Part 19 (1/2)

and whose mother took gabapentin and valproic acid during pregnancy (Moore et al et al., 2000).

Experimental animal studies with mice, rats, and rabbits have not found an increased frequency of congenital anomalies among offspring exposed to gabapentin during embryogenesis.

Oxcarbazepine Important note: oxcarbazepine is an anticonvulsant drug closely related to a known human teratogen, carbamazepine. This drug has been part of a polytherapy regimen in most published reports of its use during pregnancy, confounding its possible causal role.

Among 248 pregnancies exposed to oxcarbazepine monotherapy during pregnancy, there were six congenital anomalies (2.4 percent), which is similar to that expected in the general population. Among 61 infants whose mothers were given polytherapy that included oxcarbazepine, four birth defects (6.6 percent) occurred (Montouris, 2005), which is greater than that in the general population.

Among 35 infants born to epileptic women treated with oxcarbazepine monotherapy in one series, no congenital anomalies were found (Meischenguiser et al et al., 2004). Among 20 infants born to women who took polytherapy anticonvulsant regimen that included 176 176 Anticonvulsant drugs during pregnancy oxcarbazepine, one baby was born with a major cardiac congenital anomaly. One of nine infants born to epileptic women treated in the first trimester with oxcarbazepine monotherapy had multiple major birth defects involving the genitourinary tract (Kaaja et al et al., 2003). Isolated case reports involving polytherapy (including oxcarbazepine) of single infants with spina bifida, short spine, hypospadias, or limb reduction defects have been published (Lindhout et al et al., 1992; Lindhout and Omtzigt, 1994). The causal meaning of case reports is not possible to ascertain. Animal teratology studies (one published, Bennett et al. et al. , 1996, one unpublished) of oxcarbazepine were negative. , 1996, one unpublished) of oxcarbazepine were negative.

Tiagabine Among nine infants whose mothers took tiagabine during pregnancy, one infant had a congenital anomaly, but this was not similar to any of the anomalies in the 'fetal anticonvulsant syndrome' (Morrell, 1996).

In unpublished experimental animal studies (rats, rabbits) employing doses much higher than the human dose, and at doses toxic to the mother, there were increased frequencies of congenital anomalies in rats but not rabbits. None of this information is relevant to the a.s.sessment of human risk of birth defects following exposure to tiagabine during embryogenesis.

Topiramate In a case series three normal infants were reported whose mothers were treated with topiramate sometime during gestation (Morrell, 1996). In another case report, a pattern of minor anomalies similar to the 'fetal anticonvulsant syndrome' were observed in an infant whose mother took topiramate monotherapy throughout pregnancy (Hoyme et et al al., 1998). The relevance of these anecdotal reports, if any, to human risks following exposure to topiramate during embryogenesis is unknown.

The results of studies of rats, mice, and rabbits exposed to topiramate during embryogenesis are conflicting. Rats had limb defects at the highest doses, mice had craniofacial defects, and rabbits had vertebral anomalies. The inconsistent findings and the lack of peer review of these unpublished studies confound any possible interpretation of these data.

Vigabatrin Among 47 infants born to women who took vigabatrin during the first trimester two (4.3 percent) had congenital anomalies (Wilton et al et al., 1998).

In several studies, major anomalies were increased among mice exposed to vigabatrin during embryogenesis, and cleft palate occurred among rabbits exposed to maternally and fetotoxic doses. No increased frequency of congenital anomalies was found among rats exposed to vigabatrin during embryogenesis.

Zonisamide Zonisamide is an anticonvulsant used either in monotherapy or polytherapy to treat a broad spectrum of epileptic conditions (Oguni et al et al., 1988; Schmidt et al et al., 1993). In one Special considerations Special considerations 177.

small prospective case series of 26 infants born to women treated throughout pregnancy with zonisamide as part of a polytherapy anticonvulsant regimen, two infants (7.7 percent) were reported with major congenital anomalies (anencephaly, atrial septal defect) (Kondo et al et al., 1996). A child whose mother took zonisamide, carbamazepine, phenytoin, sodium valproate, and a barbiturate during pregnancy was reported with features of anticonvulsant embryopathy (Noda et al et al., 1996).

Increased frequencies of congenital anomalies were found in animal studies of teratogenicity of zonisamide in rats (cardiac), mice (visceral, skeletal), dogs (cardiac), and monkeys (pregnancy wastage) (Terada et al et al., 1987a,b,c).

SPECIAL CONSIDERATIONS.

In general, women with epilepsy should be given preconceptual counseling, and a management plan developed (Box 9.5). If a pregnant woman presents on anticonvulsant therapy, she should be given counseling regarding the two- to three-fold increased risk of malformations.

