Individualised dosing of follitropin delta affects live birth and safety in IVF: an individual participant data meta-analysis of randomised controlled trials

Objective: To undertake a one-stage meta-analysis of individual patient data from randomized trials comparing individualized dosing of follitropin delta vs. other forms of follitropin (alpha and beta) for live birth (LB) rates (LBR) and safety parameters in women undergoing ovarian stimulation for in vitro fertilization treatment. Design: Systematic review with individual patient data meta-analysis. Setting: Not applicable. Patients: Women undergoing ovarian stimulation for in vitro fertilization treatment. Interventions: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Web of Science to identify eligible phase 3 trials between January 1, 2000, and February 1, 2023. Main Outcome Measures: All analyses were based on individual participant data. We used a general linear mixed effects logistic regression model using fixed effects for treatment drugs interacting with log (AMH) level, age, and random effects for country and trial to compare the primary efficacy and safety outcomes of LB and early ovarian hyperstimulation syndrome (OHSS) and/or the need for OHSS preventative measures, with ovarian stimulation parameters and neonatal outcomes also assessed. PROSPERO registration: CRD42023399711. Results: Three trials met inclusion criteria and included 2,685 women undertaking 2,682 cycles between October 2013 and May 2020, with LB follow-up through to February 1, 2023. For women with an elevated AMH level (≥15 pmol/L), there was high-quality evidence that the use of individualized dosing of follitropin delta was associated with an increased LB rate (adjusted odds ratio [adj OR] 1.64, 95% confidence interval [CI] 1.14, 2.36). Safety outcomes were also improved with a reduced risk of both early OHSS and/or the need for preventative interventions (adj OR 0.27, 95% CI 0.15, 0.49) and early moderate or severe OHSS (adj OR 0.30, 95% CI 0.16, 0.58). These improvements in outcomes were obtained with a lower total dose of gonadotropin (−48.7 μg, 95% CI −53.7, −43.8) and no adjustments in the daily dose. In contrast, similar LB rates (adj OR 0.86, 95% CI 0.63, 1.17) and safety outcomes (adj OR 1.92, 95% CI 0.76, 4.87) were observed for women with an AMH level of <15 pmol/L. There were no clinically meaningful differences in neonatal outcomes. Conclusion: Using follitropin delta in an AMH level and weight-based algorithm rather than conventional licensed dosing of follitropin alpha or beta for ovarian stimulation in women is associated with improved LB rates and safety outcomes for women with elevated AMH levels.