Importance: For women undertaking assisted conception, the dose of gonadotropin has historically been driven by clinical experience. A different and individualised strategy was developed for follitropin delta, a human cell line derived recombinant follicle stimulating hormone, with dose based on anti-Müllerian hormone (AMH) stratification; for women with a high ovarian reserve (AMH ≥15pmol/l; approx. 2.1ng/ml) the dose is based on the combination of AMH and body weight in a continuous manner. The clinical effectiveness of this approach to dosing for ovarian stimulation on live birth and safety is unknown.
Objective: Undertake a one-stage meta-analysis of individual patient data from randomised trials comparing individualised dosing of follitropin delta versus other forms of follitropin (alpha, beta) for live birth rates and safety parameters in women undergoing ovarian stimulation for IVF.
Evidence review: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science to identify eligible phase 3 trials between Jan 1 2000 and Feb 1 2023. All analyses were based on individual participant data. We used a general linear mixed effects logistic regression model using fixed effects for treatment drug interacting with log(AMH), age, and random effects for country and trial to compare the primary efficacy and safety outcomes of live birth 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.
Findings: Three trials met inclusion criteria and included 2685 women undertaking 2,682 cycles between October 2013, and May 2020, with live birth follow-up through to February 1, 2023. For women with an elevated AMH (≥15 pmol/L), there was high quality evidence that the use of individualised dosing of follitropin delta was associated with an increased live birth rate (adjusted OR 1.64, 95%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 (-48.7μg, 95%CI -53.7, -43.8) and no adjustments in the daily dose. In contrast, similar live birth 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 <15pmol/l. There were no clinical meaningful differences in neonatal outcomes.
Conclusion and relevance: Using follitropin delta in an AMH and weight-based algorithm rather than conventional licenced dosing of follitropin alpha or beta for ovarian stimulation women is associated with improved live birth rates and safety outcomes for women with elevated AMH levels.
Keywords: Follitropin delta; anti- Müllerian hormone; in-vitro fertilisation; live birth; ovarian hyperstimulation syndrome.
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