Fetal Neuroprotection by choline supplementation in heavy drinking pregnant women

PROJECT SUMMARY Fetal alcohol spectrum disorders represent the most prevalent cause of preventable intellectual disability. Prevalence in high-risk communities in the Western Cape region of South Africa may be as high as 20.9%. Prenatal alcohol exposure (PAE) impacts the developing brain, resulting in cognitive deficits, growth restriction and structural brain changes. Despite psychosocial interventions, heavy drinking during pregnancy continues to be a major public health challenge in the Western Cape, U.S. and worldwide. In a recent preliminary study, we showed that high dose maternal choline supplementation during pregnancy mitigates adverse effects of PAE on infant growth and cognitive development, as well as neonatal brain structure. This proposal will add on to a recently NIH-funded fully-powered, double-blind, randomized placebo-controlled trial in which 288 heavy drinking Western Cape women will be given choline or placebo during pregnancy and infants will be assessed through 12 months of age. We propose the addition of neonatal neuroimaging, including brain anatomical, diffusion and metabolic spectral imaging, to examine neural mechanisms mediating the beneficial effects of maternal choline supplementation on infant developmental outcomes. We hypothesize that choline supplementation in heavy drinking pregnant women will reduce the adverse impact of PAE on the developing fetal brain by normalizing anatomical development, connectivity, and brain energy metabolism. Brain development is energy demanding and highly sensitive to nutritional reserves. Alcohol measurably disrupts brain metabolites. Choline is a precursor to acetylcholine, a metabolite critical in healthy cell development. Depletion of choline reserves coupled with alcohol-induced disruption adversely affects fetal brain development. Our preliminary infant brain anatomical data show clear developmental effects of PAE and the mitigating effects of maternal choline supplementation. We will combine the clinical and nutritional information and infant cognitive test results from the clinical trial with the brain anatomical, connectivity and metabolic measurements from the current study to augment our understanding of the mechanistic underpinnings of the neuroprotective benefits of prenatal maternal choline supplementation on the developing fetus in the setting of PAE. We will develop capacity for acquiring region-specific neurometabolic information using magnetic resonance spectroscopic imaging (MRSI) and deep learning to identify neonatal brain regions. This project builds on the decades-long collaborations between Drs. Meintjes (University of Cape Town), S. and J. Jacobson (Wayne State University School of Medicine), van der Kouwe (Massachusetts General Hospital) and Carter (Columbia University). Drs. Choi and Lee, experts on measuring energy metabolism in prescribed brain regions using MRSI, will serve as consultants on this study.