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

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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.