Meta-analysis combines results of 12 studies that compare IVF trigger shots

A 2024 meta-analysis combined the results of 12 studies comparing different IVF trigger shots, including hCG, GnRH agonist, and dual and double triggers. Triggers showed variable outcomes, highlighting the need for a personalized medicine approach.

In IVF, the hCG trigger is used to trigger final egg maturation so the eggs can be retrieved and fertilized. The trigger is meant to mimic the natural luteinizing hormone (LH) surge that initiates ovulation during the menstrual cycle. However, hCG can sometimes cause excessive reactions, leading to a potentially dangerous condition known as ovarian hyperstimulation syndrome (OHSS).

To reduce the risk of OHSS, GnRH agonist triggers have been used to induce an LH surge that mimics the natural LH surge in the body. However, GnRH agonists cause a shorter LH surge that can result in corpus luteum defects, resulting in lower pregnancy rates and higher miscarriages during fresh transfers (Humaidan et al. 2015).

This led to the development of new triggering methods for fresh transfers, such as the dual trigger and double trigger. Both methods combine a GnRH agonist with low-dose hCG, but the double trigger administers the two shots at separate times. These strategies help lower OHSS risks without compromising the corpus luteum.

This post is a summary of a meta-analysis by Beebeejaun et al. (2024), who combined the results of 12 randomized controlled trials that compared these different trigger types.

Only RCTs were included involving normal responders (8-15 eggs predicted at retrieval) doing a fresh transfer. Studies that used GnRH agonist triggers also included luteal phase support (progesterone supplementation). From 6179 publications, the researchers included 12 RCTs, representing nearly 2000 cycles.

In this study, researchers used both a pairwise and network meta-analysis. The pairwise meta-analysis allowed them to compare two treatments directly and assess outcomes like pregnancy rates. The network meta-analysis allowed them to evaluate multiple treatments simultaneously, helping determine the most effective and safe option.

As we’ll see, in some cases there’s differences with the network meta-analysis due to “indirect evidence.” This refers to conclusions drawn from comparisons between treatments that have not been directly compared in the same study but are connected through a common comparator in different studies. For example, if you have Treatment A compared to Treatment B in some studies, and Treatment B compared to Treatment C in other studies, you can indirectly estimate the effect of Treatment A versus Treatment C through their common comparison to Treatment B.

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🔗 Original studies are referenced in this post or within the linked Remembryo posts.

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Table of Contents

GnRH agonist trigger vs hCG trigger

Clinical pregnancy: No difference (3 studies, I2= 8%). Low quality of evidence.
Live birth rate: No difference (3 studies, I2= 85%). Low quality of evidence. The large I2 value indicates a high amount of variability in the studies.
Number of eggs retrieved: No difference in the pairwise meta-analysis (9 studies, I2= 91%), but there was an increase with GnRH in the network meta-analysis (increase of 2.35 eggs, 95% CI: 0.13-4.58, low quality of evidence).
Number of mature eggs: No difference (4 studies). Very low quality of evidence.
OHSS risk: Lower risk with GnRH vs hCG by about half (relative risk 0.56, 95% CI: 0.19-1.75, I2= 64%, 5 studies). Low quality of evidence.
Miscarriage rate: No difference (2 studies, I2= 44%). Low quality of evidence.

Overall, for GnRH agonist vs hCG as a trigger, the network meta-analysis suggests an increase in the number of eggs retrieved, and there is evidence of a decrease in OHSS risk, although these findings are based on low-quality evidence.

Dual trigger vs hCG trigger

Clinical pregnancy: No difference (4 studies, I2= 0%). Low quality of evidence. The low I2 value indicates that the results were consistent between studies.
Live birth rate: Increase in live birth rate with dual trigger by a factor of 1.31 (relative risk 1.31, 95% CI: 1.00-1.70, 1 study). Low quality of evidence.
Number of eggs retrieved: No difference (3 studies, I2= 0%). Low quality of evidence.
Number of mature eggs: No difference (13 studies). Low quality of evidence.
Miscarriage rate: No difference (2 studies, I2= 25%). Low quality of evidence.

Overall, for dual trigger vs hCG trigger, there was an increase in the live birth rate but this was based on only a single study and was rated as low quality. There were no differences in the other outcomes, based on low quality of evidence.

Double trigger vs hCG trigger

Clinical pregnancy: No difference (1 study). Very low quality of evidence.
Number of eggs retrieved: No difference (1 study). Low quality of evidence.
Miscarriage rate: No difference (1 study). Very low quality of evidence.

Overall, for double trigger vs hCG, there was no differences in the outcomes, but this was based on 1 study and the quality of evidence was very low to low.

