Part 18 (1/2)

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.