10 Epilepsy C LINICAL N EUROLOGY N EWS • August 2006 G UEST E DITORIAL Anticonvulsants in Pregnancy lthough it has been known for years facial abnormalities. Other defects, such In contrast, first-generation AEDs that for the other second-generation agents: that some first-generation as those involving the heart and growth, do not appear to be associated with a sig- felbamate (Felbatol), gabapentin (Neu- Aantiepileptic drugs (AEDs) cause are commonly observed. A syndrome nificant risk of birth defects include the rontin), pregabalin (Lyrica), levetiracetam birth defects, intrauterine growth retar- with carbamazepine consisting of minor benzodiazepines (clonazepam [Klonopin], (Keppra), tiagabine (Gabitril), and topira- dation (IUGR), and, possibly, develop- craniofacial defects, fingernail hypoplasia, clorazepate [Tranxene], diazepam [Vali- mate (Topamax). mental delay, these toxicities were not and developmental delay has been ob- um], and lorazepam [Ativan]) and succin- Although the data also are limited for thought to apply to the second-generation served; this drug may also cause neural- imides (ethosuximide [Zarontin] and zonisamide (Zonegran), the drug is ter- AEDs. New information has challenged tube defects (NTDs). methsuximide [Celontin]). However, some atogenic in three animal species and em- that belief. The defects observed with primidone of these drugs have very little human bryo lethal in a fourth and therefore is best The first-generation AEDs known to are similar to those in FHS. Phenobarbi- data, and the benzodiazepines are known avoided in the first trimester. Oxcar- cause birth defects and oth- tal has been associated with to cause toxicity in the newborn, most no- bazepine (Trileptal), a drug closely related er developmental toxicities an increase in congenital de- tably, floppy infant syndrome and with- to carbamazepine, has been associated include the hydantoins fects when used for epilepsy, drawal syndrome. In addition, the risk for with minor facial defects, but the data are (ethotoin [Peganone], fos- but not when used for other birth defects from seizures alone is at least too limited to assess the risk in humans. phenytoin [Cerebyx], indications. The use of val- two to three times greater than the back- To summarize, women with epilepsy mephenytoin [Mesantoin], proic acid derivatives be- ground risk of 2%-3%. should not be denied treatment with the and phenytoin [Dilantin]), tween the 17th and 30th day Until recently, the second-generation most effective agents for their condition phenobarbital, primidone after fertilization is associat- AEDs had not been associated with con- because of pregnancy or nursing. They (Mysoline), carbamazepine ed with a 1%-2% risk of genital defects. However, new data from should be treated with the lowest dose and (Tegretol), and valproic acid NTDs. Other defects are the North American AED Pregnancy Reg- the fewest drugs possible to control their derivatives (Depakene, De- those of the head and face, istry and five other pregnancy registries seizures. Periodic serum levels are needed pakote). In a 2001 study, the digits, urogenital tract, and have shown a very significant risk of iso- throughout pregnancy to ensure that ther- BY GERALD G. incidence of embryopathy BRIGGS, B.PHARM. mental and physical growth. lated, nonsyndromic oral clefts after first- apeutic levels are maintained. They should (major and minor anom- Carbamazepine, phenytoin, trimester exposure to lamotrigine (Lam- take folic acid (4-5 mg/day), and vitamin alies, microcephaly, and primidone, and phenobarbi- ictal) monotherapy (Birth Defects Res. A K should be given to the newborns. ■ IUGR) after first-trimester monotherapy tal affect folate metabolism or absorption, Clin. Mol. Teratol. 2006;76:313-428). was 21% (phenytoin), 27% (phenobarbi- and this may increase the risk of birth de- The prevalence of oral clefts in the MR. BRIGGS is pharmacist clinical specialist, tal), 14% (carbamazepine), 21% (any fects, including NTDs. Women taking North American registry was 8.9/1,000, Women’s Pavilion, Miller Children’s monotherapy), and 28% (polytherapy) (N. these agents should take folic acid 4-5 even though all of the mothers had been Hospital, Long Beach, Calif.; clinical Engl. J. Med. 2001;344:1132-8). mg/day, preferably starting before con- supplemented with folic acid before con- professor of pharmacy, University of Phenytoin also causes a pattern of de- ception. The hydantoins and barbiturates, ception. This was significantly higher than California, San Francisco; and adjunct fects collectively called the fetal hydantoin are related to hemorrhagic disease of the the prevalence of 0.37/1,000 in a com- professor of pharmacy, University of syndrome (FHS), characterized by vari- newborn, so adequate doses of vitamin K parison group. Southern California, Los Angeles. He is also able degrees of hypoplasia