Gabapentin +.

Lamotrigene

Oxcarbazepine

Topiramate +.

Vigabatrin ?.

Zonisamide +.

NTDs, Neural tube defects (especially spina bifida); CHD, congenital heart defect; UGD, urogenital defect.

aTrimethadione, paramethadione Compiled from published reports (Dansky and Finnell, 1991; Dieterich et al., 1980; Eller et al., 1997; Hanson 1986; Iqbal et al., 2001; Jager-Roman et al., 1986; Koch et al., 1996; Lajeunie et al., 2001; McMahon and Braddock, 2001; Nulman et al., 1997; Ornoy et al., 1998; Rodriguez-Pinilla, 2000; Samren et al., 1997, 1999; Waters et al., 1994; Williams et al., 2001; Yerby and Devinsky, 1994).

169.

170.

Anticonvulsant drugs during pregnancy polytherapy, the frequency of congenital anomalies was significantly increased (Morrow et al et al., 2006).

ANTICONVULSANT POLYTHERAPY.

Use of multiple anticonvulsant drugs during pregnancy increases the frequency of fetal malformations. For example, four (7 percent) of 55 newborns with in utero in utero exposure to two epileptic drugs had congenital anomalies, compared to six (17 percent) of 36 exposure to two epileptic drugs had congenital anomalies, compared to six (17 percent) of 36 exposed to three agents and four (25 percent) of 16 exposed to four anticonvulsant agents (Lindhout et al et al., 1984). Some combinations carry a greater risk than others.

Carbamazepine, phen.o.barbital, and valproic acid (with or without phenytoin) polytherapy was reported to be a.s.sociated with congenital anomalies in seven (58 percent) of 12 infants compared to only three (7.5 percent) of 40 infants with birth defects who were exposed to other combinations of three or four anticonvulsants (Lindhout et al et al., 1984).

The authors argue that combinations of certain anticonvulsants may result in acc.u.mulation of toxic epoxide intermediates. The frequency of congenital anomalies was reported to be 1.6 to 4.2 times higher among fetuses of women taking four anticonvulsants compared to those taking only two (Hauser and Hesdorffer, 1990). Polytherapy for epilepsy during the first trimester is uniformly a.s.sociated with an increased risk for congenital anomalies (Perucca, 2005).

BIRTH DEFECTS, EPILEPSY, AND ANTICONVULSANTS.

Cleft lip and/or palate appear to be the most common malformation encountered in these pregnancies. Among 28 reports there were 73 newborns with cleft lip/palate, an estimated rate of 13.8 percent per 1000 compared to the expected background rate of 1.5 per 1000 (Kelly, 1984). Among infants born to mothers, treated with an anticonvulsant who had epilepsy, compared to infants of untreated mothers with the disease, the rate of cleft lip/palate was 15.9 per 1000 and 1.6 per 1000, respectively. Congenital heart defects appeared to be the second most common malformation encountered, with rates reported to be one in 200 (0.5 percent) compared to an expected rate of one in 300 (0.33 percent) (Kelly, 1984). Several other craniofacial and limb defects may also occur and as the list becomes more exhaustive, almost all types of congenital anomalies have been reported in a.s.sociation with epilepsy (Janz, 1982) or its treatment.

One case of fetal myeloschisis was reported in the offspring of a woman who took 4.8 g of carbamazepine during embryogenesis in a suicide attempt (Little et al et al., 1993).

ANTICONVULSANT AGENTS.

Numerous anticonvulsant agents are Food and Drug Administration (FDA) approved for use in the USA. All anticonvulsant drugs cross the placenta. It is not usually possible for women with epilepsy to discontinue medication preconceptually or during pregnancy. A twofold increase in congenital anomalies was reported in infants exposed to anticonvulsant drugs in utero in utero, but there was no drug specificity to the malformations (Speidel and Meadow, 1972). A constellation of anomalies were observed among infants exposed in utero in utero to phenytoin; this is referred to as 'the fetal hydantoin syndrome' to phenytoin; this is referred to as 'the fetal hydantoin syndrome'

Anticonvulsant agents 171.

