Pharmacogenetic screening for susceptibility to fetal malformations in women

OBJECTIVE: TO present a review of the literature and research on the pharma cogenetics of congenital defects, with a focus on the need for predictive m aternal genotype assays. DATA SOURCE: MEDLINE searches (January 1985-January 1999), past reference r eviews, and unpublished research. STUDY SELECTION: Review of relevant human, animal, and basic science studie s. DATA EXTRACTION: Data on research on polymorphisms, genotyping, cytochrome P450 enzyme systems, epoxide hydrolase, folate metabolism, metabolism of an ticonvulsant medications, molecular genetics of neural tube defects, variat ions in drug metabolism, environmental exposures were evaluated. DATA SYNTHESIS: Data synthesis includes not only a review of the literature hut suggests ways such data might be used to facilitate the development of maternal genotype assays, with the goal of preventing birth defects. CONCLUSIONS: Individuals vary in how they metabolize drugs and handle toxic environmental exposures. In an ideal pregnancy, there is no or limited exp osure to medications and environmental agents. However, in women with chron ic medical conditions such heart disease and seizures, this is often not po ssible. Unfortunately no techniques have been available to identify those a t risk in population. Gene polymorphisms for a specific enzyme may result i n an absence or reduction in the level of enzyme activity or in no change a t all, with little effect on the structure/function of the gene product(s); they are not associated with clinical phenotypes in either the mother or t he fetus. Other polymorphisms may be only markers. Thus, developing genotyp ing assays for women that are predictive of phenotype expression in the fet us is the key to screening for polymorphisms. As more mutations are identif ied and clinical, pharmacologic, biologic, and pharmacokinetic relationship s are established, using these polymorphisms to develop a genotyping assay for women may become a clinical reality, possibly leading to preventive pre pregnancy or prenatal treatment that may play an increasingly effective rol e in maternal care.