Yes (2) Bologa et al. (1991) Primidone 14.1040 PO.

No Nau et al. (1982a) Primidone 7.1640 PO.

Yes (2) Dam et al. (1979) Vaproic acid 1.28.PO.

No Nau et al. (1982b) Source: Little BB. Obstet Gynecol 1999; 93 93: 858.

167.

EGA, estimated gestational age; AUC, area under the curve; V , volume of distribution; C , peak plasma concentration; C , steady-state concentration; t , half-life; Cl, d max SS.

1/2.

clearance; PPB, plasma protein binding; PO, by mouth; denotes a decrease during pregnancy compared with nonpregnant values; denotes an increase during pregnancy compared with nonpregnant values; = denotes no difference between pregnant and nonpregnant values; IV, intravenous, IM, intramuscular.

aControl groups: 1, nonpregnant women; 2, same individuals studied postpartum; 3, historic adult controls (s.e.x not given); 4, adult male controls; 5, adult male and female controls combined.

168.

Anticonvulsant drugs during pregnancy Janz, 1975, 1982; Kelly, 1984). A review of approximately 750 000 pregnancies (13 separate cohort studies) indicated that the birth defect rate for newborns of epileptic mothers was 7 percent compared to 3 percent for controls (Kelly, 1984).

ETIOLOGY OF MALFORMATIONS.

The pathophysiology of congenital malformations a.s.sociated with epilepsy is unknown.

Evidence suggests that it is a combination of exposure to anticonvulsant medication in an individual with epilepsy who may be 'genetically' susceptible to poor metabolism of the drugs. It is thought that teratogenic effects of certain anticonvulsant drugs may be secondary to a genetic 'defect' (lowered or no activity) in the epoxide hydrolase enzyme system, resulting in an inability to completely metabolize 'toxic' intermediary oxidative metabolites (Bielec et al et al., 1995; Buehler et al et al., 1990; Finnell et al et al., 1992; Jones et al et al., 1989; Stickler et al et al., 1985; Van d.y.k.e et al et al., 2000).

Some anticonvulsants, especially of the phenytoin type, may be a.s.sociated with folic acid anemia and may also depress vitamin D (Lane and Hathaway, 1985). Therefore, vitamin (D and K) and folic acid supplements have been recommended for the pregnant woman with epilepsy who is taking anticonvulsant medications (Yerby, 2003).

Phenytoin and other anticonvulsants may be a.s.sociated with hemorrhagic disease in the neonate, which may progress to be severe or fatal if it occurs in the first 24 h following delivery (Allen et al et al., 1980; Lane and Hathaway, 1985). Other than avoiding salicylates during pregnancy, vitamin K supplementation during the last 2 months of pregnancy (10 mg PO) or in the last 2 weeks (20 mg PO) was recommended (Lane and Hathaway, 1985).

SYNDROMES AND ISOLATED CONGENITAL ANOMALIES.

a.s.sOCIATED WITH ANTICONVULSANTS.

The range of dysmorphic features that have been a.s.sociated with exposure to anticonvulsants during embryogenesis is wide (Table 9.3). Syndromologists who are 'splitters'

a.s.sign a new syndrome name to each drug's collection of defects. Those who are 'lumpers' use the 'fetal anticonvulsant syndrome' as an umbrella for all the defects that occur with all anticonvulsants. On balance, each drug seems to have a signature constellation of anomalies, ranging from minor craniofacial dysmorphia to spina bifida (Table 9.3). Dysmorphic features a.s.sociated with older anticonvulsants have been studied extensively, but newer ones have not been studied as thoroughly.

The overall frequency of congenital anomalies was 4.2 percent among 3607 cases of anticonvulsant exposure during pregnancy in the UK Epilepsy and Pregnancy Register, a prospective, observational, registration, and follow-up study. Decomposing the rates among the congenital anomalies, 6.0 percent of infants exposed to polytherapy had congenital anomalies compared to 3.7 percent among those exposed only to monotherapy during gestation. Valproic acid was a.s.sociated with a higher frequency of congenital anomalies (6.3 percent) than other anticonvulsants in the study. Notably, high doses (>200 mg) of lamotrigene were a.s.sociated with an increased frequency of congenital anomalies (5.4 percent). Similarly, high doses of valproic acid (>800 mg) were a.s.sociated with a 9.1 percent congenital anomaly rate. When valproic acid was a component of Table 9.3 Table 9.3 Syndromic features a.s.sociated with exposure to antiepileptic drugs (AEDs) during embryogenesis Syndromic features a.s.sociated with exposure to antiepileptic drugs (AEDs) during embryogenesis Syndromes and isolated congenital anomalies a.s.sociated with anticonvulsants Syndromes and isolated congenital anomalies a.s.sociated with anticonvulsants Drug Drug Distinctive Facial Cleft lip/ Growth Microcephaly NTDs Hypoplastic distal CHD.

UGD.

facies clefting palate delay phalanges Carbemazepine +.

Clorazepam +.

Dionesa +.

Phen.o.barbital +.

Phenytoin +.

Primidone +.

Valproic acid +.

New generation AEDs Felbamate ?.