Identifying the optimal timing for embryo transfer in modified natural and natural FETs

Researchers in a 2022 study compared timing of euploid transfers and found that 160 h was optimal for modified natural FETs, while they found no optimal time for natural FETs.

To maximize the chance of implantation, an embryo needs to be transferred to the endometrium when it’s most receptive (aka the window of implantation). The optimal timing for natural and modified natural frozen embryo transfers (FETs) isn’t clear. Check here if you want to learn more about different FET protocols.

Gia Linh An et al. (2022), in their multicenter retrospective study, compared the timing of a single euploid transfer in natural and modified natural FETs between 2015 and 2019 in Australia.

There were a total of 1,170 single euploid transfers performed, with 917 natural cycle FETs and 253 modified natural cycle FETs.

FETs were performed at different times after the onset of the LH surge (in natural FETs) or hCG trigger (in modified natural FETs). They compared live birth rates after 136 h, 148 h, 160 h, 172 h and 184 h (along with the ranges ±4, ±6, ±8 and ±12 h).

Some might find it helpful to compare this to timing of ovulation or medicated FETs. According to the authors, ovulation occurs ~40 h after hCG trigger in modified natural FETs, and ~24-56 h after the onset of the LH surge in natural cycles. So 160 h after hCG trigger in a modified cycle would be about 120 h after ovulation (or 120 h of progesterone in a medicated FET, except there’s no ovulation here and this study isn’t looking at medicated FETs!). Check here if you want to learn more about different FET protocols and more about the ovulation cycle.

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No difference in natural or modified natural FET live birth rates

When the researchers compared the overall live birth rates between natural and modified natural FETs, they found an increase with modified natural FETs compared to natural FETs but this wasn’t statistically significant (34.9% vs 41.1%, p=0.054).

Modified natural cycles showed optimal timing, not natural cycles

They compared live birth rates after transferring euploids in a modified natural or a natural cycle FETs, after different times (as shown above).

Modified natural cycles

For modified natural FETs, live birth rates were highest when euploids were transferred 160±4 h after hCG trigger compared to the other times, and this was statistically significant (55.8% vs 36.7%, adjusted relative risk [95% CI]: 1.52 [1.15-1.99]).

There were no statistically significant differences between the other times (136 h, 148 h, 172 h and 184 h). In other words, only 160 h showed an improvement in live birth rates (55.8% for ±4 h), while live birth rates for transfers occurring at 136 h, 148 h, 172 h and 184 h (±4, ±6, ±8 and ±12) were all comparable to 36.7%.

As for the 160h ±6 h, ±8 h and ±12 h time ranges, the researchers didn’t report the live birth rates. However, they did report the adjusted relative risks (1.35, 1.37 and 1.42 respectively – all statistically significant). We can calculate a rough estimate of the live births from this, with the big assumption that the average value of all the other times was 36.7%: 49.5% (for the ±6 h range), 50.3% (±8 h) and 52.1% (±12 h).

The sample size for this analysis was very small in some cases, particularly after 160 h (which had 41 and 8 participants for 172±12 h and 184±12 h respectively). While the authors didn’t mention this as a limitation, I consider it to be since the smaller sample size may not be enough to see any differences at these later time points. Larger studies should be done to confirm this.

Natural cycle FETs

For natural cycle FETs, there were no statistically significant differences for any of the times examined, and the average live birth rate was 36.8%. So, at least based on this data, the timing of euploid transfer after the onset of the LH surge for a natural cycle FET seems less important compared to the timing in modified natural cycles.

The sample size was large for each of the times examined (all in the hundreds, with the exception of the 184±12 h timepoint which had 78 participants).

Conclusions

This study found that live birth rates were maximized in modified natural FETs when embryos were transferred 160±4 h from hCG trigger (120±4 h after ovulation). Significant improvements were seen in a range as wide as 160±12 h. The remaining timepoints (136 h, 148 h, 172 h and 184 h) had lower live birth rates and were comparable to one another (however 172 h and 184 h had a smaller sample size).

There were no differences across any of the timepoints for natural cycle FETs. This suggests that timing of transfer is less important for natural cycle FETs. This was based on a large sample size, except for the 184 h timepoint.

The authors believe that the improvement in modified natural FETs was due to the ability to control when ovulation occurred using hCG. In natural cycle FETs, the timing of ovulation is less predictable because of individual variations in hormone levels and the rate of LH rise.

Reference

An BGL, Chapman M, Tilia L, Venetis C. Is there an optimal window of time for transferring single frozen-thawed euploid blastocysts? A cohort study of 1170 embryo transfers. Hum Reprod. 2022 Nov 24;37(12):2797-2807. doi: 10.1093/humrep/deac227. PMID: 36305795.

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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.