First-Generation Anticonvulsants

Although it has been known for years that some first-generation antiepileptic drugs (AEDs) cause birth defects, intrauterine growth retardation (IUGR), and, possibly, developmental delay, these toxicities were not thought to apply to the second-generation AEDs. New information has challenged that belief.

The first-generation AEDs known to cause birth defects and other developmental toxicities include the hydantoins (ethotoin [Peganone], fosphenytoin [Cerebyx], mephenytoin [Mesantoin], and phenytoin [Dilantin]), phenobarbital, primidone (Mysoline), carbamazepine (Tegretol), and valproic acid derivatives (Depakene, Depakote). In a 2001 study, the incidence of embryopathy (major and minor anomalies, microcephaly, and IUGR) after first-trimester monotherapy was 21% (phenytoin), 27% (phenobarbital), 14% (carbamazepine), 21% any monotherapy, and 28% (polytherapy) (N. Engl. J. Med. 2001;344:1132–8).

Phenytoin also causes a pattern of defects collectively called the fetal hydantoin syndrome (FHS), characterized by variable degrees of hypoplasia and ossification of the distal phalanges and craniofacial abnormalities. Other defects, such as those involving the heart and growth, are commonly observed. A syndrome with carbamazepine consisting of minor craniofacial defects, fingernail hypoplasia, and developmental delay has been observed; this drug may also cause neural-tube defects (NTDs).

The defects observed with primidone are similar to those in FHS. Phenobarbital has been associated with an increase in congenital defects when used for epilepsy, but not when used for other indications. The use of valproic acid derivatives between the 17th and 30th day after fertilization is associated with a 1%–2% risk of NTDs. Other defects are those of the head and face, digits, urogenital tract, and mental and physical growth. Carbamazepine, phenytoin, primidone, and phenobarbital affect folate metabolism or absorption, and this may increase the risk of birth defects, including NTDs. Women taking these agents should take folic acid 4–5 mg/day, preferably starting before conception. Moreover, anticonvulsants, particularly the hydantoins and barbiturates, are related to hemorrhagic disease of the newborn, so adequate doses of vitamin K should be administered to newborns exposed to AEDs in utero.

In contrast, first-generation AEDs that do not appear to be associated with a significant risk of birth defects include the benzodiazepines (clonazepam [Klonopin], clorazepate [Tranxene], diazepam [Valium], and lorazepam [Ativan]) and succinimides (ethosuximide [Zarontin] and methsuximide [Celontin]). However, some of these drugs have very little human data, and the benzodiazepines are known to cause toxicity in the newborn, most notably, floppy infant syndrome and withdrawal syndrome. In addition, the risk for birth defects from seizures alone is at least two to three times greater than the background risk of 2%–3%.

Until recently, the second-generation AEDs had not been associated with congenital defects. However, new data from the North American AED Pregnancy Registry and five other pregnancy registries have shown a very significant risk of isolated, nonsyndromic oral clefts after first-trimester exposure to lamotrigine (Lamictal) monotherapy (Birth Defects Res. A Clin. Mol. Teratol. 2006;76:313–428). The prevalence of oral clefts in the North American registry was 8.9/1,000, even though all of the mothers had been supplemented with folic acid before conception. This was significantly higher than the prevalence of 0.37/1,000 in a comparison group.

The human pregnancy experience is too limited to assess the embryo/fetal risk for the other second-generation agents: felbamate (Felbatol), gabapentin (Neurontin), pregabalin (Lyrica), levetiracetam (Keppra), tiagabine (Gabitril), and topiramate (Topamax). Although the data also are limited for zonisamide (Zonegran), the drug is teratogenic in three animal species and embryo lethal in a fourth and therefore is best avoided in the first trimester. Oxcarbazepine (Trileptal), a drug closely related to carbamazepine, has been associated with minor facial defects, but the data are too limited to assess the risk in humans.

To summarize, women with epilepsy should not be denied treatment with the most effective agents for their condition because of pregnancy or nursing. They should be treated with the lowest dose and the fewest drugs possible to control their seizures. Periodic serum levels are needed throughout pregnancy to ensure that therapeutic levels are maintained. They should take folic acid (4–5 mg/day), and vitamin K should be given to the newborns.

It is also important to counsel that seizures are a risk to both the mother and the embryo/fetus, as is the drug therapy. AEDs that appear to have the lowest risk for major birth defects are the benzodiazepines, the succinimides, and the second-generation agents. However, the human pregnancy data are very limited for many of these agents.

Carbamazepine and phenytoin are considered compatible with breast-feeding, and gabapentin, levetiracetam, oxcarbazepine, and tiagabine are probably compatible. Two AEDs (primidone and phenobarbital) are known to cause toxicity in the nursing infant and should not be given during breast-feeding. There are no data for the remaining AEDs, but they have the potential to cause toxicity and, if used during breast-feeding, the infants should be closely monitored.