(Hanson and Smith, 1975). In the ensuing 30 years, various syndromes were reported in a.s.sociation with (1) phenytoin (Hanson and Smith, 1975), (2) phen.o.barbitone (Seip, 1976), (3) carbamazepine (Jones et al et al., 1989), (4) primidone (Rudd and Freedom, 1979), (5) trimethadione (Zackai et al et al., 1975), and (6) valproic acid (DiLiberti et al et al., 1984). Some have advocated 'lumping' these into a spectrum of major and minor anomalies to be referred to as 'the fetal anticonvulsant drug syndrome' (Zackai et al et al., 1975).

Phenytoin Phenytoin or hydantoin (Dilantin, Diphenylan, Mesantoin, Peganone) is an anticonvulsant, chemically related to the barbiturates, and has been available for over 50 years.

Other than epilepsy, it is used to treat arrhythmias, trigeminal neuralgia, and myotonic muscular dystrophy. The 'fetal hydantoin syndrome' was first described in 1975 (Hanson and Smith, 1975), but the a.s.sociation of birth defects with phenytoin was suspected before the syndrome was described. The fetal hydantoin syndrome is characterized by a pattern of multiple minor and major craniofacial and limb anomalies (Box 9.1). Phenytoin is the most commonly prescribed anticonvulsant drug. Hemorrhagic complications in the neonate have also been reported in the offspring of mothers receiving phenytoin (Gimovsky and Petrie, 1986; Solomon et al et al., 1972). IQ was decreased by approximately 10 points among preschool and school-aged children exposed in utero in utero to phenytoin in three prospective studies compared to controls (Gladstone to phenytoin in three prospective studies compared to controls (Gladstone et al et al., 1992; Scolnick et al et al., 1994; Vanoverloop et al et al., 1992). Importantly, none of the children was considered mentally r.e.t.a.r.ded.

Cleft palate, cardiac anomalies, and skeletal defects were increased in the offspring of experimental animals which received phenytoin (Finnell, 1981; Finnell and Chernof, 1984; McClain and Langhoff, 1980).

Box 9.1 Characteristics of the fetal hydantoin syndrome Craniofacial anomalies Craniofacial anomalies Growth deficiency Cleft lip/palate Limb defects Broad nasal bridge Hypoplasia of distal phalanges, nails Hypertelorism Mental deficiency Epicanthal folds Hanson and Smith, 1975.

Carbamazepine Carbamazepine (Tegretol) is another widely prescribed anticonvulsant that is also used as an a.n.a.lgesic for trigeminal neuralgia. This agent was thought to be ideal for use during pregnancy, and in one review of 94 exposed infants, the rate of congenital anomalies was not increased over the expected rate (Niebyl et al et al., 1979). However, recent data indicate that carbamazepine (Jones et al et al., 1989) is a.s.sociated with a pattern of congenital anomalies similar to that of phenytoin (Box 9.2). The reason for similarities in malformations is probably 172 172 Anticonvulsant drugs during pregnancy Box 9.2 Characteristics of the fetal carbamazepine syndrome Craniofacial abnormalities Craniofacial abnormalities Growth deficiency Upslanting palpebral fissures Limb defects Short nose Hypoplasia of distal phalanges, nails Epicanthal folds Mental deficiency Neural tube defects Jones et al., 1989; Rosa, 1991.

related to the similarity in toxic intermediates when epoxide hydrolase activity is lowered.

However, as with phenytoin, it is uncertain as to whether these anomalies are caused by the disease process itself, the medication, a metabolite, an enzyme deficiency, or a combination thereof (Scialli and Lione, 1989). In 1991, it was reported that neural tube defects may occur in up to 1 percent of offspring of pregnant mothers taking carbamazepine, similar to valproic acid (Rosa, 1991). No decrease in IQ was found in carbemazepine-exposed compared to controls among preschool and school-aged children (Scolnick et al et al., 1994). A case report of a large lumbar meningomyelocele in a patient given megadose carbamazepine during the period of neural tube closure has been published (Little et al et al., 1993). In a small case series of carbamazepine-exposed infants ( n n = 23), one infant had an identical neural tube defect (myeloschisis) and multiple other congenital anomalies (Gladstone = 23), one infant had an identical neural tube defect (myeloschisis) and multiple other congenital anomalies (Gladstone et al et al., 1992). An excess risk of spina bifida was demonstrated among 3625 infants from Sweden whose mothers had used carbamazepine during pregnancy (Kallen, 1994).

Anomalies have been reported in the offspring of pregnant animals receiving carbamazepine, including central nervous system anomalies (Finnell et al et al., 1986; Paulson et et al al., 1979).

