Pregnancy can affect seizure disorder which worsens in about a third, improves in a third, and remains unchanged in the remainder. Ideally, patients should have their seizure disorder properly investigated and treated before pregnancy with the best control achieved on the lowest dose of the least teratogenic drug. Major seizures are harmful to the developing fetus because of the possibility of anoxia and metabolic disorder. Minor seizures are probably harmless and therefore need not be eradicated. Patients should be advised of the necessity of taking folic acid supplements, since some antiepilepsy drugs affect folic acid metabolism and folic acid deficiency is a risk factor for neural tube defects. Hepatic enzyme inducing antiepilepsy drugs lower the mother's concentration of vitamin K, which can aggravate any postpartum haemorrhage. Pregnant mothers should therefore be given an oral vitamin K for the last two weeks of pregnancy.
The total plasma concentration of drug falls, especially towards the end of pregnancy, due to haemodilution, but the therapeutically important free (unbound) fraction in plasma is less affected. In practice, the patient's clinical state is observed closely and the dose of drug is increased if seizures occur more often than expected. Hepatic drug metabolism tends to increase during pregnancy. After delivery, the pharmacokinetics revert to the prepregnancy state over a few days.
Antiepilepsy drugs pass into breast milk (see p. 116), phenobarbital, primidone and ethosuximide in significant quantities, phenytoin and sodium valproate less so. There is a risk that the baby will become sedated or suckle poorly but, provided a watch is maintained for these effects, the balance of advantage favours breast feeding whilst taking antiepilepsy drugs.
Children of mothers taking antiepilepsy drugs have an approximately 2-3 x increased frequency of malformations at birth. In a case-control study of pregnant women, the frequency of malformation was 20.6% in infants whose mothers took one anticonvulsant drug and 28.0% with two or more such drugs, compared to 8.5% in matched controls.3 Infants of mothers who gave a history of epilepsy but did not take antiepilepsy drugs did not have a higher frequency than the controls, indicating that malformations are largely due to the antiepilepsy
3 Holmes LB et al 2001 New England Journal of Medicine
drugs themselves (rather than to factors related to the mother or her epilepsy).
The features of what has collectively become known as anticonvulsant embryopathy comprise: major malformations (often cardiac), microcephaly, growth retardation, and hypoplasia of the midface and fingers. The frequency of most malformations was increased in infants exposed to phenytoin alone or phenobarbital alone. Carbamazepine was associated with major malformations, microcephaly and growth retardation but not hypoplasia of the mid-face and fingers. In general, the major malformations were not distinct from those occurring among infants whose mothers had not taken antiepilepsy drugs, with two exceptions: marked hypoplasia of the nails and stiff joints were strongly associated with phenytoin with or without phenobarbitone, and lumbosacral spina bifida was commoner in infants exposed to carbamazepine or sodium valproate.
With current information, carbamazepine seems to be the safest drug for use during pregnancy. Data on lamotrigine (more recently introduced) are increasing but it has not been shown to be strongly associated with malformations.
When counselling whether or not to treat, and with which drug, factors such as the severity and type of seizure disorder also need to be taken in to account since control of major seizures is of fundamental importance.
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