The cumulative live birth rates of 18 593 women with progestin-primed ovarian stimulation-related protocols and frozen-thawed transfer cycles

Abstract

Study question: What are the odds of achieving pregnancy when adopting progestin-primed ovarian stimulation (PPOS)-related protocols combined with repetitive frozen-thawed transfer (FET) cycles in patients with different clinical characteristics?

Summary answer: The cumulative live birth rates (CLBRs) of women undergoing different PPOS-related protocols can be significantly and consistently enhanced within six FET cycles when the female age is <40 years (or even <45 years) and when >5 oocytes are retrieved, regardless of antral follicle count (AFC).

What is known already: There have been numerous studies on the live birth rate of the first FET cycle in patients with PPOS-related protocols. These studies have focused mainly on comparing pregnancy outcomes with those of other stimulation protocols. However, owing to the unique features of the PPOS-related strategy, such as its flexible timing of oocyte retrieval and repeated transfer of frozen embryos, studies using the CLBR as an overall indicator of success and investigating which types of patients would benefit from this protocol are lacking.

Study design size duration: This retrospective cohort study included 18 593 women who underwent PPOS-related protocols (dydrogesterone + hMG, medroxyprogesterone acetate + hMG, micronized progesterone + hMG treatment, and luteal-phase ovarian stimulation protocol) from 1 March 2011 to 31 September 2022 in our centre.

Participants/materials setting methods: The population was categorized by female age, number of oocytes retrieved, and AFC in the analysis of CLBR within six FET cycles. The age groups (Groups 1-5, respectively) were <30, 30-34, 35-39, 40-44, and ≥45 years. The number of oocytes retrieved was grouped as 1-5, 6-10, 11-15, 16-20, and >20. AFC was grouped as <5, 5-10, 11-15, and >15. The Kaplan-Meier analysis (optimistic method), which hypothesized that patients who did not continue treatment had the same chance of achieving a live birth as those who continued, and the competing risk method (conservative method) which hypothesized they had no chance of achieving a live birth, were applied. In further analyses, the Cox model and Fine-Gray model were adopted: the former corresponds to the optimistic scenario, and the latter corresponds to the pessimistic scenario.

Main results and the role of chance: CLBR had a declining trend with female age over six FET cycles (Groups 1-5, respectively: optimistic: 96.9%, 96.6%, 91.4%, 67.3%, and 11.7%; conservative: 87.3%, 85.0%, 74.0%, 41.3%, and 7.5%), requiring more FET cycles to achieve a success rate of at least 50% (Groups 1-5, respectively: optimistic: 2, 2, 2, 4, and >6 cycles; conservative: 2, 2, 2, >,6 and >6 cycles). CLBR showed an increasing trend with the number of oocytes retrieved (Groups 1-5, respectively: optimistic: 93.8%, 94.3%, 95.8%, 96.0%, and 95.6%; conservative: 66.2%, 78.3%, 85.6%, 88.9%, and 91.0%). All groups needed the same number of FET cycles to achieve a success rate of at least 50% (Groups 1-5, respectively: optimistic: 2, 2, 2, 2, and 2 cycles; conservative: 2, 2, 2, 2, and 2 cycles). Furthermore, the CLBR within six FET cycles had an increasing trend with AFC number (Groups 1-4, respectively: optimistic: 89.2%, 94.8%, 95.9%, and 96.3%; conservative: 67.4%, 78.2%, 83.9%, and 88.1%), with all four groups achieving a success rate of at least 50% by the second FET cycle.

Limitations reasons for caution: The current research is limited by its retrospective design and single-centre nature, which may restrict the generalizability of our findings.

Wider implications of the findings: This work describes two models (the Kaplan-Meier analysis and the competing risk method) to evaluate the clinical outcome of patients using PPOS-related protocols, which are especially useful for patients of advanced age or those with diminished ovarian reserve. Our findings encourage patients below 45 years old, especially younger than 40 years, and patients with lower AFCs and fewer retrieved oocytes to try this new protocol. Moreover, this study demonstrates the degree of improvement in the CLBR within six FET cycles for patients with different clinical characteristics, providing a valuable point of reference to determine whether to continue ART after a transfer failure.

Study funding/competing interests: The study was supported by grants from the National Natural Science Foundation of China (82071603 to L.W., 82001502 to Y.L.). There are no conflicts of interest to declare.

Trial registration number: N/A.

Keywords: ART; ICSI; IVF; cumulative live birth rate; frozen embryo transfer; progestin-primed ovarian stimulation-related protocol.

Figure 1.

Flowchart illustrating the study population, including the criteria for inclusion and exclusion. Patients with pure PPOS-related protocols were included in the primary analysis, while patients with non-pure PPOS-related protocols were included in the supplementary analysis. Patients enrolled in pure PPOS-related protocols exclusively underwent ovarian stimulation cycles utilizing dydrogesterone + hMG, medroxyprogesterone acetate + hMG, micronized progesterone + hMG treatment, or luteal-phase ovarian stimulation protocol. Patients enrolled in non-pure PPOS-related protocols underwent ovarian stimulation cycles involving alternative stimulation protocols, not limited to these PPOS-related ovarian stimulation protocols. PPOS, progestin-primed ovarian stimulation; FET, frozen-thawed transfer; CLBR, cumulative live birth rate; AFC, antral follicle count.

Figure 2.

Cumulative live birth curves for patients undergoing six frozen embryo transfer cycles, stratified by female age, number of oocytes retrieved and antral follicle count. (A) The women were categorized by age (years). The CLBR was calculated by Kaplan–Meier analysis (the optimistic method) (A1) and the competing risk method (the conservative method) (A2). (B) The women were stratified according to the number of oocytes retrieved from their first oocyte retrieval cycle. The CLBR was calculated by Kaplan–Meier analysis (the optimistic method) (B1) and the competing risk method (the conservative method) (B2). (C) The women were stratified according to the AFC. The CLBR was calculated by Kaplan–Meier analysis (the optimistic method) (C1) and the competing risk method (the conservative method) (C2). The result of the pairwise comparison between the five groups is displayed by an adjusted pairwise log-rank test. P < 0.05 was significant. The distinct letters a, b, c, d, and e above the group legends indicate statistically significant differences between the groups. CLBR, cumulative live birth rate; FET, frozen embryo transfer; AFC, antral follicle count.

Figure 3.

Factors influencing the cumulative live birth rate (CLBR) within six frozen embryo transfer cycles. The impact of female age (years), the number of oocytes retrieved, antral follicle count (AFC), and female BMI (kg/m²) on the CLBR was assessed using both the Cox model (A) and Fine–Gray model (B) under multivariable analysis. The following factors were adjusted for in both models: duration of infertility, male age, infertility type, infertility reason, PCOS, oocyte pick-up (OPU) number, frozen embryo transfer number, total oocyte number, total embryo number, number of embryos transferred, number of good-quality embryos transferred, and the patient’s first OPU year. Statistical significance was accepted at P < 0.05. The reference groups were defined as <30 years for female age, 1–5 for number of oocytes recovered, and <5 for AFC. HR, hazard ratio; CLBR, cumulative live birth rate; AFC, antral follicle count.