Dual trigger vs GnRH agonist trigger

Clinical pregnancy: No difference (1 study). Low quality of evidence.
Live birth rate: Increased with dual trigger by a factor of 1.60 (relative risk 1.60, 95% CI: 1.05-2.43, 1 study). Very low quality of evidence.
Number of eggs retrieved: Increase in the number of eggs with the dual trigger by nearly 9 (mean difference 8.99, 95% CI: 3.26-14.72, 1 study). The network meta-analysis found no difference. Low quality of evidence.
Number of mature eggs: No difference (1 study). Low quality of evidence.
Miscarriage rate: No difference (1 study). Very low quality of evidence.

Overall, for dual trigger vs GnRH agonist, there was an increase in the live birth rate and number of eggs retrieved, although this was based on very low to low quality evidence.

Double trigger vs GnRH agonist trigger

Clinical pregnancy: Lower with GnRH by about a third (relative risk 0.34, 95% CI: 0.17-0.67, indirect evidence from the network meta-analysis). Very low quality of evidence.
Number of eggs retrieved: No difference. Low quality of evidence.
Miscarriage rate: No difference. Very low quality of evidence.

Overall, for double trigger vs GnRH agonist, there was a decrease in the clinical pregnancy rate (with GnRH agonist trigger), but no differences in the other outcomes, based on very low to low quality evidence.

Double trigger vs dual trigger

Clinical pregnancy: Lower with dual trigger by about a third (relative risk 0.31, 95% CI: 0.16-0.60, indirect evidence). Very low quality of evidence.
Number of eggs retrieved: No difference. Low quality of evidence.
Miscarriage rate: No difference. Very low quality of evidence.

Overall, for double trigger vs dual, there was a decrease in the clinical pregnancy rate (with the dual trigger), but no difference in the other outcomes, based on very low to low quality evidence.

Ranking trigger shots for IVF with a separate analysis

The researchers also did a Surface Under the Cumulative Ranking (SUCRA) analysis to rank different triggers. This analysis uses all available direct and indirect evidence from the network meta-analysis. The higher the SUCRA %, the better the treatment. If a SUCRA analysis is 100% for treatment A, then all other treatments are inferior to A.

Note that this is a separate analysis and may not agree with the results above.

For clinical pregnancy:

Dual trigger (85.1%) was the best
GnRH agonist trigger (70.6%)
hCG trigger (44.3%)
Double trigger (0%) was the worst

For the number of eggs retrieved:

Double trigger (87.2%) was the best
GnRH agonist trigger (67.7%)
Dual trigger (28.8%)
hCG trigger (16.2%) was the worst

For miscarriage rate:

Double trigger (70.6%) was the worst — it had the highest risk of miscarriage
Dual trigger (59.3%)
hCG trigger (47.7%)
GnRH agonist trigger (22.5%) was the best — it had the lowest risk of miscarriage

Conclusions

Compared to hCG, there was no difference in clinical pregnancy rates for any of the other triggers.

Clinical pregnancy rates were lower for GnRH agonist (vs double trigger) and for dual trigger (vs double trigger). Double trigger was best, which was confirmed with the SUCRA analysis.

Live birth rates were higher with the dual trigger (vs hCG and GnRH agonist triggers).

Number of eggs retrieved was increased with GnRH agonist (vs hCG) and with the dual trigger (vs GnRH agonist). Double trigger was best, based on the SUCRA analysis.

For the number of mature eggs, there was no difference between the triggers.

For miscarriage rates, there was no difference between the triggers. GnRH agonist was best, based on the SUCRA analysis.

OHSS rates were decreased with GnRH vs hCG, but no other triggers were examined.

Other meta-analyses have reported varying outcomes (linked below), with some indicating that hCG outperforms GnRH agonist, or that the dual trigger is more effective than hCG. The authors attribute these differences to their exclusive focus on high-quality RCTs in their meta-analysis.

Overall, some triggers may offer improvements, and the authors believe this highlights the need for personalized medicine approaches. They also emphasize the need for more RCTs to draw conclusions.

Related studies

To learn more about this topic, you can check out a number of studies referenced in this study below (3 links):

Reference

Beebeejaun Y, Copeland T, Duffy JMN, Sarris I, Showell M, Wang R, Sunkara SK. Triggering oocyte maturation in IVF treatment in normal responders: a systematic review and network meta-analysis. Fertil Steril. 2024 Nov 13:S0015-0282(24)02389-6. doi: 10.1016/j.fertnstert.2024.11.011. Epub ahead of print. PMID: 39547644.

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About Embryoman

Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.