Phenotype-driven protocol switching is associated with improved ART outcomes under constant gonadotropin dosage: a self-controlled analysis of 4,632 cycles.

Background: Managing failure after an initial assisted reproductive technology (ART) cycle remains a significant clinical challenge. Clinicians often face a dilemma between repeating the index protocol, escalating gonadotropin (Gn) dosages, or switching to an alternative strategy. We aimed to evaluate whether phenotype-driven protocol switching, specifically addressing issues like over-suppression or poor embryo quality, is more effective than repeating the same protocol. Methods: This large-scale, retrospective, self-controlled study involved 4,632 patients who underwent two consecutive ART cycles between January 2010 and December 2025. Patients were stratified into four pathways based on their second-cycle strategy: (i) Releasing Suppression (Long-to-Antagonist, n=1,412); (ii) Boosting Quantity (Mild-to-Antagonist, n=220); (iii) Improving Quality (Antagonist-to-Mild, n=829); and (iv) Reference (Antagonist-to-Antagonist, n=2,171). The primary outcome was the cumulative live birth rate (CLBR). Statistical analysis employed the Wilcoxon signed-rank test for paired continuous data and multivariable logistic regression to identify independent predictors of success. Results: In the Reference group, repeating the same protocol under identical Gn dosages significantly increased the CLBR (9.9% to 51.9%, P < 0.001). Beyond this baseline, individualised switching yielded distinct benefits. The Long-to-Antagonist switch significantly increased the median oocyte retrieval (8.0 [5.0-12.0] vs 9.0 [6.0-13.0], P < 0.001). The Mild-to-Antagonist switch successfully expanded the oocyte cohort in low responders (2.0 [1.0-4.0] vs 3.0 [2.0-5.2], P < 0.001). Conversely, the Antagonist-to-Mild switch did not increase oocyte yield (P = 0.642) but significantly improved the good embryo rate (median 0.0% vs 16.7%, P < 0.001). Multivariable regression confirmed that while age and anti-Müllerian hormone remained dominant prognostic factors, appropriate protocol triage neutralised risks without requiring dose escalation (P > 0.05 for protocol switch strategies). Conclusions: Phenotype-driven "quantity" or "quality" rescue is associated with significant clinical improvements following ART failure while keeping Gn dosages constant. While tactical switching is effective, a substantial proportion of the success in a second attempt is driven by natural biological variation (regression to the mean)."