Physiological challenges and metabolic adaptations during human fetal development and at delivery

Demographic shifts driven by both social and biological factors underscore the need to improve pregnancy care and early childhood interventions to achieve lasting health benefits. From implantation to birth, tightly coordinated physiological and metabolic processes in embryonic and fetal development, coupled with maternal–fetal nutrient exchange, ensure that oxygen supply meets the energy demands of the growing fetus. Critical mechanisms include the higher oxygen affinity of fetal hemoglobin, which facilitates maternal-to-fetal oxygen transfer; endocrine regulators such as human chorionic gonadotropin, which promote placental development; and hypoxia-inducible factors, which support adaptation to low oxygen availability by enhancing glucose utilization, shaping oxygen and lactate metabolism, and contributing to implantation and immune modulation. Additional adaptations—such as shifts in fetal temperature, blood flow, and pH relative to the mother—further optimize oxygen release from fetal blood to tissues. At birth, the neonate undergoes profound respiratory, cardiovascular, and metabolic transitions required for survival in the extrauterine environment. In this review, we examine the central physiological and metabolic mechanisms that enable human embryos and fetuses to grow and survive under these developmental constraints and through delivery. We further discuss how perinatal metabolic adaptations not only secure immediate survival but also influence lifelong health trajectories, including susceptibility to chronic non-communicable diseases influenced by epigenetics factors. A deeper understanding of these processes may guide interventions aimed at optimizing fetal development, improving pregnancy outcomes, and promoting long-term human health.