Cost-Effectiveness and Clinical Outcomes of Controlled Ovarian Stimulation With Follitropin Delta and Follitropin Alfa: A Retrospective Study

Abstract

Aim: This study compared the cost-effectiveness of two recombinant follicle-stimulating hormones (rFSH) formulations, Follitropin Delta and Follitropin Alfa, in controlled ovarian stimulation using cumulative live birth rates as an efficacy indicator.

Methodology: This retrospective study was conducted across five clinics in Japan from April 2022 to December 2023, involving 446 first assisted reproductive technology (ART) cycles (200 with Follitropin Delta and 246 with Follitropin Alfa) were treated with rFSH monotherapy using either Follitropin Delta or Follitropin Alfa. We compared clinical outcomes such as cumulative pregnancy and live birth rates and analyzed cost-effectiveness using the cumulative live birth rates as the efficacy indicator and the incremental cost-effectiveness ratio (ICER).

Results: The Follitropin Delta group had a significantly lower incidence of ovarian hyperstimulation syndrome (15.90% vs. 27.00%, P = 0.045) and higher cumulative pregnancy rates than the Follitropin Alfa group (87.30% vs. 76.20 %; P = 0.03) after propensity score matching (PSM). Although cumulative live birth rates showed no significant differences (85.70% vs. 76.20%, P = 0.08) and Follitropin Delta demonstrated higher cost than Follitropin AlfaFollitropin Alfa (832,036 yen and 826,936 yen), ICER indicated low costs per percentage of live births (538.58 yen/%: 95% confidence interval [CI]: 275.34-12,568.69 yen).

Conclusions: Using Follitropin Delta for controlled ovarian stimulation in ART may be more cost-effective than Follitropin Alfa under Japan's Health Care Insurance System, offering higher cumulative live birth rates and minimal additional costs.

Keywords: cost effectiveness; cumulative live birth rate; follitropin alfa; follitropin delta; incremental cost-effectiveness ratio (icer).

Figure 1. Flowchart of patient selection and score matching process.

This flowchart illustrates the patient selection process and score matching for Delta and Alfa groups in a clinical study. This flowchart highlights the systematic approach to ensure balanced comparison between the two groups. Image credit: Masato Kobanawa HMG, human menopausal gonadotropin; uFSH, urinary follicle-stimulating hormone; AMH, anti-Müllerian hormone; AFC, antral follicle count; COS protocol, controlled ovarian stimulation protocol; FET protocol, frozen embryo transfer protocol

Figure 2. Decision tree: OPU freezing and frozen embryo transfer.

The decision tree illustrates the number of components in each process of assisted reproductive treatment under the Japanese insurance system, along with the method for calculating the expected values. Image credit: Masato Kobanawa OPU, oocyte pick-up; ET, embryo transfer; ICSI, intracytoplasmic sperm injection; c-IVF, conventional in vitro fertilization

Figure 3. Comparison of cumulative cost to each process between two groups before PSM.

(A) Comparison of cumulative cost between the two groups before PSM. Each process is from COS to OPU, fertilization, vitrification, embryo transfer, and live birth. The cumulative cost is the sum of the expected values of each process. (B) The bar graph illustrates the total expenses incurred by patients from COS to live births in two groups. PSM, propensity score matching; COS, controlled ovarian stimulation; OPU, oocyte pick-up

Figure 4. Histogram of ICER before PSM, calculated using the bootstrap method.

This graph shows the distribution of ICER for different cumulative live birth rate differences. The ICER represents the cost per 1% increase in live birth rates. A total of 1,000 bootstrap samples were generated, with live birth rate differences ranging from 3.6% to 15.0% (95% confidence interval [CI]) and a fixed cost difference of 9,620 yen. The dashed line indicates the median ICER value. ICER, incremental cost-effectiveness ratio

Figure 5. Comparison of cumulative cost to each process between two groups after PSM.

(A) This graph shows the comparison of cumulative cost between the two groups after PSM. Each process is from COS to OPU, fertilization, vitrification, embryo transfer, and live birth. The cumulative cost is the sum of the expected values of each process. (B) This bar graph illustrates the total expenses incurred by patients from COS to live births in two groups. PSM, propensity score matching; COS, controlled ovarian stimulation; OPU, oocyte pick-up

Figure 6. Histogram of ICER after PSM, calculated using the bootstrap method.

This graph displays the distribution of ICER for different cumulative live birth rate differences based on a bootstrap analysis. The ICER measures the cost per 1% increase in live birth rates. A total of 1,000 bootstrap samples were generated, with cumulative live birth rate differences ranging from -0.1% to 19.1% (95% confidence interval [CI]) and a fixed cost difference of 5,100 yen. The dashed line represents the median ICER value. ICER, incremental cost-effectiveness ratio; PSM, propensity score matching

Figure 7. Cost-effectiveness acceptability curve (CEAC).

This CEAC shows the probability that the intervention is cost-effective, given a cost difference of 5,100 yen and a cumulative live birth rate difference range of -0.1% to 19.1%. The X-axis represents the willingness-to-pay (WTP) from 0 to 30,000 yen (¥), and the Y-axis shows the probability of cost-effectiveness. The curve rises sharply, reaching nearly 100% around a WTP of 10,000 yen, and then levels off. This suggests that the intervention is highly cost-effective at WTP values above 10,000 yen.