Translational Research in Obstetric Pharmacology: Historical Trends, Prenatal Pharmacogenomics, and an Opportunistic Study of Placental ABCG2 and Fetal Glyburide Exposure

Abstract

This dissertation is principally comprised of three distinct but related projects. The first is an assessment of the quantity and nature of obstetric pharmacology clinical trials conducted in the past decade, as well as a comparison of these trials to non-obstetric trials, in order to identify whether the challenges and complexities of conducting research in this field are reflected in the aggregate study data available through ClinicalTrials.gov. The analysis identified several significant differences between obstetric and non-obstetric trials, which have implications for program planning and funding needs. Second is an overview of the ways in which the fetal genome may be informative of fetal outcomes with regard to medication and other chemical exposures during pregnancy, and the attendant research prioritization of this area and clinical testing opportunities made possible by non-invasive prenatal genetic tests that utilize cell-free fetal DNA in a pregnant woman’s blood. Finally, an opportunistic clinical study was conducted, assessing whether fetal genotype for the placental efflux transporter breast cancer resistance protein (BCRP, ABCG2) is predictive of relative fetal exposure to the oral hypoglycemic agent glyburide, which is used, off-label as an alternative to insulin, to treat gestational diabetes. The results of the study showed no association between fetal ABCG2 Q141K genotype and relative glyburide exposure at term, which was unexpected given the extensive, albeit indirect, supporting evidence that formed the basis of the initial hypothesis. This result has clinical implications related to the optimal use of glyburide to treat gestational diabetes, and also underscores the complexity of drug disposition during pregnancy and the need to study pregnant women directly.