Dual trigger with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin versus gonadotropin-releasing hormone agonist alone in predicted high responders using antagonist protocol: a systematic review and meta-analysis

Optimizing oocyte maturation in high ovarian responders undergoing in vitro fertilization is crucial for reproductive outcomes and minimizing ovarian hyperstimulation syndrome (OHSS). It remains uncertain whether a gonadotropin-releasing hormone agonist (GnRH-a) combined with low-dose hCG (dual trigger) provides advantages over GnRH-a. This meta-analysis evaluated the efficacy and safety of dual trigger versus GnRH-a trigger in high ovarian responders. A systematic search of PubMed, Embase, Web of Science, the Cochrane Library, and China National Knowledge Infrastructure was conducted to identify randomized controlled trials (RCTs) and cohort studies comparing dual trigger with GnRH-a trigger alone in high responders. The primary outcomes were metaphase II (MII) oocyte rate and moderate or severe OHSS. Secondary outcomes included the number of retrieved oocytes, embryos, and high-quality embryos; normal fertilization rate; clinical pregnancy rate (CPR); miscarriage rate; and live birth rate. The study analyzed binary and continuous variables using relative risk (RR) and weighted mean difference (WMD), with 95% CI. Fourteen studies (2 RCTs and 12 cohort studies) involving 4,427 women were included. Dual trigger did not improve MII oocyte rates compared with GnRH-a alone (WMD = 0.52; 95% CI: -1.37, 2.42; 11 studies) but significantly increased the risk of moderate or severe OHSS (RR = 4.42; 95% CI: 2.44, 8.01; 10 studies). None of the prespecified secondary outcomes differed significantly between the dual trigger and GnRH-a groups. Among women undergoing fresh embryo transfer (ET), dual trigger had a higher CPR (RR = 1.33; 95% CI: 1.15, 1.54; 4 studies) and a higher risk of OHSS (RR = 6.29; 95% CI: 0.94, 41.84; 3 studies). An increased risk of OHSS remained in dual trigger with hCG ≤ 1000 IU, with statistical imprecision (RR = 11.43, 95% CI: 1.49, 87.73; 3 studies). PROSPERO: CRD420251003498. This meta-analysis found that dual trigger with GnRH-a and low-dose hCG did not improve oocyte maturation or reproductive outcomes compared with GnRH alone and was associated with an increased risk of moderate or severe OHSS in high responders. The higher CPR in the fresh ET subgroup was exploratory and based on limited studies. More randomized trials are needed to identify the best trigger options.