Phenotype-driven protocol switching is associated with improved ART outcomes under constant gonadotropin dosage: a...

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.

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.

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).

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)."