development of biological markers for the identification of intrauterine alcohol exposure.
Published: 2004
Language: eng
Number of pages: 281
Description: Confirmation of gestational ethanol exposure is required for the diagnosis of Fetal Alcohol Spectrum Disorder. The development of a novel neonatal screening test for fatty acid ethyl esters (FAEE) in meconium was investigated in this thesis.The potential application of meconium FAEE screening in the absence of maternal drinking history was investigated in a high-risk population. A substantial proportion of neonates (14%) suspected of intrauterine substance exposure were likely exposed to heavy maternal drinking, as identified by meconium screening.Baseline FAEE measurements in the meconium of neonates (n = 183) born to non-drinking mothers from Jerusalem and Toronto were investigated. Certain FAEE (ethyl laurate and myristate) were detected mostly at trace levels among non-exposed neonates. The presence of elevated levels of multiple FAEE (5--25 fold) and the presence of longer chain FAEE (ethyl palmitate, stearate, oleate, linoleate) were characteristic of neonates born to drinking mothers (n = 6). The use of cumulative FAEE measurements &ge;2 nmol/g (excluding ethyl laurate and myristate) as a positive cut-off distinguished neonates with and without heavy prenatal alcohol exposure with the highest sensitivity (100%) and specificity (98%).The transfer and metabolic handling of FAEE by the human placenta was investigated to elucidate the origin of meconium FAEE. In vitro placental perfusion of 4 FAEE (ethyl palmitate, stearate, oleate, linoleate) at low and high concentrations (2--20 muM) in the absence and presence of a physiologic carrier, albumin, did not result in maternal-fetal transfer. Subsequent kinetic studies using subcellular preparations revealed that the majority of maternally derived FAEE were taken up and metabolized by enzymatic activities localized in the microsomal fraction of the human placenta (Mean Km 35--95 muM; Vmax 0.6--1.8 nmol/min/mg). Hence, FAEE detected in meconium were likely produced by the fetus from the ethanol that has been transferred to and metabolized by the fetus.These findings strongly support further validation of meconium FAEE as biomarkers of prenatal alcohol exposure. Future use of meconium FAEE screening as an objective and non-invasive method for the confirmation of intrauterine ethanol exposure can potentially facilitate earlier diagnosis and interventions in the affected children, leading to more favourable outcomes.
Notes: Adviser:  Gideon Koren.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 5094.