O-114 Improved safety and efficiency of individualised versus conventional gonadotropin dosing for ovarian stimulation in IVF/ICSI: an individual patient meta-analysis (IPD-MA)
Authors: Janse F , Eijkemans M , Fauser B 
Published: August 2021

Abstract

Study question
Does an individualised, weight- and AMH-based dosing approach with follitropin delta improve live birth rate, safety, and efficiency, compared to conventional dosing in IVF/ICSI?

Summary answer
Individualised ovarian stimulation performs similarly for live birth rate (increased in normal-high AMH), and reduces the incidence of OHSS and total FSH dosage.

What is known already
Previous studies investigated the effect of individualized gonadotropin dosing in IVF/ICSI using ovarian reserve tests such as anti-Müllerian hormone (AMH) and antral follicle count (AFC). A Cochrane Review concluded that individualised dosing in IVF is associated with a reduction of ovarian hyperstimulation syndrome (OHSS), but no effect on live birth rate. It is hypothesized that an individualised dosing approach is predominantly beneficial in the patients who are potentially normal or high responders. This study addresses the performance of a new human recombinant FSH (follitropin delta) with individualised dosing based on AMH and body weight.

Study design, size, duration
This is an individual participant data meta-analysis (IPD-MA) of three follitropin delta phase 3 trials, executed in Europe and North- and South America, South-East Asia, and Japan. All trials were randomized, controlled, assessor-blinded, multicenter studies in which individualised follitropin delta vs. conventional follitropin alpha or beta were compared. Women were followed from inclusion, at start of their first fresh IVF/ICSI cycle, until 4 weeks after live birth.

Participants/materials, setting, methods
Women aged 20-40 yrs, undergoing their first IVF/ICSI cycle, were randomly assigned to follitropin delta (AMH &lt; 15 pmol/L: 12 µg/day; AMH ≥ 15 pmol/L: 0.10-0.19 µg/kg/day: maximum 12 µg/day) or conventional follitropin alpha or beta (150 IU/day for 5 days, possible subsequent dose adjustments). The IPD-MA was performed using logistic regression analysis. Planned subgroup analyses were performed for expected normal/high responders (serum AMH ≥15 pmol/L), and expected low responders (serum AMH &lt;15 pmol/L).

Main results and the role of chance
Nearly 2,700 women were randomised and exposed: n = 1,348 for conventional dosing regimen with follitropin alpha or beta, and n = 1,334 for individualised dosing with follitropin delta. Live birth rate was similar for both groups (29.5% in follitropin delta vs. 26.9% in follitropin alpha/beta; OR 1.14 (0.96-1.35)). However, in expected normal to high responders live birth rate was significantly increased for those receiving individualised follitropin delta (31.4% vs. 25.9%; OR 1.31 (1.06 - 1.62)). Mean number of transferred embryos/blastocysts was comparable (0.95 vs. 0.94, respectively; mean difference 0.0076; NS), and did not differ when subgroup analyses were performed for normal/high AMH and low AMH. The occurrence of early OHSS was significantly reduced in individualised follitropin delta (4.0% vs. 6.4%; OR 0.62 (95% CI 0.43-0.88)), in subgroup analyses a similar reduction was identified. Total dosage of FSH was significantly lower in individualized follitropin delta (84.5 vs. 112.1 µg; mean difference -27.5 µg (95% CI -30.0 - -25.1)), with a more pronounced effect in normal to high AMH (mean difference -36.5 µg (95% CI -39.2 - -33.7)). Gestational age and birth weight were similar. The IPD-MA identified similar findings among women from the three studies with their different ethnic backgrounds.

Limitations, reasons for caution
For individualised dosing with follitropin delta, it was observed that the number of cryopreserved embryos was significantly lower (2.4 vs. 3.0, mean difference -0.67 (p &lt; 0.05)), and it remains unclear whether this affects cumulative live birth rate.

Wider implications of the findings
Individualised dosing with gonadotropin delta is similarly successful in terms of live birth (increased for normal-high AMH women), reduces safety risks, and is more effective with regard to gonadotropin dosage, compared with conventional dosing in IVF/ICSI. Treatment costs are reduced by prescription of lower gonadotropin doses and OHSS reduction.

Trial registration number
NCT01956110, NCT03228680, NCT03296527