DRUGS AND PREGNANCY
The treatment of epileptic
pregnant women poses par-ticularly difficult questions. There is good evidence
of an increased risk of congenital malformations in infants born of women taking
antiseizure medication during pregnancy, although most such women give birth to
nor-mal infants. Because most patients are taking multiple medications and
congenital malformations can occur even without medication, it is difficult or
impossible to demonstrate a cause and effect relationship for most agents. In
some cases the evidence is clearer. Valproic acid has been known to cause spina
bifida in a small percentage of cases. Phenytoin has also long been im-plicated
in causing birth defects, and a specific fetal hy-dantoin syndrome has been
suggested. The most com-mon abnormality seen in children of mothers receiving
antiepileptic therapy is cleft palate.
Withdrawal of medication from
an epileptic preg-nant woman is not without its hazards, to the patient and
possibly to the fetus. It is not clear whether mater-nal seizures can directly
affect the fetus. If it is feasible, the physician should prescribe only one
drug at the low-est effective dosage to minimize teratogenic risks.
The U. S. Food and Drug Administration
has devel-oped a use-in-pregnancy rating system that attempts to provide
physicians with information that they can use to evaluate the risk to the fetus
compared to the bene-fit to the patient. This classification uses five
categories: (A) controlled studies show no risk; (B) no evidence of risk to
humans; (C) risk cannot be ruled out; (D) posi-tive evidence of risk; and (X)
contraindicated in preg-nancy. Using this classification, all approved AEDs are
in pregnancy category C except carbamazepine, which is in pregnancy category D.
Neither phenytoin nor val-proic acid is classified, but both have black box
warnings regarding teratogenicity.
A deficiency of folate during
gestation has been as-sociated with abnormal fetal growth and development.
Since most AEDs cause some degree of folate defi-ciency, it is considered
worthwhile to administer folate daily as a supplement during the period of
organogene-sis in the first trimester.
Another concern in infants of
mothers with epilepsy is a serious hemorrhagic disorder that is associated with
a high (25–35%) mortality. This probably results from the finding that many
AEDs can act as competitive in-hibitors of vitamin K–dependent clotting
factors. The competitive inhibition can be overcome by the adminis-tration of
oral vitamin K+ supplements to the mother during the last week or 10
days of pregnancy.