She should also be offered high-resolution ultrasound and alpha-fetoprotein screening at appropriate gestational intervals. It should be emphasized that these techniques, although helpful, may not rule out anticonvulsant embryopathy. Anticonvulsant therapy should be continued if necessary. It may be possible to discontinue medications in certain patients who have been seizure-free for protracted periods of time, especially in patients who have had pet.i.t mal seizures. Trimethadione and paramethadione are generally contraindicated during pregnancy, and valproic acid should be avoided if possible. One of the succinimides, ethosuximide, would appear to be a better choice for pet.i.t mal seizures in the rare pregnant patient where it is indicated. Monitoring of serum levels of anticonvulsants may be indicated in some pregnant women, especially those with increased seizure activity. A suggested management protocol for pregnant patients with epilepsy is summarized in Box 9.5.

Patients should be counseled that anticonvulsant therapy during pregnancy is a.s.sociated with risks of serious birth defects. For example, with valproic acid and carbamazepine, the risk for neural tube defects, spina bifida in particular, is increased with exposure during the first trimester (Table 9.4). Risks for other congenital anomalies are increased when a.s.sociated with exposure to other anticonvulsants during embryogenesis (Table 9.3). Risk for valproic acid-a.s.sociated neural tube defects is increased at (1) high doses (> 800 mg/day) and (2) polytherapy. Interestingly, recent a.n.a.lyses indicate that the risk for neural tube defects with exposure to oxcarbazepine or to lamotrigene is not different from the risk with carbamazepine (Perucca, 2005).

Table 9.4 Frequency of spina bifida in a.s.sociation with anticonvulsants Valproic acid n/N Frequency of spina bifida in a.s.sociation with anticonvulsants Valproic acid n/N Carbamazepine n/N Other n/N Total 10/740.

10/1132.

6/4489.

Unconfounded total 9/612.

9/984.

6/4489.

Proportion 1/68.

1/109.

1/748.

Number expected (background risk) 1/1500.

n, number affected; N, number exposed.

Adapted from Rosa, 1991.

178.

Anticonvulsant drugs during pregnancy Box 9.5 Suggested protocol for counseling management of pregnant women with epilepsy pregnant women with epilepsy Counsel regarding a possible epilepsy-a.s.sociated two- to three-fold increased risk of malformations above background (3.55%) Indicate that risk for neural tube defects (NTDs) is increased (see Table 9.4), as indicated Continue anticonvulsants if necessary to control seizures Seizures may cause congenital anomalies and threaten maternal health; therefore, controlling seizures is a high priority During embryogenesis [210 weeks estimated gestation age (EGA) by menstrual dates, or first 8 weeks of gestation by conception dates] avoid certain anticonvulsants if possible: *

Avoid trimethadione and paramethadione if possible *

Avoid valproic acid if possible *

Avoid carbamazepine if possible *

Avoid polytherapy if possible *

Avoid large anticonvulsant doses, use minimal necessary to control seizures Discontinue anticonvulsants in only select patients and with neurological medical consultation Serial high-resolution ultrasound examinations at appropriate intervals Maternal alpha-fetoprotein screening at appropriate intervals Serum anticonvulsant level monitoring Dose t.i.tration to achieve therapeutic levels Bear in mind that pregnancy changes the pharmac.o.kinetics of anticonvulsants, which may indicate the need to adjust dose and/or frequency to prevent maternal seizures *

Clearance is uniformly increased during pregnancy *

C (steady state concentration) is lowered ss *

Plasma protein binding (PPB) is decreased during pregnancy for anticonvulsants that have been studied Ratings by the FDA Pregnancy Risk Categories and Teratogen Information System (TERIS) Risk for Congenital Anomalies (Table 9.5) provide informative support for clinical decisions.

Pharmacogenetics The metabolism of folic acid is inhibited by many anticonvulsant drugs. This alteration in folate metabolism is presumed to be provoked by hepatic enzyme induction and folate malabsorption (Janz, 1982; Maxwell et al et al., 1972). Phen.o.barbitone, phenytoin, carbamazepine, valproic acid, and primidone have been implicated in these metabolic alterations (Donaldson, 1991). Human and animal studies support the finding that folic acid supplementation decreases the rate of congenital malformations in infants of epileptic mothers who are receiving anticonvulsants during pregnancy (Biale and Lewenthal, 1984; Dansky et al et al., 1987; Zhu and Zhou, 1989). Therefore, it is recommended that all Special considerations Special considerations 179.

Table 9.5 Comparison of Teratogen Information System (TERIS) risk for congenital anomalies and the Food and Drug Administration (FDA) pregnancy risk categories Drug Comparison of Teratogen Information System (TERIS) risk for congenital anomalies and the Food and Drug Administration (FDA) pregnancy risk categories Drug TERIS risk FDA pregnancy risk rating Phenytoin/Fosphenytoin Small to moderate D.

Carbamazepine Small to moderate Dm Valproic acid Fetal valproate syndrome: moderate Dm Neural tube defects: small to moderate Other malformations: small Neurobehavioral abnormalities: small Primidone Small to moderate D.

Trimethadione/ Paramethadione High D.

Ethosuximide Undetermined C.

Methsuximide Undetermined C.

Phensuximide Undetermined D.

Phen.o.barbital Chronic anticonvulsive treatment: small D.