Intrauterine hCG for IVF patients improves pregnancy rates

A 2022 meta-analysis combined the results of 18 studies, finding that intrauterine hCG improved clinical pregnancy rates in IVF patients, with no change in miscarriage rates.

Intrauterine hCG involves administration of hCG using a catheter into the uterus before embryo transfer. Intrauterine hCG may improve IVF success rates by making the endometrium more receptive to implantation.

This post reviews a meta-analysis by Conforti et al. (2022), who combined the results of 18 randomized controlled trials (RCTs) that evaluated intrauterine hCG in IVF patients.

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Higher pregnancy rate after intrauterine hCG

This meta-analysis found an increase in clinical pregnancy rates for patients who had intrauterine hCG vs those who didn’t (42.5% vs 34.7%, risk ratio [95% CI]: 1.38 [1.17-1.62]; 17 studies, 4391 patients; I2= 69%).

They split the data up into subgroups, and combined studies that involved only blastocysts, only blastocysts OR cleavage stage embryos, and only cleavage stage embryos.

• Most studies involved only cleavage stage transfers, and there was an increase in clinical pregnancy rates for this group (45.1% vs 33.1%, risk ratio [95% CI]: 1.39 [1.15-1.67]; 12 studies, 2564 patients; I2= 65%).
• There wasn’t any difference when only looking at the blastocyst transfer studies (4 studies, 1429 patients).
• Studies that included blastocyst OR cleavage stage transfers showed a benefit.

No change in miscarriage rates and other outcomes with intrauterine hCG

Thirteen studies were combined that showed that patients who received intrauterine hCG had no change in miscarriage rates (13 studies, 1474 patients, I2= 34%). This was also seen for studies that involved only blastocysts, only blastocysts OR cleavage stage embryos, and only cleavage stage embryos.

There was also no difference in live birth rates (5 studies, 2238 patients, I2= 67%).

There was no difference in the rate of adverse pregnancy outcomes, including ectopic pregnancy rates (9 studies, 1887 patients, I2= 0%) and stillbirths (3 studies, 1078 patients, I2= 0%).

Conclusions

This study found an improvement in clinical pregnancy rates in IVF patients that had intrauterine hCG treatment. Patients that had intrauterine hCG showed no increases in miscarriage rates, live birth rates, or adverse pregnancy outcomes (ectopic pregnancies and stillbirths).

The increase in pregnancy rates was only seen in patients who transferred cleavage stage embryos. It’s not clear why this is the case, but other studies that weren’t included in this meta-analysis have found a benefit with blastocyst transfers.

Studies have shown the hCG can support early pregnancy by promoting embryo implantation, for example by promoting the invasion of the embryo into the decidua, and causing the expression of key receptors involved in implantation.

The results of this study are essentially an update to the 2018 Cochrane review, which included fewer RCTs and found similar results. Another 2019 meta-analysis that combined 15 studies also found an improvement in clinical pregnancy rates, along with an increase in live births and a decrease in miscarriage rates. You can read more about this study in my post hCG injection before embryo transfer improves success rates.

There was quite a bit of variability in the RCTs (heterogeneity — dictated by the high “I2” percentages in the results, check the glossary for clarification). This is because the studies were conducted differently: some used different amounts of hCG (ie. 500 IU, 1000 IU), different times of administration (ie. before ET, during egg retrieval), included different patients (ie. some with or without implantation failures, different age ranges), or different stages of embryos transferred. Additionally, 11 of the RCTs presented here had a high risk of bias (lack of blinding, incomplete outcome data, most studies had a regional bias and involved women from the Middle East). The authors state that higher quality RCTs are needed.

There was a recent 2024 meta-analysis conducted on this topic that included different study designs (mostly retrospective and prospective) in RIF patients, which had lower heterogeneity and provided some interesting details not seen here:

• Improvement in clinical pregnancy rate (47.8% vs 33.9%, risk ratio [95% CI]: 1.42 [1.28-1.57]; 13 studies, 2157 patients; I2= 29%).
• Improvement in live birth rate (34.8% vs 23.6%, risk ratio [95% CI]: 1.57 [1.25-1.97]; 4 studies, 753 patients; I2= 0%).
• No change in miscarriage rates (11 studies, 744 patients, I2= 0%)
• Improvement in clinical pregnancy rates with certain hCG dosages (500 IU and 1000 IU hCG, but not 2000 IU).
• Improvements in clinical pregnancy rates regardless of the volume of hCG (<100, 500 or 1000 uL) or concentration (0.5, 1, 2, >5 IU/uL).
• Improvements in clinical pregnancy rates 3+ days before transfer or on the day of transfer, but not the day before transfer.
• Improvements in clinical pregnancy rate for fresh and frozen transfers.
• Improvement in clinical pregnancy rate using cleavage stage or blastocyst stage transfers.

(For those wondering — the reason I reviewed the 2022 meta-analysis here instead of this newer 2024 meta-analysis was because the 2022 study included only higher-quality RCT studies and was essentially an update of the 2018 Cochrane review. Many of studies in the 2024 meta-analysis were not RCTs and were Chinese, some of which I couldn’t access).

Reference

Conforti A, Longobardi S, Carbone L, Iorio GG, Cariati F, Campitiello MR, Strina I, Palese M, D’Hooghe T, Alviggi C. Does Intrauterine Injection of hCG Improve IVF Outcome? A Systematic Review and a Meta-Analysis. Int J Mol Sci. 2022 Oct 13;23(20):12193. doi: 10.3390/ijms232012193. PMID: 36293052; PMCID: PMC9603006.

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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.

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