Caffeine Supplementation Enhances Aged Human Oocyte Quality and Embryo Development in In Vitro Fertilization: A Retrospective Paired Study

ABSTRACT Purpose To evaluate whether in vitro caffeine supplementation can improve spindle integrity, embryo development, and clinical outcomes in IVF. Methods This retrospective paired‐cohort study included 704 women aged ≥ 35 years who underwent two ICSI cycles (one caffeine‐supplemented and one non‐caffeine) within 12 months. Oocytes in caffeine cycles were exposed to 1.25 mM caffeine for 4 h before fertilization. Outcomes included spindle positioning, embryo quality, blastocyst development and euploidy rates, and neonatal outcomes from 20 women (24 neonates). Paired comparisons were performed using the Wilcoxon signed‐rank and McNemar's tests. Results Caffeine cycles showed higher rates of normal spindle positioning (80.2% vs. 61.2%, p < 0.001), high‐quality cleavage embryos (63.2% vs. 53.6%, p < 0.001), high‐quality blastocysts (39.2% vs. 26.1%, p < 0.001), and euploid embryos (22.9% vs. 10.9%, p = 0.002) than non‐caffeine cycles. The fertilization rates were similar between the groups (81.4% vs. 80.8%, p = 0.628). Clinical pregnancy rate was 39.1%, and neonatal outcomes were reassuring. Conclusions Short‐term in vitro caffeine exposure may enhance oocyte and embryo competence in older women undergoing IVF, especially those with prior IVF failures. These findings support caffeine as a simple, practical laboratory intervention. Prospective multicenter studies are warranted to confirm efficacy and safety.