David G. Vossler, M.D.
Epilepsy Center at Washington Neuroscience Institute
Pregnancy is probably the most complex issue for women with epilepsy (WWE). One-half of 1% of all pregnancies occur in women with epilepsy. The pregnant WWE must balance the risks posed by seizures with the risks associated with antiepileptic drug (AED) exposure. Seizure frequency is increased in roughly one-third of women during pregnancy, but it remains the same in another third, and may actually decrease in another third.
A major concern is pregnancy complications. WWE whose seizures are poorly controlled have higher rates of toxemia, vaginal bleeding, premature labor, failure to progress in delivery, and cesarean section. The infants have higher death rates, decreased fetal growth and health, and a higher risk of intrauterine growth retardation. Well-treated patients, however, mostly have typical pregnancies and deliveries. Therefore, planning ahead for pregnancy with your health-care provider and keeping your seizures as well-controlled as possible with the proper medication are both extremely important.
A factor associated with an increase in seizure frequency as pregnancy progresses is changes in AED pharmacokinetics. Pharmacokinetics refers to how drugs move into, through, and out of the body. As pregnancy progresses, body volume, kidney drug clearance, or liver drug metabolism may increase, resulting in a decrease in the total AED blood levels. Total blood levels are only part of the story: A few AEDs, like phenytoin (Dilantin, Phenytek) and valproate (Depakote), are highly bound to blood proteins like albumin. Changes in protein binding during pregnancy can alter the ratio of the free blood level to the total blood level. It is the free level that accounts for the AEDs antiseizure benefits and side effects. Also, natural pregnancy hormone changes cause some AED levels, like lamotrigine (Lamictal), to fall to as low as 33% of normal in the third trimester. As a result of these various changes, neurologists often regularly monitor AED blood levels throughout pregnancy.
In completely healthy women without epilepsy, major birth malformations (teratogenesis) occur in roughly 2-3% of infants. Research studies have variably estimated that major malformations affect 3.5-6% of infants born to mothers with epilepsy; minor abnormalities affect 6-20%. From 1996-2005 the U.K. Epilepsy and Pregnancy Register (UKEPR) studied 237 WWE untreated during pregnancy and found a major malformation rate of 3.5%. Major malformations include cleft palate/lip, spina bifida, and congenital heart disease. Minor abnormalities include wide-spaced eyes, epicanthal folds, nasal growth deficiency, abnormal ears, low hairline, distal finger and toe development, small fingernails, and others. Some conditions causing epilepsy, such as tuberous sclerosis and malformations of cortical development, are associated an increased risk of defects.
All of the older AEDs are associated with an increased risk of birth defects. The North American AED Pregnancy Registry (NAPR) has reported that the major malformation rate in babies born to WWE taking one of the older AEDs was 6.5% for phenobarbital and 10.7% for valproate (NAPR report, Winter 2006). There is evidence that the use of more than one AED, and higher doses of either valproate or lamotrigine, increase the risk of congenital malformations (UKEPR 2006, and NAPR 2006). For the newer AEDs (ones approved by the FDA since 1993) some data are emerging. For lamotrigine, the NAPR and several other international registries are estimating a major malformation rate around 2.9%, with a mild increase in cleft lip and cleft palate in some, but not all, registries.
Data presented at the April 2007 American Academy of Neurology annual meeting by Dr. Kimford Meador and the Neurodevelopmental Effects of AED (NEAD) group showed that at age 2 years, children exposed in the womb to valproic acid had significantly lower scores on the Mental Developmental Index compared to children exposed to carbamazepine, lamotrigine, or phenytoin. The negative impact of valproate was related to the dose. Further information on the long-term effects of AEDs on the intelligence of children will come from this important ongoing study.
Folic acid 2 – 4 mg/day and one prenatal vitamin per day are recommended before and during pregnancy, to reduce the risk of congenital malformations. A high-level detailed ultrasound and a “quad screen” blood test are often recommended during weeks 16-20 of pregnancy. Close monitoring of AED blood levels during pregnancy can be important because generalized tonic-clonic seizures can cause physical injury or asphyxia to the fetus or miscarriage.
Another risk to infants with older AEDs like phenytoin is decreases in vitamin K levels in mother and baby. This can lead to serious hemorrhages in infants. In Washington State, infants do receive an intramuscular injection of vitamin K. However, it is recommended that vitamin K 10 mg/day should be taken orally during the last 1-4 weeks of pregnancy with older AEDs. This may be less of an issue with newer AEDs. Practice parameters have been published by the American Academy of Neurology (Epilepsia 1998;39:1226-31).
All of the older antiepileptic drugs, and some of the newer antiepileptic drugs, cross into breast milk to some degree. Some of them, such as primidone (Mysoline), cross extensively over into breast milk. A physician should be consulted about whether or not nursing should occur, but in most cases nursing is usually recommended for infants already exposed to the AED in the womb.
In summary, much is known about pregnancy in epilepsy. However, much still needs to be learned, especially with the newest medications. Planning ahead for pregnancy can greatly reduce the risk of many of the risks and adverse outcomes listed above. For example, it may be possible to change from riskier medications, such as valproate, to other less risky ones. Also, working with your health-care provider, it may be possible to get seizures under better control before becoming pregnant. Once you are pregnant, careful frequent consultations with knowledgeable health-care professionals to monitor your seizures and AEDs, run needed tests, and ensure you get the proper vitamins and good general care can help the vast majority of WWE have successful, safe pregnancies and healthy babies.
These are general guidelines that should not be taken as specific advice, for women with epilepsy. Please consult your physicians about all of these issues. These points are made for discussion only, and to encourage further research and investigation into these issues.