Drug and Environmental Factors Associated with Adverse Pregnancy Outcomes Part I: Antiepileptic Drugs, Contraceptives, Smoking, and Folate

Abstract

OBJECTIVE: Part I of this review examines the relationship between antiepileptic drugs (AEDs) and pregnancy outcomes. Drug-induced folate deficiency and the role of AED metabolism are emphasized. Part II will discuss periconceptional folate supplementation for prevention of birth defects. Part III will discuss the mechanism of folate's protective effect, therapeutic recommendations, compliance, and cost. DATA SOURCES: A MEDLINE search was conducted for journal articles published through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included phenytoin, carbamazepine, phenobarbital, primidone, valproic acid, oral contraceptives, clomiphene, drug-induced abnormalities, spina bifida, anencephaly, neural tube defect, folate, folic acid, and folic acid deficiency. STUDY SELECTION: Relevant animal and human studies examining the effects of AEDs, smoking, and oral contraceptives on folate status and pregnancy outcome are reviewed. DATA EXTRACTION: Studies and case reports were interpreted. Data extracted included dosing, serum and red blood cell folate concentrations, teratogenicity of anticonvulsant medications, metabolism of AEDs and folate, and genetic susceptibility to AED-induced teratogenicity. DATA SYNTHESIS: Low serum and red blood cell folate concentrations are associated with adverse pregnancy outcomes. Decreases in serum folate are seen with AEDs, oral contraceptives, and smoking. Since similar birth defects are observed with multiple AEDs, metabolism of aromatic AEDs to epoxide metabolites and genetic factors may play a role in teratogenesis. CONCLUSIONS: Adequate prepregnancy planning is essential for women who have epilepsy. Women receiving folate-lowering drugs may be at increased risk of adverse pregnancy outcomes. Therefore, epileptic women contemplating pregnancy should be treated with the minimum number of folate-lowering drugs possible and receive folic acid supplementation.