Placental and Fetal Metabolic Reprogramming in Pregnancies with Intrauterine Growth Restriction

The high-altitude hypoxia model demonstrates that insufficiently oxygenated placentas activate compensatory mechanisms to ensure fetal survival, hinging on the transcription factor hypoxia-inducible factor-1. The aim of the present study is to investigate whether and when similar mechanisms are also activated during intrauterine growth restriction (IUGR). A retrospective observational study evaluated a series of umbilical cord blood samples, which provide a realistic representation of the fetal intrauterine status, collected from a cohort of preterm and term neonates, both affected and not affected by IUGR. Results demonstrate that preterm IUGR fetuses receive a lower supply of oxygen and glucose from the placenta, along with a greater provision of lactate and carbon dioxide compared to non-IUGR neonates. Simultaneously, preterm IUGR fetuses increase oxygen extraction and reduce lactate production. These differences between IUGR and non-IUGR placentas and fetuses disappear as the term of pregnancy approaches. In conclusion, this study suggests that hypoperfused placentas in preterm pregnancies with IUGR activate a metabolic reprogramming aimed at favoring glycolytic metabolism to ensure fetal oxygenation, even though the availability of glucose for the fetus is reduced. Consequently, preterm IUGR fetuses activate gluconeogenetic metabolic reprogramming, despite it being energetically expensive. These metabolic adaptations disappear in the last weeks of pregnancy, likely due to physiological placental aging that increases the fetoplacental availability of oxygen. Placental oxygenation appears to be the main driver of metabolic reprogramming; however, further studies are necessary to identify the underlying biological mechanisms modulated by oxygen.