial degree of authoritative acceptance, whether in their own field of special interest or another. The items ofprogress listed below were selected by the Advisory Panel to the Section on Neurology ofthe California Medical Association, and the summaries were prepared under its direction. Reprint requests to Division of Scientific and Educational Activities, California Medical Association, PO Box 7690, San Francisco, CA 94120-7690
Use of Antiepileptic Drugs in Pregnancy THE TREATMENT OF epileptic women of childbearing age is highly controversial. All antiepileptic drugs have the potential for causing birth defects, although genetics and socioeconomic status play roles as well. These birth defects may be caused by direct drug effect, drug interactions, drug metabolites (epoxides), or folate deficiency caused by certain antiepileptic drugs. Congenital malformations (defined as requiring medical or surgical intervention) such as spina bifida, cleft lip-palate, and congenital heart defects are the main concerns when using these drugs. These defects occur in approximately 7.3% of children of epileptic mothersmore than double that for infants not having exposure to the drugs. It is now known that the risk of birth defects increases with the use of multiple drugs and higher drug levels. Trimethadione, although now rarely used, causes a 50% rate of birth defects and is absolutely contraindicated for use in pregnancy. Taking valproic acid causes a 1.5% to 2% risk of spina bifida, 20 times higher than in the general population. Carbamazepine therapy has also been found to cause a 0.5% to 1% risk of spina bifida. In the past, certain drugs were thought to cause specific congenital anomalies, such as the "fetal hydantoin syndrome." Researchers now prefer the term "fetal anticonvulsant syndrome" because all drugs used to treat epilepsy in women may produce dysmorphic features in their children. It should be noted that dysmorphic features were noted in the offspring of epileptic women before the use of anticonvulsant drugs. The significance of these anomalies is unclear, and research is underway to determine the cause of minor anomalies. Prenatal counseling is the most important aspect in the treatment of epileptic women of childbearing age because the teratogenic effects occur during the first trimester. Women should be cautioned regarding the risks of congenital malformations and of the risks of seizures for themselves and their unborn children should they decide to discontinue their medication. Although rare, there have been reports of fetal death after a generalized tonic-clonic seizure. While it might seem reasonable to discontinue all antiepileptic drugs before conceptioii, this is not wise because a third of all women experience atn increased rate of seizures during pregnancy. The
mechanism of this increase is not clear but is not necessarily related to falling drug levels. A decrease of serum anticonvulsant levels in itself does not justify an increased dosage. For example, total concentrations of phenytoin and valproic acid may fall, but free levels-which should be monitored monthly-may remain stable. Patients should be seen frequently during pregnancy and their drug levels monitored regularly. Pregnant women who have seizures have an increased risk for toxemia. Certain steps can be taken before conception to minimize the risk of malformations. Because there is an increased risk of birth defects with the use of multiple drugs and higher drug levels, a switch to single-drug therapy, if possible, should be made, and the lowest effective dose should be used. Multivitamins and folic acid should be given because birth defects may be caused by folate deficiency. If valproic acid, carbamazepine, or both are used, abdominal ultrasonography should be done and a-fetoprotein levels in the amniotic fluid should be measured. Finally, phytonadione vitamin K1 therapy, 20 mg per day, should be begun during the last four weeks of pregnancy to prevent neonatal hemorrhage. Although all antiepileptic drugs except valproic acid are present in breast milk, few problems are linked to breastfeeding. Breast-feeding should be discontinued if sedation is noted in the infant, however. If breast-feeding is discontinued, drug withdrawal may occur in the infant. Although the risk of congenital malformations in children of epileptic women using antiepileptic drugs is twice that of the general population, epileptic women should be informed that the overall outcome is usually good and that more than 90% have normal children. MARIAN V. SOWA, MD
Long Beach, California REFERENCES
Commission on Genetics, Pregnancy and the Child, International League Against Epilepsy: Guidelines for the care of epileptic women of childbearing age. Epilepsia 1989; 30:409-410 Epilepsy Management Report-International Symposium on Pregnancy, Teratogenesis, and Genetics in Epilepsy. Pearl River, NY, William J. Miller Assoc, 1990. pp 1-10
Wladimiroff JW, Stewart PA, Reuss A, van Swaay E, Lindbout D, Sachs ES: The role of ultrasound in the early diagnosis of fetal structural defects following maternal anticonvulsant therapy. Ultrasound Med Biol 1988; 14:657-660 Yerby MS: Pregnancy and epilepsy, In Hauser WA (Ed): Current Trends in Epilepsy: A Self-Study Course for Physicians. Landover, Md, Epilepsy Foundation of America, 1990. pp 48-57