Paramethadione and trimethadione The dione anticonvulsants, paramethadione (Paradione) and trimethadione (Tridione) were used primarily for the treatment of pet.i.t mal seizures. The a.s.sociation between trimethadione and malformed newborns was published in 1970 (German et al et al., 1970). Following this 1970 report, numerous reports of fetal malformations a.s.sociated with maternal dione use were published. A review of 65 in utero in utero exposures to either trimethadione or paramethadione was summarized in the statement: 'a normal child resulting from such a preg-Box 9.3 Characteristics of the fetal trimethadione syndrome Craniofacial abnormalities exposures to either trimethadione or paramethadione was summarized in the statement: 'a normal child resulting from such a preg-Box 9.3 Characteristics of the fetal trimethadione syndrome Craniofacial abnormalities Cardiac anomalies Cleft palate Growth deficiency V-shaped eyebrows Hearing loss Irregular teeth Mental deficiency Epicanthal folds Microcephaly Backwards-sloped ears Simian Creases Speech difficulty Kelly, 1984; Zackai et al., 1975.

Anticonvulsant agents 173.

nancy is the exception' (Kelly, 1984). No controlled studies have been published of birth defects following exposure during embryogenesis with either of these agents. However, a distinct syndrome has been described for trimethadione (Zackai et al et al., 1975), termed the 'trimethadione syndrome' (Box 9.3). Note that this syndrome differs from the hydantoin and carbamazepine syndromes only in the absence of distal digital hypoplasia (Kelly, 1984).

Dione anticonvulsants are contraindicated for use during pregnancy.

Valproic acid Valproic acid (Depakane, Myproic Acid, Depakote) is used to treat pet.i.t mal seizures. It is also used to treat myoclonic and tonicclonic (grand mal) seizures. Use of valproic acid and an increased risk of neural tube defects and microcephaly was reported in 1980 (Dalens et et al al., 1980; Gomez, 1981). Valproic acid during the first trimester increases the risk for neural tube defects to approximately 2 percent, compared to about 0.1 percent (one per 1000) in the general population (CDC, 1983; Jager-Roman et al et al., 1986; Jeavons, 1982; Koch et et al al., 1983; Lindhout and Schmidt, 1986; Lindhout et al et al., 1992; Omtzigt et al et al., 1992; Padmanabhan and Hameed, 1994; Yerby et al et al., 1992). Major and minor anomalies comprise the constellation malformations called the 'fetal valproate syndrome' (Box 9.4).

Increased frequency of congenital anomalies was reported in offspring of pregnant animals who received valproic acid (Mast et al et al., 1986; Moffa et al et al., 1984).

Box 9.4 Malformations reported to be a.s.sociated with valproic acid: fetal valproate syndrome acid: fetal valproate syndrome Brachycephaly Hypospadias Cleft palate Low-set ears Congenital heart defects Neural tube defects Hypertelorism Small nose and mouth Dalens et al., 1980; DLiberti et al., 1984; Jager-Roman et al., 1986; Jeavons, 1982; Koch et al., 1983; Lindhout and Meinardi, 1984; Lindhout and Schmidt, 1986 Mastroiacovo et al., 1983; Tein and MacGregor, 1985; Thomas and Buchanan, 1981.

Succinimides Ethosuximide (Zarontin), methsuximide (Celontin), and phensuximide (Milontin) are succinimide anticonvulsants utilized primarily for pet.i.t mal seizures. Among more than 90 (42 and 57) infants exposed to ethosuximide during the first trimester, the frequency of congenital anomalies was not increased among the population background risk for epileptics (911 percent) (Samren et al et al., 1997, 1999). Importantly, these drugs are anticonvulsant medications and are probably a.s.sociated with a higher risk of congenital anomalies than these two small series indicate.

Skeletal and central nervous system and other congenital anomalies have been observed in the offspring of pregnant animals that received ethosuximide (el-Sayed et al et al., 1983; Sullivan and McElhatton, 1977) or methsuximide (Kao et al et al., 1979).

174.

Anticonvulsant drugs during pregnancy Ethosuximide use in late pregnancy has been reported to be a.s.sociated with neonatal hemorrhage (Bleyer and Skinner, 1976) similar to phenytoin.

