Pharmacogenetic Screening for Susceptibility to Fetal Malformations in Women

Abstract

Individuals vary in how they metabolize drugs and handle toxic environmental exposures. In an ideal pregnancy, there is no or limited exposure to medications and environmental agents. However, in women with chronic medical conditions such as heart disease and seizures, this is often not possible. Unfortunately, no techniques have been available to identify those at risk in this population. Gene polymorphisms for a specific enzyme may result in an absence or reduction in the level of enzyme activity or in no change at 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 the fetus. Other polymorphisms may be only markers. Thus, developing genotyping assays for women that are predictive of phenotype expression in the fetus is the key to screening for polymorphisms. As more mutations are identified and clinical, pharmacologic, biologic, and pharmacokinetic relationships are established, using these polymorphisms to develop a genotyping assay for women may become a clinical reality, possibly leading to preventive prepregnancy or prenatal treatment that may play an increasingly effective role in maternal care.

The clinical impact of pharmacogenetics on the treatment of epilepsy

“…In that respect, it may be of interest that in addition to VPA, TPM and the major carboxylic acid metabolite of levetiracetam (LEV) in humans, but not LEV itself, have been shown in vitro to inhibit HDACs (Eyal et al, 2004). The challenges in linking genetic polymorphisms to fetal phenotype have been reviewed by Van Dyke et al (2000). At the time of their review, insufficient correlations between polymorphisms and phenotype were noted.…”

Folic acid and prevention of birth defects

“…57,58 Some anticonvulsant medications such as phenytoin, carbemazapine, valproic acid, phenobarbitol, and primidone may lower serum folate levels. 11,57,58 Other medications and folic acid antagonists such as trimethoprim, sulfamethoxazole, methotrexate, oral contraceptives, triamterene, primethanine, and trimetrexate affect various steps in the folic acid pathway. 37,57,58 Smoking and alcohol also may have an effect.…”

“…11,57,58 Other medications and folic acid antagonists such as trimethoprim, sulfamethoxazole, methotrexate, oral contraceptives, triamterene, primethanine, and trimetrexate affect various steps in the folic acid pathway. 37,57,58 Smoking and alcohol also may have an effect. 37 Use of folic acid antagonists during pregnancy may increase the risk of some birth defects in some women.…”

Drug target-gene signatures that predict teratogenicity are enriched for developmentally related genes

“…As such, high-throughput innovations of previously described “predictive teratology” approaches [6, 7] would be of tremendous value in assessing developmental toxicity risks. The identification of relevant mutations and polymorphisms is central to the innovation of pre-pregnancy teratogen risk assays [8]. …”