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Why Frozen Embryo Transfers Are the Best

For almost the last 5 years, ACFS has realized that the key to improved IVF success is not to do a fresh transfer, culture all embryos to the blastocyst stage, do PGS or pre-implantation screening with subsequent FET or frozen embryo transfer.

Currently, ACFS only does frozen embryo transfers.

WHY?

We have consistently found up to 30% higher pregnancy rates when embryos are cultured out to the blastocyst stage, undergo PGS, cryopreserved and subsequently transferred in a prepared cycle. When embryos are transferred on a fresh cycle, even at the blastocyst stage, the uterine environment or endometrial lining has been over-stimulated from the fertility medications needed to produce multiple follicles (eggs) and uterine receptivity can be altered, making the window of implantation (WOI) less than optimal. The newer data suggests that you can do endometrial receptor assays (ERA) to better determine this “WOI” but they are still controversial and not accurate enough. The best success rates for implantation can be achieved by transferring the best day 5 blastocysts that are chromosomally normal in a prepared cycle. This is where all the signals from the brain to the ovary are shut down or down regulated and the uterine environment is prepared with natural estrogen and progesterone.

This actually works out quit well, since ACFS strongly recommends chromosome testing or PGS for all their patients; and since we do not receive those results for about 5 days; thus necessitating cryopreserving or freezing all embryos.

Prior to a frozen embryo transfer, all other causes of infertility should be evaluated and appropriately treated, as to not overlook something, "possibly simple", that can interfere with the frozen embryo transfer (FET) being successful. Just because a woman was successful in a previous attempt, does not mean she will be successful on her next attempt. Things can change between pregnancies or over time, and a common mistake is to assume that things "are status quo". Blood tests need to be updated if they are a year or older, Hysterosalpingogram (HSG) needs to be done to document that the fallopian tubes are still open and Arizona Center for Fertility Studies requires a Sonohysterogram (SHG) within 3 months of a transfer to rule-out any uterine pathology, like polyps or fibroids.

Once all the appropriate testing has been done, preparation for a FET (frozen embryo transfer cycle can start.  Both the older literature as well as the new literature, as well as ACFS experience, has shown that a prepared cycle with down-regulation (shutting down the signals from the brain to the ovaries) and subsequent estrogen and progesterone preparation of the uterus (endometrial lining) results in higher pregnancy rates and live births than transferring on a woman's natural cycle or an a low dose mediated cycle with gonadotropins.

This may be due to several reasons. In the older reproductive woman, her "older eggs" may not be able to optimally prepare the cycle; and in a younger woman, it is thought that by eliminating all signals from the brain to the ovary, implantation rates and subsequent pregnancy rates are higher, suggesting that "these normal signals" may somehow interrupt the optimum uterine preparation. If a woman has to do a natural cycle transfer, usually from persistent simple cyst development from Lupron or "an allergy" or "problems" with taking progesterone injections or gel, pregnancy rates are still good. If a natural cycle is done, then follicular growth of a single follicle is followed with frequent ultrasounds and when the follicle reaches 18 mm in size, ovulation is triggered with 10,000 IU of hCG, estrogen is checked to confirm that the egg follicle is "mature"; the embryos are thawed and embryo transfer is done 5 days later corresponding to the day the embryos were frozen. Sometimes these cycles are supplemented with oral estrogen and low dose natural oral progesterone. Since natural cycles are difficult to control, it might mean working on Saturday or Sunday; but that's okay.

In doing Frozen Embryo Transfer (FET), in order to "prepare" the cycle, all the signals from the brain to the ovary are blocked with a drug called Lupron, which temporarily puts the woman in menopause. Don't worry, it is always reversible and the symptoms are only for a few weeks. Lupron is started on day 1 of a bright red bleed, after an ultrasound is done to rule-out any simple ovarian cysts. Lupron can actually stimulate these simple cysts before suppressing the cycle. After 30 days on Lupron, another ultrasound is done to confirm that there are no ovarian cysts, and the woman is started on oral estrogen (E2), or Estrace, to start to build-up and prepare the uterine lining, or endometrium, for implantation. After 18 days of Estrace, Lupron is stopped, and progesterone (P4) injections are started for the final preparation and maturation of the uterine lining so that implantation can occur (Should I use progesterone after IUI or In-Vitro Fertilization (IVF)?). Oral progesterone does not work because you cannot give a high enough dose to support the lining. Prior to the start of progesterone, the final ultrasound is done to measure the "thickness" of the uterine lining to make sure that estrogen prepared it properly for implantation. In ACFS experience, the endometrial lining should measure 10 mm or greater to be prepared for implantation. Progesterone is continued for 5 days before the embryos are thawed. The actual number of days on progesterone is based on the age in days that the embryos were frozen.

At ACFS, all embryos are cultured to the blastocyst stage, so they are transferred on the 5th day of progesterone. Uterine embryo transfer (UET) of the appropriate number of embryos is carried out based on ASRM guidelines (In-Vitro Fertilization (IVF)). After the embryo transfer, the woman is continued on Estrace (E2) and progesterone (P4). A blood pregnancy test is done 9 days later. When the test is positive, the estrogen (E2) and progesterone (P4) are continued until 12 weeks of pregnancy. At that point in the pregnancy, the placenta is fully functional and is making all the hormones that the ongoing pregnancy needs, and (E2) and (P4) can be stopped. An initial ultrasound is done at 6 weeks (at no charge) and then every 1-2 weeks (again at no charge) until 12-14 weeks when the woman is referred back to her obstetrician for continuing OB care.

