Results: Frozen-Thawed Embryo Transfer

The survey was compiled by:
Dr. Ariel Weissman,
IVF Unit, Wolfson Medical center
Holon, Tel-Aviv, Israel

Cryopreservation of supernumerary embryos following IVF has been widely practiced as a safe and cost-effective method to increase cumulative pregnancy rates per oocyte retrieval. The current trend towards decreasing the number of embryos being transferred, and the increased implementation of single embryo transfer (SET) policy in many IVF programs emphasize the relevance and importance of frozen embryo transfer (FET).The current survey examines variations in attitudes and therapeutic approaches related to cryopreservation and thawing of supernumerary embryos around the world. As can be seen, variations exist, and to a large extent reflect lack of solid and evidenced-based data in this field.We have received results from 179 IVF centers representing 56 countries. The results relate to 133,290 IVF cycles, of which 39,152 are FET. The following graph shows the distribution based on the various continents.
The following graph shows the distribution based on the continents.

Cycles per continents	Total IVF cycles	FET cycles
USA and Canada	25240	6730
Europe	47350	15832
South America	6400	1260
Australia & New Zealand	21300	8240
Asia	30100	6920
Africa	2900	170
Total	133290	39152

The timing of embryo freezing is almost equally divided between day 2, 3 and the blastocyst stage. Only a small minority prefers to freeze zygotes, since true embryo quality is unknown at that stage. Freezing on day 2 or 3 of cleavage stage embryos is widely practiced, and results for day 2 or 3 are very similar, as in fresh cleavage stage transfer.
Freezing at the blastocyst stage may occur under the following circumstances:
1. Elective freezing of suprasumerary blastocysts following elective blastocyst transfer.
2. Uncertainty about the quality of cleavage stage embryos which are left in culture after day 2 or 3 transfer, and only those who make it to the blastocyst stage are frozen. The survey did not address the relative proportion of each indication.

Geography. There are wide variations in the use of FET worldwide. One may wonder why? It takes a lot of time, effort and expertise to build a successful cryopreservation program. Perhaps this goal has not been equally achieved world wide.

The timing of embryo freezing is almost equally divided between day 2, 3 and the blastocyst stage. Only a small minority prefers to freeze zygotes, since true embryo quality is unknown at that stage. Freezing on day 2 or 3 of cleavage stage embryos is widely practiced, and results for day 2 or 3 are very similar, as in fresh cleavage stage transfer.
Freezing at the blastocyst stage may occur under the following circumstances:
1. Elective freezing of suprasumerary blastocysts following elective blastocyst transfer.
2. Uncertainty about the quality of cleavage stage embryos which are left in culture after day 2 or 3 transfer, and only those who make it to the blastocyst stage are frozen. The survey did not address the relative proportion of each indication.

The vast majority of ART clinics worldwide require a washout period between the fresh and the FET cycle. Both medical and practical considerations may be involved.
From the medical point of view:
Such a need has not been investigated and is certainly of interest.
From a practical point of view:
The hypothalamic-pituitary-ovarian axis may take time to recover in a patient who failed to conceive following a long agonist protocol, especially if a depot preparation of the agonist was used.
Therefore, waiting for spontaneous ovulation may be a long and tiring process. Under such circumstances, hormone replacement may be more practical, and a washout period might not be necessary.
It is interesting to know whether units require a washout period when hormone replacement cycles are used.

Preparation for FET is almost equally divided between hormone replacement and natural cycle. Since both have shown to yield similar results, practical considerations may also apply.
Hormone replacement cycles:
More convenient for the clinic, and patients, since the date of thaw and transfer can be pre-selected according to the work load at the clinic and the convenience of the staff and patients.
It requires less intensive monitoring compared to natural cycle FET.
Nevertheless, it also requires prolonged medical treatment with estrogen and progesterone preparations throughout the first trimester, and therefore some patients may not chose this option, if they are given a proper explanation and a choice.

It is interesting to note the large proportion of NC-FET cycles that are monitored by urinary LH kits. These kits are sensitive and reliable especially in patients with regular cycles, and make the monitoring stage simple and relatively cheap. They are of greater importance when patients live in rural areas, far from the major or satellite clinics, and have no simple access to other means of monitoring.

All methods for ovulation detection/triggering seem to be equally effective, and therefore a wide variability in their used is seen.

All together, there is a strong agreement (~60%) that a minimum of 7 mm is necessary. It interesting that 22% of clinics require no minimum and 11% are satisfied with 6 mm.

There is no definite proof that in NC-FET after spontaneous ovulation there is a need for luteal support. This, like many other practices in our field, is based on personal experience or beliefs, without solid scientific basis.

It is noteworthy that vaginal progesterone has become the predominant means of luteal support. This reflects a shift and a change from IM progesterone over the years.

It is probably safe enough to stop luteal supporting between 5-6 gestational weeks, and only the minority continue support after 10 gestational weeks.

There is hardly and data addressing this question, and the confusion and diversity are clearly reflected. This certainly calls for a study that would address this question.
Reaching pituitary suppression may be both difficult and expensive for patients. Spontaneous ovulation during a replacement cycle is rare and doesn't necessarily mean cycle cancellation. It is possible to proceed with thawing and transfer if ovulation is accurately detected. There is no strong evidence in the literature to justify pituitary suppression. Still, a considerable proportion of HRT-FET cycles are conducted under pituitary suppression.

An interesting use of GnRH antagonist would be to suppress ovulation during hormone replacement if a dominant follicle appears prematurely. Such follicles usually disappear within a few days of antagonist administration, allowing ample time for further endometrial development.

Oral estrogen is the most popular route of administration. In some patients, however, oral administration of estrogen is inefficient because of limited absorption or accelerated degradation in the GIT, which results in a thin lining and low serum estradiol levels. Any other route (vaginal, transderdermal or IM) should be satisfactory under such circumstances.

Vaginal progesterone is widely accepted as an efficient mean for progesterone supplementation.

It is believed that ultrasound is the major tool for follow-up (93%). Around 38% of physicians feel that adding a blood test would improve their results.

It is acceptable by most physicians (84%) think that a suitable endometrium should be between 6 and 8 mm. Only 8% do not take endometrial thickness into consideration.

Again, no firm data on this subject. Following HRT-FET, lack of ovulation and corpus luteum formation may necessitate much longer luteal support than in NC-FET, similar to support protocols for egg recipients. Properly designed studies are needed.

Ovulation induction prior to FET should be soft and simple. GnRH analogs should be rarely used, under special circumstances.

Interestingly, in a considerable proportion of OI-FET cycles clomiphene citrate is used. This treatment is simple and cheap. Negative effects on endometrial thickness, which may adversely affect pregnancy rates, may occur. Thus, clinics that use CC must have favorable results, which would be interesting to look at.

It seems as if most of the participating centers prefer to wait 24 hours to further observe the development of the thawed embryos before replacement.