Teratogenicity and antiepileptic drugs: potential mechanisms.

Congenital malformations often the most concerning risk of taking antiepileptic drugs (AEDs) during pregnancy for both the patient and the physician. This chapter reviews aspects of the association between AEDs and congenital malformations, including a historical perspective, type and patterns of congenital malformations, possible confounding factors, and potential mechanisms of teratogenicity. The role of folic acid in preventing birth defects in the general population and in setting of taking AEDs is also presented. One of the most serious congenital malformations, spina bifida (SB), and its association with intrauterine valproate exposure, is discussed in depth.

Risks and management of pregnancy in women with epilepsy.

Most women with epilepsy today can conceive and bear normal, healthy children, but their pregnancies present an increased risk for complications. Pregnancy can exacerbate seizure frequency in some women with epilepsy, and both maternal epilepsy and in utero exposure to antiepileptic drugs can increase the risk of adverse outcomes in children born to women with epilepsy. These outcomes include fetal loss and perinatal death, congenital malformations and anomalies, neonatal hemorrhage, low birth weight, developmental delay, and childhood epilepsy. After reviewing these risks, this article concludes with practical recommendations for reducing these risks and optimizing the management of pregnant women with epilepsy.

Management issues for women with epilepsy: neural tube defects and folic acid supplementation.

For infants exposed to antiepileptic drugs (AEDs) in utero, the risk for congenital malformations is approximately 4 to 6%, twice the rate reported in the general population. A variety of malformations have been reported in association with prenatal exposure to AEDs. However, a particular association of valproate and carbamazepine with neural tube defects (NTDs)--specifically, with spina bifida aperta (SB)--has been identified. The prevalence of SB is approximately 1 to 2% with valproate exposure and 0.5% with carbamazepine. Reported risk factors for NTDs include previous pregnancy with an NTD, maternal insulin-dependent diabetes mellitus, various nutritional deficiencies and occupational exposures, and high prepregnancy weight. Deficiencies of folate have been implicated in the development of birth defects, including NTDs. The value of periconceptional folic acid supplementation for women in the general population is accepted. However, it is unclear whether folic acid supplementation protects against the embryotoxic and teratogenic effects of AEDs because animal and human studies and case reports have shown variable results. Nevertheless, folic acid supplementation is recommended for women with epilepsy as it is for other women of childbearing age. Even with supplementary folic acid, women taking valproate or carbamazepine should undergo perinatal diagnostic ultrasound to rule out NTDs.

Clinical care of pregnant women with epilepsy: neural tube defects and folic acid supplementation.

Women with epilepsy (WWE) have a risk of bearing children with congenital malformations that is approximately twice that of the general population. Most antiepileptic drugs (AEDs) have been associated with such risk. Valproate and carbamazepine have been associated specifically with the development of neural tube defects (NTDs), especially spina bifida. Other factors may contribute to the risk, including concomitant diseases such as diabetes mellitus, occupational exposure to teratogens, excessive prepregnancy weight, and various nutrient deficiencies. In the general population, maternal folate deficiency, in particular, has been linked with the development of NTDs, and periconceptional folate supplementation with a reduction of risk. It is unclear whether folate supplementation has a comparable protective effect for WWE. Data concerning the risk for congenital malformations associated with the newer AEDs (gabapentin, felbamate, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide) are still limited. Several pregnancy registries for women taking AEDs have been established. Comprehensive postmarketing surveillance, regionally or nationally, might be the ideal method of monitoring medication safety, but government support for such an undertaking has for the most part been lacking. Despite uncertainty about the efficacy of periconceptional folate supplementation in WWE, these women should receive such supplementation at dosage levels recommended for the general population of women of childbearing age. Seizure control must not be neglected in a pregnant woman with epilepsy since seizures are associated with harm to the fetus as well as the mother. Risk may be minimized by using a single AED at the lowest effective dosage.