This journey started about 7 years ago when ACFS was one of the first clinics in the US to “see” the true value of chromosome testing or PGS (preimplantation genetic screening. We subsequently began to offer PGS to all our patients doing IVF. Although, truly revolutionary in producing better outcomes, it was early criticized as “not making a difference in IVF outcomes and would damage the embryo”. Early PGS was done on day 3 embryos using weak acids to dissolve the egg’s outer wall or zona pellucida. Early on, these techniques concerned us at ACFS; and although we never damaged a single embryo, the use of a weak acid anywhere near the embryo was worrisome.

But something much bigger changed our minds in how this new technology should be used:

First, ACFS was driven to be successful on each patient’s first attempt at IVF (for many obvious reasons).

Second, we had a number of biopsied day 3 embryos that made “beautiful” day 5 embryos or blastocysts but came back chromosomally abnormal. There had been speculation that embryos could “self-correct” but there was no scientific proof of that. With patients’ permission and informed consent, ACFS asked to re-biopsy these abnormal day 5 blastocysts to see what percentage of them, if any, had “self-corrected”. In collaboration with 3 other clinics we found that in the first 24 day 5-6 embryos re-biopsied, 64% had “self-corrected” and were read as normal. ACFS, along with 3 other major clinics, published what we believed at the time to be the first scientific paper showing the embryos could “self-correct” by day 5-6 of development.

That was the last time ACFS did day 3 embryo transfers and/or biopsies. However, this change demanded and pushed ACFS to get proficient with culturing embryos out to the blastocyst stage, using the new and expensive laser technology to biopsy day 5-6 embryos, replacing the use of weak acids (thank god). Since PGS results could take up to a week to get back, ACFS needed to get very proficient in embryo freezing or vitrification.

This actually worked to ACFS advantage because we were starting to realize that frozen embryo transfers (FET) were showing up to 30% higher pregnancy rates and significantly reduced the risks of ovarian hyperstimulation syndrome (OHSS) allowing ACFS to use more aggressive stimulation protocols that proved instrumental in recovering increased quality and quantity of eggs with resulting higher numbers of “quality” embryos for transfer and more remaining to cryopreserve.

But than you may ask, "is a frozen or cryopreserved cycle as good as a fresh cycle?"

In ACFS experience, a frozen cycle is better than a fresh cycle. Why? For three reasons:

First, you do not want to put embryos back in a "physiologically" over-stimulated cycle (having adverse effects on endometrial receptivity and endometrial DNA patterns)

Second, only the "best of the best" embryos survive the freeze-thaw process.

Third, it significantly decreases (or can eliminate) the risk of OHSS allowing you to use more aggressive stimulation protocols that prove instrumental in recovering increased quality and quantity of eggs with resulting higher numbers of “quality” embryos for transfer and more remaining embryos to cryopreserve. Also, since you are not getting pregnant in the cycle where the eggs are retrieved; if needed, you can be put on medications that can further reduce your risks of OHSS.

This is based on the assumption that your ART laboratory operates at a high level of excellence.

ACFS was not able to say this 5-6 years ago, but if your embryos were not able to reach the blastocyst stage (day 5) in ACFS-ART laboratory culture system, than they would not have made it in you if they were transferred. The same is true of frozen embryos. Based on extensive experience with blastocyst culture and vitrification (freezing), ACFS can say with confidence, that if your blastocyst embryos do not survive the freeze/thaw process (vitrification) than they would not have survived if transferred in a fresh transfer.

There are clinics that disagree with these conclusions and prefer to do a fresh day 3 or day 5 embryo transfer but the overall experience at ACFS is quit the opposite. Recent reports in the literature (ESHRE, July 2012) support ACFS conclusions. Initial meta-analysis on this subject indicates that the chance of a clinical pregnancy is up to 30% higher when all the embryos are frozen or cryopreserved (vitrification) at the blastocyst stage for later transfer rather than doing a fresh embryo transfer. We have not done a fresh day 5-embryo or blastocyst transfer for the last 4-5 years; and we feel very comfortable with our freeze/thaw (or vitrification) program which allows us to do PGS or chromosome testing which is a very critical part of ACFS overall success.

By doing a frozen embryo transfer (FET), ACFS knows what exactly what we are asking of our patients- not do a fresh transfer and wait to do a FET or frozen embryo transferThe goal however, "is not to see how fast we can do the procedure" but to maximize the chances of getting pregnant on the first attempt at IVF.  ACFS data clearly supports this premise. Even if a couple is not doing chromosome testing or PGS, they should consider not doing a fresh transfer in a physiologically over-stimulated cycle, cryopreserve all their embryos and subsequently do a frozen embryo transfer (FET) the following cycle.

Most folks than say, "but data shows that fresh is better than frozen". Actually, in ACFS experience this is not accurate. Why? Because in a regular IVF cycle without chromosome testing, the "best" looking embryos (morphologically normal) are transferred in that fresh cycle and the "remaining" embryos are than cryopreserved. Statistically, however, "these remaining embryos" tend not to be the "best embryos" (hence, why they were frozen instead of transferred). Subsequently, when doing a future FET with these "lesser quality" embryos, pregnancy rates are not as good. In contrast, even without chromosome testing (which ACFS does not recommend), if ALL the embryos had been frozen, and only the ones that survived the freeze-thaw process were transferred (only the "best of the best" embryos survive the freeze-thaw process), pregnancy rates would be as good, if not higher, than a fresh transfer.

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