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Network meta-analysis finds GnRHa trigger reduces OHSS risk versus hCG in predicted high responders undergoing IVFStudy compares four IVF trigger methods for women at high risk of over-response

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Key Takeaway
Consider GnRHa trigger for OHSS risk reduction in predicted high responders, but note live birth data are lacking.

This systematic review and network meta-analysis evaluated the efficacy and safety of four final oocyte maturation trigger strategies—human chorionic gonadotropin (hCG), gonadotropin-releasing hormone agonist (GnRHa), dual trigger, and double trigger—in predicted high responders undergoing in vitro fertilization (IVF) with GnRH antagonist protocols. The analysis included 7 high-quality randomized controlled trials (RCTs) comprising 632 women defined as high responders based on elevated antral follicle count, anti-Müllerian hormone, or estradiol levels.

The primary comparisons were between the different trigger strategies. The analysis found no statistically significant differences between any of the triggers for key efficacy outcomes: the number of oocytes retrieved, mature oocyte yield, clinical pregnancy rate, and miscarriage rate. However, for the critical safety outcome of moderate to severe ovarian hyperstimulation syndrome (OHSS), GnRHa trigger was associated with a significantly lower risk compared with hCG trigger, with a relative risk (RR) of 0.23 (95% CI 0.07 to 0.82). Comparisons for OHSS risk between dual trigger and hCG, and between GnRHa and dual trigger, were not significant.

Safety and tolerability data for the interventions were not reported in the analysis. A key limitation is that live birth outcomes were not evaluated, and the potential role of the double trigger in this population was not assessed. The authors note that larger multicenter RCTs are required to address these gaps. In practice, while GnRHa trigger appears to offer a superior safety profile regarding OHSS risk in this specific high-risk population, clinicians should interpret the lack of efficacy differences cautiously due to the absence of live birth data.

Researchers reviewed existing studies to compare four different hormone 'trigger' shots used at the end of IVF treatment. These shots help eggs mature before they are retrieved. The study focused on women who are predicted to have a high response to fertility drugs, meaning they produce many eggs, which also puts them at higher risk for a painful complication called ovarian hyperstimulation syndrome (OHSS).

The analysis combined data from 632 women across seven previous studies. It compared four trigger strategies: hCG, GnRHa, a dual trigger (both hCG and GnRHa), and a double trigger (two doses). The main goal was to see which method worked best and was safest.

The review found no significant differences between the four methods in key outcomes like the number of eggs retrieved, the number of mature eggs, clinical pregnancy rates, or miscarriage rates. However, using a GnRHa trigger was associated with a much lower risk of developing moderate to severe OHSS compared to using hCG alone.

It's important to be cautious because this was a review of other studies, not a new clinical trial. The most critical outcome for patients—how many treatments resulted in a live birth—was not evaluated in this analysis. The results suggest that for women at high risk of OHSS, a GnRHa trigger may be a safer option, but more research is needed to confirm its effects on having a baby.

What this means for you:
For high responders in IVF, different trigger shots had similar pregnancy results, but one may lower OHSS risk. Live birth data is still needed.

Study Details

Study typeMeta analysis
EvidenceLevel 1
PublishedApr 2026
View Original Abstract ↓
ObjectiveThe aim of this study was to compare and rank the efficacy and safety of four final oocyte maturation trigger strategies—human chorionic gonadotropin (hCG), gonadotropin-releasing hormone agonist (GnRHa), dual, and double trigger—in predicted high responders undergoing in vitro fertilization (IVF) with GnRH antagonist protocols, using a network meta-analysis (NMA) approach.MethodsA systematic search of MEDLINE, EMBASE, CENTRAL, clinical trial registries, and the Cochrane Database of Systematic Reviews was conducted through December 2024. Eligible studies were randomized controlled trials (RCTs) including high responders, defined by elevated antral follicle count, anti-Müllerian hormone, or estradiol levels. Studies using GnRHa triggers followed by fresh embryo transfer were included only if intensive luteal phase support was provided. Oocyte donation cycles, quasi-randomized designs, and trials lacking outcome data were excluded. Data extraction and risk of bias assessment were independently conducted by two reviewers. Study integrity was evaluated using the TRACT checklist. NMA was performed in STATA (v16), and treatment ranking was based on Surface Under the Cumulative Ranking curve (SUCRA).ResultsSeven high-quality RCTs comprising 632 women were included. There were no significant differences in the number of oocytes retrieved between GnRHa and hCG triggers (mean difference [MD] 1.08, 95% CI –1.06 to 3.22), dual and hCG (MD 0.61, 95% CI –1.53 to 2.74), or GnRHa and dual (MD 1.08, 95% CI –1.06 to 3.22). Similarly, there were no significant differences in mature oocyte yield, clinical pregnancy rate (CPR), or miscarriage rate across comparisons. However, GnRHa trigger significantly reduced the risk of moderate to severe ovarian hyperstimulation syndrome (OHSS) compared with hCG (RR 0.23, 95% CI 0.07–0.82). There were no significant differences in OHSS risk between dual and hCG (RR 0.28, 95% CI 0.05–1.64) or between GnRHa and dual (RR 0.28, 95% CI 0.05–1.64).ConclusionGnRHa, hCG, and dual triggers demonstrate similar efficacy in terms of oocyte yield, maturity, and clinical pregnancy rates in predicted high responders. The GnRHa trigger, however, offers a superior safety profile by significantly lowering the risk of OHSS. Larger multicenter RCTs are required to evaluate live birth outcomes and the potential role of the double trigger in this population.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022351423.
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