Phen.o.barbital Phen.o.barbital is often used in combination with other anticonvulsants. It has also been used for many years in pregnant women for a variety of other indications. There is no firm scientific evidence that phen.o.barbital is teratogenic, although it is often implicated because of its frequent use with other anticonvulsants. Specifically, facial clefts and heart defects seem to be increased in frequency among infants whose mothers took phen.o.barbital during the first trimester. Detailed dysmorphic examinations indicated that phen.o.barbital monotherapy during pregnancy was a.s.sociated with minor congenital anomalies previously a.s.sociated with the fetal anticonvulsant syndrome (Holmes et al et al., 2001). A mild reduction in the IQs of adult males exposed to phen.o.barbital prenatally was found in one study (Reinisch et al et al., 1995) and in other investigations (Dessens et al et al., 2000).

Felbamate No studies of human neonates born after exposure to felbamate during the first trimester have been published. Two experimental animal studies were published that found no increased frequency of congenital anomalies in rats or rabbits that were exposed during embryogenesis.

Lamotrigine The FDA warning label for use of lamotrigine during pregnancy indicates a 20- to 30-fold increase in the incidence of nonsyndromic (i.e. isolated) cleft palate with the use of this drug during the first trimester. Congenital anomalies were increased in frequency ( n n = 6, 12 percent) among 51 infants whose mothers took lamotrigine during the first trimester (Lamotrigine Pregnancy Registry, 2004; Mackay = 6, 12 percent) among 51 infants whose mothers took lamotrigine during the first trimester (Lamotrigine Pregnancy Registry, 2004; Mackay et al et al., 1997; Wilton et al et al., 1998). Among 414 infants exposed to lamotrigine monotherapy in a registry-based study only 12 (2.9 percent) had congenital anomalies (Lamotrigine Pregnancy Registry, 2004; Tennis and Eldridge, 2002). The frequency of congenital anomalies appeared to be increased among 270 infants whose mothers took lamotrigine polytherapy (combined with one or more other anticonvulsants) during embryogenesis, 16 (5.9 percent).

Frequency of major congenital anomalies was greatest among infants whose mothers took lamotrigine with valproic acid during the first trimester (11 of 88, 12.5 percent).

The frequency of congenital anomalies (2.1 percent) was not increased among 390 infants born to women who took lamotrigine monotherapy during the first trimester of pregnancy in another registry-based study (Morrow et al et al., 2003). No birth defects were reported in 61 infants whose mothers were treated with lamotrigine monotherapy during pregnancy. Four major congenital anomalies (5.9 percent) were found in 68 infants born to women treated with an anticonvulsant polytherapy that contained lamotrigine (Vajda et al et al., 2003). The frequency of birth defects ( n n = 1, or 2 percent) was not increased among 51 infants born following lamotrigine monotherapy during the first trimester (Sabers = 1, or 2 percent) was not increased among 51 infants born following lamotrigine monotherapy during the first trimester (Sabers et al et al., 2004). Importantly, at least 16 fetuses or infants with neural tube Anticonvulsant agents Anticonvulsant agents 175.

defects have been reported when the mother took lamotrigine, often in polytherapy with valproic acid or carbamazepine, during the first trimester (Lamotrigine Pregnancy Registry, 2004).

Experimental animal studies of lamotrigene during embryogenesis are equivocal, with a report of no increased frequency of congenital anomalies, and another reporting an increased frequency of birth defects.

Levetiracetam No epidemiological studies of infants born after exposure to levetiracetam during the first or subsequent trimester of gestation have been published. Nonetheless, the nature of the disease being treated (seizure disorder) and the drug (anticonvulsive agent) raise concerns that infants exposed to levetirecetam during gestation may be at an increased risk of birth defects.

Gabapentin Congenital anomalies have been reported among 44 women who used gabapentin during pregnancy (Montouris, 2003), but (1) the anomalies (hypospadias, renal agenesis) are not consistent with the fetal anticonvulsant syndrome and (2) it is not clear from the published report precisely when during pregnancy the women were exposed. A case report of an infant with holoprosencephaly and cyclopia whose mother took carbamazepine and gabapentin during pregnancy has been published (Rosa, 1995), but it is unclear what, if any, a.s.sociation this has with prenatal drug exposure. Other isolated case reports have also been published (Bruni, 1998; Morrell, 1996), but their relationship to risks a.s.sociated with gabapentin use during pregnancy is unknown. A case report described a child whose features resembled the 'fetal anticonvulsant syndrome'