and ossifica- should be administered to newborns ex- The human pregnancy experience is coauthor of the reference book “Drugs in tion of the distal phalanges and cranio- posed to AEDs in utero. too limited to assess the embryo/fetal risk Pregnancy and Lactation.” Valproate Associated With Worse Use of AEDs May Undermine Fetal Outcome Than Other AEDs Effect of Contraceptive Implant mplanon, the first long-term cacy is associated with low BY MIRIAM E. TUCKER both the 110 whose mothers who used carba- Iimplantable contraceptive to serum progestin levels, “contra- Senior Writer mazepine and for the 56 infants exposed to pheny- win FDA approval and become ceptive implants and progestin- toin. Mean age of the children at the time of analy- available in the United States only OCs do not represent opti- alproate poses by far the greatest teratogenic sis ranged from 2.7 years with lamotrigine to 3.5 since 2000 when Wyeth stopped mal contraceptives for women Vrisk of all the commonly prescribed antiepilep- years for valproate and carbamazepine. marketing Norplant, may not who take (or will soon initiate) tic drugs, according to Dr. Kimford J. Meador of Major congenital malformation or fetal death oc- be effective in women taking anticonvulsants or other con- the University of Florida, Gainesville, and his as- curred in 20.3% with valproate, 10.7% with pheny- antiepileptic drugs, said Dr. An- comitant medications, which in- sociates in the Neurodevelopmental Effects of toin, 8.2% carbamazepine, and 1.02% with lamot- drew M. Kaunitz. duce hepatic enzymes.” Dr. Antiepileptic Drugs Study Group. rigine. Not only was the valproate risk A single-rod contraceptive im- Kaunitz’s department has con- “We advise that [valproate] not be used as the approximately twice that of the other AEDs, but plant that is about the size of a ducted clinical trials for AED of first choice for women of childbearing po- valproate was the only one to show a dose-response Organon. tential, and, when used, its dose should be limit- relationship: The mean valproate dose for the preg- The label includes a ed, if possible,” the group wrote (Neurology nancies with serious adverse fetal outcomes was Implants and warning and precau- 2006;67:407-12). 1,268 mg/day compared with just 844 mg/day for progestin-only OCs tions about Implanon Current guidelines from the American Academy those without serious adverse outcomes. could induce and antiepileptic inter- of Neurology advise a variety of ways to minimize The differences in risk between the AEDs were hepatic enzymes actions and other the risk of teratogenicity with AEDs, including use accounted for by congenital malformation rather in those taking drugs that are potent of monotherapy if possible, use of the lowest ef- than death. Indeed, death rates were actually anticonvulsants. inducers of hepatic en- fective dose, supplementation with folate, and slightly higher for both carbamazepine and pheny- zymes, because coad- treatment of the infant with vitamin K at birth toin (3.6%) than for valproate (2.9%). There were DR. KAUNITZ ministration may sub- (Neurology 1998;51:944-8). However, no current no deaths with lamotrigine. Congenital malfor- stantially lower etono- recommendation addresses the differential terato- mations, on the other hand, occurred in 17.4% matchstick, Implanon is highly gestrel levels and reduce the ef- genetic risk associated with individual AEDs, Dr. with valproate compared with 7.1% with pheny- effective for up to 3 years in fectiveness of the contraceptive. Meador and his associates noted. toin, 4.5% carbamazepine, and 1.0% lamotrigine. women who do not take anti- The drugs include phenytoin, The data come from an ongoing prospective ob- Clinicians are urged to encourage their pregnant seizure medication. carbamazepine, felbamate, top- servational study of mother/child pairs across 25 patients on AEDs to join one of the pregnancy reg- In an interview, Dr. Kaunitz, iramate, and oxcarbazepine. epilepsy centers in the United States and United istries around the world that are seeking additional professor and assistant chairman In trials, bleeding irregulari- Kingdom. A total of 323 mothers and 333 children information on AED risk for anatomic teratogen- of the department of obstetrics ties were frequent and were the were available for analysis. Mean gestational ages esis. The North American Pregnancy Registry has and gynecology at the Univer- most common reason for at the time of enrollment were 17 weeks for the a toll-free number, 1-888-AED-AED4. The EURAP sity of Florida Health Science choosing to discontinue the 69 infants exposed to valproate, 18 weeks for the registry, covering Europe and elsewhere, is online Center, Jacksonville, said that contraceptive. 98 lamotrigine-exposed infants, and 19 weeks for at www.eurapinternational.org. ■ because their contraceptive effi- —Elizabeth Mechcatie.