Amniotic fluid as a novel delivery route of 3-hydroxybutyrate during fetal brain development

Understanding how fetuses receive essential nutrients during pregnancy is crucial for optimal brain development. We observed significantly higher levels of 3-hydroxybutyrate (3HB) in the amniotic fluid surrounding human fetuses during healthy late pregnancy compared to maternal blood. 3HB concentrations in the maternal blood were 0.12 mmol/L, while those in the amniotic fluid were 0.56 mmol/L. The rate-limiting enzyme of ketogenesis, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), was highly expressed in the cells of the chorionic plate. The placenta likely plays a crucial role in producing 3HB into the amniotic fluid, via a system involving placental HMGCS2. Here, we propose a novel delivery route for 3HB to the fetus through the amniotic fluid, in addition to the previously known route through umbilical vein. As a potential link to fetal brain development, this study suggests that complementary routes via the amniotic fluid and umbilical vein contribute significantly to the fetal 3HB supply during late pregnancy.