Epilepsy and Pregnancy

Though issues related to epilepsy and pregnancy are complex, there are two basic topics of consideration: matters related to anti-seizure drugs, and matters related to seizure frequency or seizure occurrence. Women of child-bearing age who have epilepsy often want to know, first, if they need to be on anti-seizure medication, and if so how much, and second, what the risks of anti-seizure medication are in relation to fetal development, labor, delivery, and breast feeding. The impact of breakthrough or poorly controlled seizures on pregnancy, fetal development, and labor is not always a primary consideration.

Fetal malformations represent a spectrum of developmental abnormalities, which at one end can be minor and insignificant, and at the other end can be major and potential life threatening. Less significant malformations include a cleft lip, which can be surgically corrected. Moderate abnormalities include skeletal defects, dysmorphic features (small head, low set ears, etc). Major malformations include cardiac and nervous system abnormalities, such as Tetralogy of Fallot, and neural tube defects (e.g. spina bifida), respectively. The risk of a fetal malformations occurring in an otherwise healthy woman not on medication is 0.5-2%, though this figure varies by literature and may be higher with advancing maternal age. The risk increases to 2-4% in a woman on a single anti-seizure medication, 4-8% in a woman on two anti-seizure drugs, and 6-12% in a woman on 3 or more anti-seizure drugs. The prevalence of neural tube defects is roughly 1 per 1,000 live births. Valproic acid, specifically, increases the risk of neural tube defects significantly. Presently, the use of anti-seizure drugs are not linked to an increased incidence of certain chromosomal abnormalities, such as Down's Syndrome (Trisomy 21), Turner's Syndrome (XO), and other aneuploidies. However, neural tube defects are associated with other chromosomal and single-gene disorders.

Virtually all anti-seizure drugs have been rated as either Class D or Class C drugs in pregnancy. Class D drugs, which are known to cause abnormal fetal development in humans, include phenytoin, carbamazepine, valproic acid, mysoline, and Phenobarbital. Class C drugs, which are known to cause abnormal fetal development in animals, but not necessarily in humans, include lamotrigine, topiramate, gabapentin, zonisamide, leviteracetam, oxcarbazepine. Anti-seizure drugs are not linked to premature induction of labor or to other pregnancy-related complications such as gestational diabetes, pregnancy-induced hypertension, or toxemia of pregnancy.

The main aim of anti-seizure drug therapy during pregnancy is to establish the lowest effective dose to control seizures. For reasons that are not readily apparent, a proportion of women may show a decrease or an increase in seizure frequency, resulting in adjustments in dose. As pregnancy is a dynamic process, serum levels of anti-seizure drug may be helpful in adjusting drug dosage, if a particular free drug concentration was previously established to be associated with a seizure-free state.

Despite best efforts, breakthrough seizures can occur during pregnancy, even in the absence of a provocative state, such as sleep deprivation, hypoglycemia (with or without gestational diabetes), toxemia of pregnancy, or an intercurrent illness. The hazards of breakthrough or unpredictable seizures are numerous and include direct harm to the mother and possibly the fetus as in the case of a fall, a motor vehicle accident, drowning, and so on. However, harm to the fetus, but not the mother can also occur, as metabolic and physiologic changes during a seizure occur. First, harmful (cytotoxic) oxygen species are produced during seizures. These harmful oxygen species may result is cell damage and may precipitate developmental abnormalities. The risk of developmental or fetal abnormalities is 3-fold higher in mothers treated with anti-seizure drugs who have no seizures compared with treated mothers who experience seizures.

Vitamin supplementation has been associated with a significant reduction in congenital malformations, including neural tube defects, when initiated at least 28 days prior to conception and continued at least until the second missed menses. The only FDA-approved agent to reduce the risk of fetal malformations, specifically neural-tube defects, cranio-facial abnormalities, and cardiac defects, is folic acid. The recommended daily intake is 1-4 mg per day. Women who are on more than one anti-seizure drug or who otherwise have a significant risk for neural tube defects are recommended the higher dose of 4 mg/day. Selenium, 200 ug/day, is also suggested to minimize the risk of neural tube defects.

In addition to early and adequate vitamin supplementation, other aspects of sound medical care during pregnancy for a woman with epilepsy is to be under the care of a neurologist and a high-risk obstetrician. An alpha-fetoprotein test at 15-22 weeks and an ultrasound at 12-14 (for severe defects) and again at 18-22 weeks (for subtle cardiac, cranio-facial defects) is also recommended. Consideration may also be given to performance of an amniocentesis at 16 weeks. Knowledge and consideration of all of these factors, by discussion with family members, the neurologist and obstetrician, are likely to lead to the most desirable outcomes.