Triggering oocyte maturation in in vitro fertilization treatment in healthy responders: a systematic review and network meta-analysis

Objective: To compare efficacy and safety of human chorionic gonadotropin (hCG), gonadotropin-releasing hormone (GnRH) agonist, dual, and double triggers in predicted healthy responders undergoing ovarian stimulation and in vitro fertilization.

Design: A systematic review and network meta-analysis of randomized controlled trials (RCTs).

Data sources: Randomized controlled trials indexed in PubMed, MEDLINE, EMBASE, clinical trial registries, and Cochrane Database of Systematic Reviews up to December 2023.

Study selection and synthesis: Twelve high-integrity RCTs comprising 1,931 women were included, which compared hCG trigger with GnRH agonist trigger, dual trigger, and double trigger. Statistical analysis was performed using STATA version 16.

Main outcome measures: Key outcomes included clinical pregnancy rates (CPR), live birth rates (LBR), number of oocytes, number of mature oocytes, miscarriage rates, and rates of ovarian hyperstimulation syndrome.

Results: The network meta-analysis for CPR were risk ratio (RR), 1.13; (95% confidence interval [CI], 0.80-1.60) for hCG vs. GnRH agonist trigger, RR, 1.23 (95% CI, 0.92-1.65) for hCG vs. dual trigger, RR, 0.38 (95% CI, 0.21-0.69) for hCG vs. double trigger, RR, 1.09 (95% CI, 0.70-1.70) for GnRH agonist vs. dual trigger and 0.34 (95% CI, 0.17-0.67) for GnRH agonist vs. double trigger, and RR, 0.31 (95% CI, 0.16-0.60) for double vs. dual trigger. Dual trigger demonstrated the highest Surface Under the Cumulative Ranking (85.1%), indicating superior efficacy for CPR. For LBR, although connectivity was limited, the RR was 1.31 (95% CI, 1.00-1.70) for dual vs. hCG trigger, and RR, 1.60 (95% CI, 1.05-2.43) for dual vs. GnRH agonist trigger. Ovarian hyperstimulation syndrome rates were significantly lower with the GnRH agonist compared with hCG trigger (RR, 0.56; 95% CI, 0.19-1.75). There were no RCTs reporting ovarian hyperstimulation syndrome rates with the use of dual or double trigger. No significant differences were observed in the number of oocytes retrieved, mature oocytes, or miscarriage rates among the trigger protocols.

Conclusion and relevance: The findings indicate that there is no evidence to suggest that using GnRH agonist, dual, or double protocols is superior to hCG trigger in improving CPR. Although LBR may benefit from dual trigger, results are limited by available RCTs. Larger, multicenter trials are needed for further evaluation of LBR and understanding of long-term outcomes.