Antioxidant Supplementation with Caffeine During Rescue In Vitro Maturation Improves Fertilization and Embryo Development in Women of Advanced Maternal Age

Age-related decline in oocyte quality is closely associated with mitochondrial dysfunction and oxidative imbalance, which disrupt redox-sensitive meiotic signaling and compromise embryo developmental competence. Rescue in vitro maturation (r-IVM) enables the utilization of immature oocytes retrieved during conventional in vitro fertilization (IVF) cycles. However, the developmental potential of r-IVM oocytes remains limited, particularly in women of advanced maternal age. This study evaluated whether transient caffeine supplementation during r-IVM improves the developmental competence of immature human oocytes in clinical assisted reproduction technology cycles. Immature oocytes obtained during conventional IVF were cultured with or without short-term caffeine exposure during r-IVM prior to standard culture conditions. After maturation, metaphase II oocytes underwent intracytoplasmic sperm injection, and embryonic development was assessed by fertilization rate, day 3 good-quality embryo formation, and blastocyst development. Although caffeine supplementation did not significantly affect nuclear maturation rates, it significantly increased fertilization efficiency and the proportion of good-quality embryos compared with controls. These effects were most pronounced in women aged ≥37 years. Time-lapse morphokinetic analysis further revealed more synchronized developmental kinetics in embryos derived from caffeine-treated oocytes, resembling those derived from in vivo-matured oocytes. Collectively, these findings suggest that transient caffeine exposure during r-IVM enhances post-fertilization developmental competence. The underlying mechanisms remain to be elucidated, and future studies are required to determine whether redox-sensitive meiotic pathways and mitochondrial function are involved.