Fresh or frozen embryo transfer? Results of the E-Freeze clinical trial

Researchers in a 2022 study reported on the results of the E-Freeze clinical trial that compared the pregnancy and perinatal/obstetric outcomes for fresh and frozen transfers. Overall, they found no statistically significant differences between the two groups.

In IVF, embryos can be transferred after oocyte retrieval in a “fresh” transfer, or can be frozen and transferred at a later time. In the case of frozen embryo transfers (FETs), there are a number of frozen transfer protocols that can be used.

There are some that believe frozen transfers are best in order to let the body recover after ovarian stimulation. Women may also be at higher risk of severe ovarian hyperstimulation syndrome (OHSS) during a fresh cycle, particularly after using hCG as a trigger and becoming pregnant (which produces additional hCG). However, OHSS is still possible with frozen transfers, as was the case with a woman who used a programmed FET cycle and had a triplet pregnancy (Yang et al. 2020).

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Maheshwari et al. (2022) compared 307 women who had a frozen embryo transfer to 309 women who had a fresh transfer, across 18 IVF clinics in the UK between 2016 and 2019. Most (>90%) transfers involved blastocysts and >80% of transfers were a single embryo. The average age was around 35 for both groups and women who had a clinical indication for OHSS before transfer, which would require embryo freezing, were excluded from this trial. Frozen transfers were done within 3 months of the retrieval.

In terms of pregnancy outcomes, there were no statistical differences between the groups for clinical pregnancy, live birth, or miscarriage. They also reported on the “healthy baby rate” which was the chance of a singleton birth at term with an appropriate weight – this was also not statistically significant between the fresh and frozen groups (24.4% vs 20.3%).

For OHSS, 3.6% of patients who had a frozen transfer developed it (with no severe cases), compared to 8.1% in the fresh transfer group (with 1.9% being severe cases). This was not statistically significant. Note: the authors state that this may be due to most participants receiving hCG as a trigger during the retrieval, however since FETs were scheduled within 3 months of the retrieval (and the hCG trigger should be gone within 2 weeks), I’m not sure how this explains OHSS in the frozen transfer group. The authors didn’t report on multiple pregnancies, so this may have had something to do with it.

In terms of obstetrics and perinatal outcomes, there were no statistical differences for:

• Gestational diabetes
• Hypertensive disorder (eclampsia or preeclampsia)
• Antepartum hemorrhage
• Preterm delivery
• Low or high birthweight
• Small or large for gestational age
• Congenital/birth defects
• Mode of delivery (vaginal or caesarean)

They also performed an economic analysis and found freeze-all cycles were more costly due to the increased number of monitoring visits. However, costs due to OHSS in the fresh cycle were higher. Overall, fresh cycles were less expensive, at least from the UK perspective.

In conclusion, this study did not find a difference between fresh and frozen transfers. Even though the live birth rate trended toward being higher with the fresh transfer group (34.2% vs 28.3% with fresh), it was not statistically significant. They also didn’t find a difference in OHSS, however women who showed clinical signs of OHSS before transfer were excluded from this trial as they required a frozen transfer.

The authors point out that they had a lot of trouble with adherence in this trial, mostly due to people deciding to switch from a frozen transfer to fresh. There was no compensation for this trial which may have contributed to this. Because of this, and due to issues with recruiting participants, the trial was ended earlier than expected (with about 300 participants per group instead of 500). Despite this, the authors are confident that additional participants wouldn’t have had an impact on the statistical significance of their results.

In addition to the E-Freeze trial, five other trials were published between 2018 and 2021 that investigated fresh vs frozen transfers, and according to the authors they shared overall similar results with this trial (Shi et al. 2018, Vuong et al. 2018, Wei et al. 2019, Stormlund et al. 2020, Wong et al. 2021).

Reference

Maheshwari A, Bell JL, Bhide P, Brison D, Child T, Chong HY, Cheong Y, Cole C, Coomarasamy A, Cutting R, Hardy P, Hamoda H, Juszczak E, Khalaf Y, Kurinczuk JJ, Lavery S, Linsell L, Macklon N, Mathur R, Pundir J, Raine-Fenning N, Rajkohwa M, Scotland G, Stanbury K, Troup S, Bhattacharya S. Elective freezing of embryos versus fresh embryo transfer in IVF: a multicentre randomized controlled trial in the UK (E-Freeze). Hum Reprod. 2022 Mar 1;37(3):476-487. doi: 10.1093/humrep/deab279. PMID: 34999830; PMCID: PMC9206534.

 

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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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