Although it has been known for years that some first-generation antiepileptic drugs (AEDs) cause birth defects, intrauterine growth retardation (IUGR), and, possibly, developmental delay, these toxicities were not thought to apply to the second-generation AEDs. New information has challenged that belief.

The first-generation AEDs known to cause birth defects and other developmental toxicities include the hydantoins (ethotoin [Peganone], fosphenytoin [Cerebyx], mephenytoin [Mesantoin], and phenytoin [Dilantin]), phenobarbital, primidone (Mysoline), carbamazepine (Tegretol), and valproic acid derivatives (Depakene, Depakote). In a 2001 study, the incidence of embryopathy (major and minor anomalies, microcephaly, and IUGR) after first-trimester monotherapy was 21% (phenytoin), 27% (phenobarbital), 14% (carbamazepine), 21% any monotherapy, and 28% (polytherapy) (N. Engl. J. Med. 2001;344:1132–8).

Phenytoin also causes a pattern of defects collectively called the fetal hydantoin syndrome (FHS), characterized by variable degrees of hypoplasia and ossification of the distal phalanges and craniofacial abnormalities. Other defects, such as those involving the heart and growth, are commonly observed. A syndrome with carbamazepine consisting of minor craniofacial defects, fingernail hypoplasia, and developmental delay has been observed; this drug may also cause neural-tube defects (NTDs).

The defects observed with primidone are similar to those in FHS. Phenobarbital has been associated with an increase in congenital defects when used for epilepsy, but not when used for other indications. The use of valproic acid derivatives between the 17th and 30th day after fertilization is associated with a 1%–2% risk of NTDs. Other defects are those of the head and face, digits, urogenital tract, and mental and physical growth. Carbamazepine, phenytoin, primidone, and phenobarbital affect folate metabolism or absorption, and this may increase the risk of birth defects, including NTDs. Women taking these agents should take folic acid 4–5 mg/day, preferably starting before conception. Moreover, anticonvulsants, particularly the hydantoins and barbiturates, are related to hemorrhagic disease of the newborn, so adequate doses of vitamin K should be administered to newborns exposed to AEDs in utero.

In contrast, first-generation AEDs that do not appear to be associated with a significant risk of birth defects include the benzodiazepines (clonazepam [Klonopin], clorazepate [Tranxene], diazepam [Valium], and lorazepam [Ativan]) and succinimides (ethosuximide [Zarontin] and methsuximide [Celontin]). However, some of these drugs have very little human data, and the benzodiazepines are known to cause toxicity in the newborn, most notably, floppy infant syndrome and withdrawal syndrome. In addition, the risk for birth defects from seizures alone is at least two to three times greater than the background risk of 2%–3%.

Until recently, the second-generation AEDs had not been associated with congenital defects. However, new data from the North American AED Pregnancy Registry and five other pregnancy registries have shown a very significant risk of isolated, nonsyndromic oral clefts after first-trimester exposure to lamotrigine (Lamictal) monotherapy (Birth Defects Res. A Clin. Mol. Teratol. 2006;76:313–428). The prevalence of oral clefts in the North American registry was 8.9/1,000, even though all of the mothers had been supplemented with folic acid before conception. This was significantly higher than the prevalence of 0.37/1,000 in a comparison group.

The human pregnancy experience is too limited to assess the embryo/fetal risk for the other second-generation agents: felbamate (Felbatol), gabapentin (Neurontin), pregabalin (Lyrica), levetiracetam (Keppra), tiagabine (Gabitril), and topiramate (Topamax). Although the data also are limited for zonisamide (Zonegran), the drug is teratogenic in three animal species and embryo lethal in a fourth and therefore is best avoided in the first trimester. Oxcarbazepine (Trileptal), a drug closely related to carbamazepine, has been associated with minor facial defects, but the data are too limited to assess the risk in humans.

To summarize, women with epilepsy should not be denied treatment with the most effective agents for their condition because of pregnancy or nursing. They should be treated with the lowest dose and the fewest drugs possible to control their seizures. Periodic serum levels are needed throughout pregnancy to ensure that therapeutic levels are maintained. They should take folic acid (4–5 mg/day), and vitamin K should be given to the newborns.

It is also important to counsel that seizures are a risk to both the mother and the embryo/fetus, as is the drug therapy. AEDs that appear to have the lowest risk for major birth defects are the benzodiazepines, the succinimides, and the second-generation agents. However, the human pregnancy data are very limited for many of these agents.

Carbamazepine and phenytoin are considered compatible with breast-feeding, and gabapentin, levetiracetam, oxcarbazepine, and tiagabine are probably compatible. Two AEDs (primidone and phenobarbital) are known to cause toxicity in the nursing infant and should not be given during breast-feeding. There are no data for the remaining AEDs, but they have the potential to cause toxicity and, if used during breast-feeding, the infants should be closely monitored.

