Background The gonadotrophin-releasing hormone antagonist (GnRH-ant) protocol in controlled ovarian stimulation (COS) has distinct advantages and become widespread. However, the dose-dependent disturbance of GnRH-ant on endometrial immune factors may negatively impact endometrial receptivity, potentially contributing to lower clinical pregnancy rates in fresh embryo transfer cycles, thereby diminishing the benefits of this protocol. Identifying strategies to mitigate these adverse effects on the endometrium is crucial for improving pregnancy outcomes in fresh embryo transfer cycles following this COS protocol. Prednisone, a primary immunosuppressive agent, has been proposed as a means to counteract the negative effects of GnRH-ant on the endometrium. This study designed a multi-center randomized clinical trial to compare the efficacy of combining prednisone with a fixed full-dose GnRH-ant protocol versus a flexible half-dose GnRH-ant protocol and a conventional fixed full-dose GnRH-ant protocol.

Methods and Findings We conducted a randomized, controlled, open-label clinical trial across three reproductive centers in China from April 2019 to November 2022, with follow-up completed in August 2023. Of the 5,042 identified patients aged 20 to 35 years undergoing in vitro fertilization and embryo transfer (IVF-ET) with the GnRH-ant protocol, 2,052 patients without contraindications for fresh embryo transfer were enrolled. Participants were randomly assigned to three groups: Group A received a fixed full-dose GnRH-ant combined with prednisone 10 mg per day from the start day of stimulation until 11 to 14 days after embryo transfer; Group B received a flexible half-dose GnRH-ant; and Group C received a fixed full-dose GnRH-ant. The primary outcome, clinical pregnancy rate (CPR), was defined as the ultrasound confirmation of an intrauterine gestation sac 30 to 35 days after embryo transfer, divided by the number of cases that underwent transfer. Of the enrolled patients, 1,512 (73.7%) underwent embryo transfer. Group A demonstrated a significantly higher CPR (63.1%) compared to Group B (54.7%; rate difference (RD) 8.4%, 95% confidence interval (CI) 2.4%–14.5%, P = 0.007) and Group C (46.4%; RD 16.7%, 95% CI 10.7%–22.7%, P < 0.001). The cancellation rate of fresh embryo transfer in Group A (18.7%) was similar to that in Group C (19.9%), but significantly lower than in Group B (24.1%). No significant differences in embryo laboratory results or in adverse events were observed among the groups.

Conclusions In patients undergoing IVF with the GnRH-ant protocol, the addition of low dose prednisone significantly improved the CPR without increasing adverse effects. These findings suggest an optimal strategy to enhance the success of the antagonist protocol in IVF-ET.

Trial registration Chinese clinical trial registry: ChiCTR1900021024.

The authors have declared no competing interest.

ChiCTR1900021024

https://www.chictr.org.cn/showproj.html?proj=32931

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Ruijin Hospital Ethics Committee, Shanghai JiaoTong University School of Medicine

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