Study finds more flexible triggering timing for modified natural cycle FETs

A 2023 study showed that modified natural FETs could be triggered between a follicle size of 13-22 mm without any change in pregnancy outcomes, making the timing for this type of transfer much more flexible for the clinic. Modified natural FETs are more desirable because they use less medications and are linked to fewer complications compared to medicated FETs.

There’s different strategies for preparing the endometrium for a frozen embryo transfer (FET), including a modified natural cycle (mNC) or a medicated approach.

In mNCs, ovulation is typically triggered with hCG around a follicle diameter of 17 mm, leading to the formation of the corpus luteum, which naturally produces progesterone and other hormones to prepare the endometrium for embryo implantation. Medicated FETs, on the other hand, involve administering estrogen and progesterone to replicate the corpus luteum’s effects.

While medicated FETs offer more predictable scheduling, they are linked to a higher risk of adverse pregnancy outcomes like preterm births, which generally aren’t seen with mNC transfers. The problem with mNC transfers is that they’re more difficult to schedule.

Scheduling mNC transfers would be easier if the triggering timing was more flexible, so this study investigated if pregnancy outcomes changed in patients who triggered at different follicle diameters. These patients had regular menstrual cycles, progesterone levels <1.5 ng/ml and endometrial thickness ≥7 mm at trigger.

Want to learn more about different FET protocols and endometrial preparation? Check my post Comparing frozen embryo transfer/FET protocols.

---

Study details

This section covers key details of how the study was performed, including patient characteristics, how they were treated, and other methods used. For those who aren’t interested in these details, and just want to see the results, you can go ahead and skip this part.

• This was a retrospective study that took place at multiple IVF centers in Spain, Portugal and Italy between 2020 and 2022.
• Patients’ hormone levels were monitored, along with their follicle diameter before triggering with hCG. Progesterone was administered 2 days after trigger. A single embryo transfer took place 7 days after trigger.
• Inclusion: Single frozen transfer of a day 5/6 good quality embryo; regular menstrual cycles; normal uterine cavity; serum progesterone <1.5 ng/ml at trigger; endometrial thickness ≥7 mm at trigger.
• The primary outcome was ongoing pregnancy rate (ongoing pregnancy after 11 weeks).

In terms of sample size, there were 2,764 patients with 3,087 mNCs, which were grouped based on follicle diameter at the time of trigger:

• 13.0-15.9 mm (124 transfers)
• 16.0-18.9 mm (2,014 transfers)
• 19.0-22 mm (949 transfers)

In terms of baseline characteristics of the above groups, there were no differences in age (average was 38.3) or BMI. There was a difference in the proportion of cycles that used egg donors (39.5% egg donors in the 13.0-15.9 mm group vs 27.9% and 27.4%) and PGT-A (19.4% in the 13.0-15.9 mm group vs 34.0% and 37.3%). These were adjusted (controlled for) in their statistical analysis.

There were also differences in serum estrogen and progesterone levels on the day of trigger. Estrogen levels were expected to change based on the size of the follicle, and the progesterone levels ranged from 0.29-0.35 ng/ml.

No change in ongoing pregnancy rates based on follicle diameter at trigger for modified natural FETs

The 3,087 mNCs were grouped based on follicle diameter at the time of trigger (13.0-15.9 mm, 16.0-18.9 mm, 19.0-22 mm). Seven days after triggering, a single good quality blastocyst was transferred and pregnancy outcomes were evaluated.

Patients that were triggered at a smaller follicle diameter had higher ongoing pregnancy rates (54.8% vs 46.8% vs 43.1%, p= 0.02). After statistical adjustment for egg donation and PGT-A cycles, there was no difference between the groups. This shows that the differences in ongoing pregnancies were due to egg donation and PGT-A cycles, and when these were controlled for there was no difference.

There were no statistically significant differences in the other pregnancy outcomes between the groups:

• hCG pregnancy rate
• Implantation rate
• Clinical pregnancy rate
• Total pregnancy loss rate
• Biochemical loss rate
• Clinical miscarriage rate

They also did an ROC analysis that showed that follicle diameter wasn’t able to predict ongoing pregnancy rate (AUC of 0.51).

They also plotted the average ongoing pregnancy rate and confidence intervals for each of the individual follicle diameters at time of trigger (13-22 mm), and found no differences using the analysis of variance test (p= 0.07).

Conclusion

This study found that there was no difference in ongoing pregnancy rates, or other pregnancy outcomes, when a natural cycle FET was triggered between follicle diameters 13-22 mm. This was for women with regular menstrual cycles, low progesterone (<1.5 ng/ml) and adequate endometrial thickness (7 mm or more).

This suggests that triggering a mNC can be done when the follicle ranges from 13 to 22 mm in size. The authors note that follicles grow at a rate of about 1-1.5 mm/day, so a 13 mm follicle wouldn’t be 22 mm until about a week later. This could make scheduling mNCs much easier for the clinic, as weekends can be avoided when there may be less staff.

Performing a mNC transfer over a medicated FET is desirable because less medications are used and there’s a lower chance of adverse pregnancy outcomes, like preterm birth.

This flexibility in the timing that we’re seeing here makes sense, because it isn’t a mature egg that we’re trying to get — we’re just interested in the corpus luteum. So the triggering timing may not matter (although women with a history of premature ovulation may need to be triggered earlier).

A requirement for mNC transfers is a normal menstrual cycle, and women with irregular cycles or who don’t ovulate can have mild stimulation with clomid, letrozole or gonadotropins.

Limitations of the study include:

• It’s retrospective
• The majority of mNC transfers involved follicle diameters of 15-19 mm, with fewer transfers in the smaller or larger diameter groups.
• Smaller follicles were triggered in women with a history of premature ovulation, so these patients may have different characteristics compared to patients without this history. These patients were also more likely to use egg donors.
• This study used ongoing pregnancy after 11 weeks as it’s primary outcome. This seems short, as it’s not even past the first trimester when most miscarriages occur. From other studies, I’ve seen ongoing pregnancies typically after 20 weeks or so.
• A large number of egg donation/PGT-A cycles were used. It’s reassuring that they didn’t find any differences in pregnancy outcomes after statistical adjustment, but it would have been nice if they separated these groups and did a subgroup analysis to see if they would get the same results.

The authors note that this is the first study to address this topic, and additional (prospective) studies should be done to confirm these results.

Reference

Alonso-Mayo C, Kohls G, Santos-Ribeiro S, Soares SR, Garcia-Velasco JA. Modified natural cycle allows a window of 7 days for frozen embryo transfer planning. Reprod Biomed Online. 2023 Dec 17:103774. doi: 10.1016/j.rbmo.2023.103774. Epub ahead of print. PMID: 38609793.

If you liked this post and want to support what I do, please consider a paid subscription, Patreon or donate through PayPal!

 

---

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.

---