Optimal timing for frozen-thawed embryo transfer: evidence from a systematic review and meta-analysis.

AIM: This study aims to evaluate the association between the duration of cryopreservation and reproductive and neonatal outcomes using a meta-analysis.

METHODS

A comprehensive search was conducted in PubMed, Embase and Medline databases up to October 1, 2025. A total of 17 studies were included in the analysis and compared reproductive/neonatal outcomes between frozen-thawed embryo transfer (FET) ≤12 vs >12 months post-storage. The meta-analysis was conducted using Review Manager 5.3 software.

RESULTS

Shorter storage (≤12 months) was associated with higher odds of live birth rate(OR 1.19, 95% CI 1.09-1.30; 15 studies, I² = 78%), biochemical pregnancy rate (OR 1.44, 95% CI 1.19-1.75; 8 studies, I² = 92%), and clinical pregnancy rate (OR 1.24, 95% CI 1.12-1.37; 15 studies, I² = 85%). However, these associations were accompanied by substantial heterogeneity (I² = 78-92%), and 95% prediction intervals crossed the null line. The multiple pregnancy rate was also higher with shorter storage (OR 1.26, 95% CI 1.03-1.55), yet this association was confined to studies permitting double-embryo transfer and likely reflects uncontrolled confounding by embryo number rather than a biological benefit. Subgroup analyses revealed that the association between shorter storage and improved outcomes was primarily driven by maternal age and studies from China. Meta-regression identified maternal age as a significant effect modifier for live birth rate (OR = 0.973, P = 0.014) and clinical pregnancy rate (OR = 0.974, P = 0.025), while no significant interactions were found for biochemical pregnancy rate. There were no significant differences between the two groups in survival rate, miscarriage rate, implantation rate, ectopic pregnancy rate, preterm birth, low birth weight, congenital malformations, or sex ratio. No significant publication bias was detected by Egger's or Begg's tests.

CONCLUSION

Although shorter storage was associated with improved pregnancy rates, all studies were retrospective cohorts, precluding causal inference. High heterogeneity, wide prediction intervals, inconsistent confounding adjustment, and marked dependence on Chinese cohorts limit generalizability. The dichotomous classification cannot capture dose-response relationships, and long-term offspring outcomes remain unreported. Storage duration should not be used alone to prioritize transfer timing. Clinical decisions must remain individualized, accounting for patient readiness, embryo quality, and clinic-specific protocols.