Recommendations for the management of GnRH-ant for ovarian stimulation in the assistant reproductive process: Benefits and harms for different ovarian response population.

Introduction: Gonadotropin-releasing hormone antagonists (GnRH-ant) are commonly used during controlled ovarian stimulation (COS) in the in vitro fertilization (IVF) process to prevent premature luteinization and to ensure follicles mature synchronously. The 2020 guideline from European Society of Human Reproduction and Embryology (ESHRE) recommends the use of GnRH-ant for patients with varying levels of ovarian response. However, the question of how to manage the protocol pathway for these patients requires further investigation. Methods: The current clinical practice guideline (CPG) adheres to the World Health Organization's (WHO) recommended development process, and covers eight clinical questions, all focusing on the application of GnRH antagonists in COS. We conducted Cochrane-standard systematic reviews, utilized GRADE for evidence certainty assessment, and employed GRADE Evidence-to-Decision Framework to derive recommendations. We pre-defined clinically important outcomes, and the common critical outcomes shared by all clinical questions as follows: live birth rate, implantation rate, clinical pregnancy rate, and moderate to severe ovarian hyperstimulation syndrome (OHSS). We strictly followed the RIGHT guideline and AGREE-II criteria throughout the CPG development. Recommendations: The guideline development group (GDG) agreed on 14 recommendations on the application of GnRH-ant during COS. In summary, low certainty of evidence supported the benefits of using GnRH-ant protocol in IVF patients with high ovarian response (HOR), following with very low certainty of evidence to use Oral Contraceptive Pill (OCP) or estrogen as pretreatment in normal ovarian response (NOR) patients, low certainty of evidence to use fixed GnRH-ant protocol and very low certainty of evidence to use GnRH agonist (GnRH-a) add on trigger. For patients using GnRH-ant protocol, very low certainty of evidence in HOR patients and low certainty of evidence in NOR patients supported the "freeze-all" strategy considering the potential risk associated with fresh embryo transfer. However, multiple fresh embryo transfer may still provide benefits in some cases.