Maternal Choline Supplementation Mitigates Alcohol-Induced Fetal Cranio-Facial Abnormalities Detected Using an Ultrasonographic Examination in A Sheep Model

Abstract

Early detection of prenatal alcohol exposure is critical for designing and testing effectiveness of interventional therapeutics. Choline supplementation during and after prenatal alcohol exposure has shown promising benefits in improving outcomes in rodent models and clinical studies. A sheep model of first trimester-equivalent binge alcohol exposure was used in this study to model the dose of maternal choline supplementation used in an ongoing prospective clinical trial involving pregnancies at risk for FASD. Pregnant sheep were randomly assigned to six groups: Saline+Placebo control, Saline+Choline, binge Alcohol+Placebo (light binging), binge Alcohol+Choline, Heavy binge Alcohol+Placebo (heavy binging) and Heavy binge Alcohol+Choline. Ewes received intravenous alcohol or saline on three consecutive days per week from gestational day (GD) 4 to 41 to mimic first trimester-equivalent weekend binge drinking paradigm. Choline (10 mg/kg in the daily food ration) was administered from GD 4 until term. On GD 76, 11 fetal ultrasonographic measurements were collected transabdominally. Heavy binge alcohol exposure reduced fetal Frontothalamic Distance (FTD), Mean Orbital Diameter (MOD) and Mean Lens Diameter (MLD) and increased Interorbital Distance (IOD) and Thalamic Width (TW). Maternal choline supplementation mitigated most of these alcohol-induced effects. Maternal choline supplementation also improved overall fetal femur and humerus bone lengths compared to their respective placebo groups. Taken together these results indicate a potential dose dependent effect that could impact the sensitivity of these ultrasonographic measures in predicting prenatal alcohol exposure. This is the first study in the sheep model to identify biomarkers of prenatal alcohol exposure in-utero with ultrasound and co-administration of maternal choline supplementation.