Mechanisms of teratogenesis: folic acid and antiepileptic therapy.

Gestational folate deficiency has been associated with abnormal growth and development in both experimental animal and human studies and has been postulated as a putative mechanism for the teratogenic effects of antiepileptic drugs (AEDs). Animal studies have shown that the administration of AEDs results in folate depletion and teratogenic effects. Attempts to prevent the teratogenic effects of AEDs by coadministration of folate have shown variable results, perhaps because of a lack of understanding about the specific effects of AEDs on folate metabolism. Our prospective study of women with epilepsy showed that blood folate levels decreased with increasing plasma AED levels and with the number of AEDs. Low blood folate levels before and/or early in pregnancy were significantly associated with spontaneous abortion and the occurrence of developmental anomalies in the offspring. These findings suggest that folate supplementation might be one means of preventing the occurrence of abnormal pregnancy outcome in women with epilepsy, including neural-tube defects in the offspring.

Parental epilepsy, anticonvulsant drugs, and reproductive outcome: epidemiologic and experimental findings spanning three decades; 1: Animal studies.

In conclusion, it is clear that the experimental animal literature has been extremely beneficial in validating the teratogenicity of selected anticonvulsant drugs such as phenytoin and valproic acid, and in providing much needed information on pharmacokinetic parameters that are involved in altering normal embryogenesis. Continued efforts are needed to further elucidate the mechanism of teratogenic action for these drugs. It is clear from the work on phenytoin that reactive intermediates are important, and care must be taken to either avoid drug therapies that promote the formation of or inhibit the rapid degradation of toxic oxidative metabolites. For valproic acid and carbamazepine the pathogenesis of congenital defects remains much less defined. Until adequate information is ascertained on just how antiepileptic drugs disrupt normal development, it will be difficult, if not impossible, to develop either alternative medications or treatment strategies that maximize clinical effectiveness without the risk of an adverse pregnancy outcome. Such information emanating from animal studies shall, hopefully, be available in the not-too-distant future.

Parental epilepsy, anticonvulsant drugs, and reproductive outcome: epidemiologic and experimental findings spanning three decades; 2: Human studies.

Evidence accumulated over the past three decades has established AEDs as human teratogens. Important developments in the delineation of these compounds as human teratogens include: the demonstration of a consistent association between in utero exposure to AEDs and an increased occurrence of single major malformations, the description of AED-induced dysmorphogenic syndromes; demonstration of a dose-response relationship, both in terms of the number and dosage of AEDs; and evidence that pharmacogenetic differences in the metabolism of AEDs are strongly correlated with the occurrence of congenital malformations. Furthermore, the experimental animal findings, having accumulated in parallel to those of human studies, strongly support the teratogenic role of AEDs. Areas that require further amplification and clarification in future studies are the relative contribution of AEDs and other factors, such as genetic predisposition and maternal seizures, particularly with respect to the occurrence of minor anomalies, growth retardation, and developmental outcome; the relative teratogenicity of specific monotherapies and polytherapies; the predictive role of pharmacogenetic differences in the metabolism of AEDs in the occurrence of structural and functional abnormalities; and characterization of the precise nature of the pharmacogenetic defect underlying the aforementioned differences in AED metabolism. Attempts should also be made in future prospective studies to monitor metabolite levels of AEDs, particularly the oxidative metabolites, in order to further elucidate the relative contribution of individual differences in metabolism in the determination of adverse fetal outcome. Similarly, further efforts should be made to assess the clinical significance of decreased growth parameters in terms of mental and neurologic development, and to ascertain whether there is any risk for such abnormalities in children who do not display overt or persistent reductions in physical growth parameters. This is critically important in light of the animal studies that have shown functional abnormalities at doses that do not necessarily produce structural defects. Future investigations would be conducted through collaborative studies that would encompass sufficiently large numbers of women to provide adequate power to the statistical analyses of the data obtained. Care would have to be exercised to establish a uniform protocol for the collaborating centers. Regionally based investigations would be preferable to studies based at special centers, in order to assess the relative role of risk factors associated with abnormal pregnancy outcomes in the epileptic population at large.(ABSTRACT TRUNCATED AT 400 WORDS)

Anticonvulsants, folate levels, and pregnancy outcome: a prospective study.

Folate levels in serum and red cells, as determined by a microbiological assay using Lactobacillus casei, and plasma anticonvulsant concentrations were monitored concurrently in nonpregnant (50 subjects) and pregnant (49 pregnancies in 46 subjects) epileptic women. Twenty-three (46%) nonpregnant women had subnormal serum folate levels and 4 nonpregnant women (8%) showed subnormal red cell folate levels. In pregnant women not taking folate supplements, the incidence of folate deficiency increased as the pregnancy advanced. Pregnant women taking folate supplements achieved normal or supranormal blood folate concentrations. In both nonpregnant and pregnant women, serum and red cell folate levels were inversely correlated with plasma concentrations of phenytoin and of phenobarbital, and with the number of anticonvulsants. In 49 pregnancies, there were 10 abnormal outcomes (20.4%): 4 spontaneous abortions (8.2%) and 6 children with major congenital malformations (12.2%). Blood folate levels were significantly lower in pregnancies with an abnormal outcome than in those with a normal outcome. The results suggest a dose-response relationship among anticonvulsants, folate, and adverse pregnancy outcome.

Genetic predisposition to phenytoin-induced birth defects.

To find out whether arene oxide metabolites of phenytoin and a genetic defect in arene oxide detoxification contribute to susceptibility to phenytoin-induced birth defects, lymphocytes from 24 children exposed to phenytoin throughout gestation and from their families were challenged in a blind protocol with phenytoin metabolites generated by a murine hepatic microsomal drug-metabolising system. 14 of the children had a "positive" assay result--ie, a significant increase in cell death associated with phenytoin metabolites. Each child with a positive result had one parent whose cells also were positive. A positive in-vitro challenge was highly correlated with major birth defects, including congenital heart disease, cleft lip/palate, microcephaly, and major genitourinary, eye, and limb defects. There was no difference between children with positive and negative results in the number or distribution of minor birth defects, including stigmata of the fetal hydantoin syndrome. Although many factors contribute to the outcome of pregnancies in epileptic women treated with phenytoin, a genetic defect in arene oxide detoxification seems to increase the risk of the baby having major birth defects.

Marriage and fertility in epileptic patients.

Marital status and fertility were compared for 100 epileptic females and 100 epileptic males. The marriage rate among male patients was 59% of expected (p less than 0.001) as compared to 83% for female patients (p less than 0.10). Patients with early onset of seizures, particularly males, had lower marriage rates than expected, unlike patients with onset after age 20. Married female patients had only 69% of the expected number of live-born children (p less than 0.001) as compared to 100% for married male patients. Marriage and fertility rates of epileptic females have improved in the last generation, while those of epileptic males have remained constant.