Although it has been known for years that some first-generation antiepileptic drugs (AEDs) cause birth defects, intrauterine growth retardation (IUGR), and, possibly, developmental delay, these toxicities were not thought to apply to the second-generation AEDs. New information has challenged that belief.

The first-generation AEDs known to cause birth defects and other developmental toxicities include the hydantoins (ethotoin [Peganone], fosphenytoin [Cerebyx], mephenytoin [Mesantoin], and phenytoin [Dilantin]), phenobarbital, primidone (Mysoline), carbamazepine (Tegretol), and valproic acid derivatives (Depakene, Depakote). In a 2001 study, the incidence of embryopathy (major and minor anomalies, microcephaly, and IUGR) after first-trimester monotherapy was 21% (phenytoin), 27% (phenobarbital), 14% (carbamazepine), 21% any monotherapy, and 28% (polytherapy) (N. Engl. J. Med. 2001;344:1132–8).

Phenytoin also causes a pattern of defects collectively called the fetal hydantoin syndrome (FHS), characterized by variable degrees of hypoplasia and ossification of the distal phalanges and craniofacial abnormalities. Other defects, such as those involving the heart and growth, are commonly observed. A syndrome with carbamazepine consisting of minor craniofacial defects, fingernail hypoplasia, and developmental delay has been observed; this drug may also cause neural-tube defects (NTDs).

The defects observed with primidone are similar to those in FHS. Phenobarbital has been associated with an increase in congenital defects when used for epilepsy, but not when used for other indications. The use of valproic acid derivatives between the 17th and 30th day after fertilization is associated with a 1%–2% risk of NTDs. Other defects are those of the head and face, digits, urogenital tract, and mental and physical growth. Carbamazepine, phenytoin, primidone, and phenobarbital affect folate metabolism or absorption, and this may increase the risk of birth defects, including NTDs. Women taking these agents should take folic acid 4–5 mg/day, preferably starting before conception. Moreover, anticonvulsants, particularly the hydantoins and barbiturates, are related to hemorrhagic disease of the newborn, so adequate doses of vitamin K should be administered to newborns exposed to AEDs in utero.

In contrast, first-generation AEDs that do not appear to be associated with a significant risk of birth defects include the benzodiazepines (clonazepam [Klonopin], clorazepate [Tranxene], diazepam [Valium], and lorazepam [Ativan]) and succinimides (ethosuximide [Zarontin] and methsuximide [Celontin]). However, some of these drugs have very little human data, and the benzodiazepines are known to cause toxicity in the newborn, most notably, floppy infant syndrome and withdrawal syndrome. In addition, the risk for birth defects from seizures alone is at least two to three times greater than the background risk of 2%–3%.

Until recently, the second-generation AEDs had not been associated with congenital defects. However, new data from the North American AED Pregnancy Registry and five other pregnancy registries have shown a very significant risk of isolated, nonsyndromic oral clefts after first-trimester exposure to lamotrigine (Lamictal) monotherapy (Birth Defects Res. A Clin. Mol. Teratol. 2006;76:313–428). The prevalence of oral clefts in the North American registry was 8.9/1,000, even though all of the mothers had been supplemented with folic acid before conception. This was significantly higher than the prevalence of 0.37/1,000 in a comparison group.

The human pregnancy experience is too limited to assess the embryo/fetal risk for the other second-generation agents: felbamate (Felbatol), gabapentin (Neurontin), pregabalin (Lyrica), levetiracetam (Keppra), tiagabine (Gabitril), and topiramate (Topamax). Although the data also are limited for zonisamide (Zonegran), the drug is teratogenic in three animal species and embryo lethal in a fourth and therefore is best avoided in the first trimester. Oxcarbazepine (Trileptal), a drug closely related to carbamazepine, has been associated with minor facial defects, but the data are too limited to assess the risk in humans.

To summarize, women with epilepsy should not be denied treatment with the most effective agents for their condition because of pregnancy or nursing. They should be treated with the lowest dose and the fewest drugs possible to control their seizures. Periodic serum levels are needed throughout pregnancy to ensure that therapeutic levels are maintained. They should take folic acid (4–5 mg/day), and vitamin K should be given to the newborns.

It is also important to counsel that seizures are a risk to both the mother and the embryo/fetus, as is the drug therapy. AEDs that appear to have the lowest risk for major birth defects are the benzodiazepines, the succinimides, and the second-generation agents. However, the human pregnancy data are very limited for many of these agents.

Carbamazepine and phenytoin are considered compatible with breast-feeding, and gabapentin, levetiracetam, oxcarbazepine, and tiagabine are probably compatible. Two AEDs (primidone and phenobarbital) are known to cause toxicity in the nursing infant and should not be given during breast-feeding. There are no data for the remaining AEDs, but they have the potential to cause toxicity and, if used during breast-feeding, the infants should be closely monitored.