Estimating fetal cholesterol synthesis rates by cord blood analysis in intrauterine growth restriction and normally grown fetuses

BACKGROUND: Cholesterol is an essential component in human development. In fetuses affected by intrauterine growth restriction (IUGR), fetal blood cholesterol levels are low. Whether this is the result of a reduced materno-fetal cholesterol transport, or due to low fetal de novo synthesis rates, remains a matter of debate. By analyzing cholesterol interbolites and plant sterols we aimed at deeper insights into transplacental cholesterol transport and fetal cholesterol handling in IUGR with potential targets for future therapy. We hypothesized that placental insufficiency results in a diminished cholesterol supply to the fetus. METHODS: Venous umbilical cord sera were sampled post-partum from fetuses delivered between 24 weeks of gestation and at full term. IUGR fetuses were matched to 49 adequate-for-age delivered preterm and term neonates (CTRL) according to gestational age at delivery. Cholesterol was measured by gas chromatography-flame ionization detection using 5a-cholestane as internal standard. Cholesterol precursors and synthesis markers, such as lanosterol, lathosterol, and desmosterol, the absorption markers, 5α-cholestanol and plant sterols, such as campesterol and sitosterol, as well as enzymatically oxidized cholesterol metabolites (oxysterols), such as 24S- or 27-hydroxycholesterol, were analyzed by gas chromatography-mass spectrometry, using epicoprostanol as internal standard for the non-cholesterol sterols and deuterium labeled oxysterols for 24S- and 27-hydroxycholesterol. RESULTS: Mean cholesterol levels were 25% lower in IUGR compared with CTRL (p < 0.0001). Lanosterol and lathosterol to cholesterol ratios were similar in IUGR and CTRL. In relation to cholesterol mean, desmosterol, 24S-hydroxycholesterol, and 27-hydroxycholesterol levels were higher by 30.0, 39.1 and 60.7%, respectively, in IUGR compared to CTRL (p < 0.0001). Equally, 5α-cholestanol, campesterol, and β-sitosterol to cholesterol ratios were higher in IUGR than in CTRL (17.2%, p < 0.004; 33.5%, p < 0.002; 29.3%, p < 0.021). CONCLUSIONS: Cholesterol deficiency in IUGR is the result of diminished fetal de novo synthesis rates rather than diminished maternal supply. However, increased oxysterol- and phytosterol to cholesterol ratios suggest a lower sterol elimination rate. This is likely caused by a restricted hepatobiliary function. Understanding the fetal cholesterol metabolism is important, not only for neonatal nutrition, but also for the development of strategies to reduce the known risk of future cardiovascular diseases in the IUGR fetus.