What is a FET?
A Frozen Embryo Transfer (FET) is a procedure in which an thawed, previously embryo is implanted in the uterus.
Protocols for frozen embryos transfer
Estrogen preparation for FET
During a normal menstrual cycle, estrogen is produced by the developing follicle. This estrogen acts on the uterus to thicken and mature the uterine lining. Estrogen is given in a FET
cycle for the same reason. There are many different ways that estrogen can be given in a frozen embryo transfer cycle:
- Estrogen pills – Estrace, Premarin
- Estrogen patches – Estraderm, Climera
- Estrogen injections – Delestrogen (estradiol valerate), Depogen (estradiol cypionate)
- Vaginal estrogen – Vagifem, Femring
There is no data that any one method works better than another and a method is usually chosen based on physician preference.
During the time when estrogen is given, the woman will come to the office periodically to be monitored. A transvaginal ultrasound is performed to determine the thickness of the uterine lining and a blood test is performed to look at the level of estrogen in the blood. On occasion, if the lining is not thickening as it should, the dose or type of estrogen must be increased or prolonged. The length of time the estrogen can be given is very flexible.
The monitoring in a thaw cycle is very flexible. Unlike a fresh IVF cycle during which the required days for monitoring are determined by the growth of the follicles in the ovary, in an FET cycle, the days can be adjusted at any time. Thus, a frozen embryo transfer cycle is much less stressful.
Progesterone in an FET cycle
Once the uterine lining has been thickened sufficiently, progesterone is added. Progesterone matures the uterine lining and makes it receptive to an embryo to implant. Once the progesterone is begun, there is a certain “window of implantation” during which the embryo must be transferred. The stage of the embryo must match the stage of development of the uterus. Therefore, the only factor that locks the patient into performing the transfer on a certain day is starting the progesterone. Once the progesterone is begun, if the embryo transfer is not performed on a certain day, the cycle must be cancelled and a new preparation with hormones must be begun after allowing a period to occur.
There are many different types of progesterone that can be used in a frozen embryo transfer cycle. Some of the more common methods include:
- Progesterone pills – Prometrium
- Progesterone injections
- Progesterone vaginal suppositories
- Progesterone vaginal gels – Crinone, Procheive
There is considerable uncertainty in the medical literature concerning which type of progesterone is the best for FET cycles. Again, the choice of progesterone for an FET cycle is up to the discretion of the physician. A few things, however, most experts would agree on. Progesterone given by mouth is unreliable due to variable absorption and subsequent metabolism in the liver.
Once the uterine lining is adequately thickened with estrogen, the progesterone is usually started on a particular day to allow for scheduling of the embryo thaw and embryo transfer for a time that is convenient for the in vitro fertilization laboratory staff.
Commonly embryos are frozen at the blastocyst stage. This is an embryo that has developed for five days in the laboratory. It must be placed into a uterus that has been exposed to progesterone for five days.
FET during a natural cycle
If a woman has regular, ovulatory menstrual cycles, a frozen embryo transfer can be performed without the use of hormone preparation. Several studies have shown that the pregnancy rates in natural FET cycles are equivalent to that of hormone prepared cycles.
A precise window of implantation for transferring frozen embryos is required. This must be maintained in a natural FET cycle as well. This requires precise determination of the time of ovulation. This can be done by using a home ovulation predictor kit. However, as anyone who has ever used these kits knows, it is sometimes difficult to read them accurately. Although the instructions accompanying the ovulation kits usually recommended that women test the urine once each morning, for FET cycles we recommend testing in the morning and evening. It is also possible to monitor natural cycles using blood tests and ultrasounds just as we do for a hormone prepared frozen embryo cycle.
Stage of cryopreservation for frozen embryos transfer
After an egg is fertilized, it can be grown in the laboratory for up to five or six days. Cryopreservation of the embryos has been accomplished at all stages of embryo development. There is no universal agreement as to which stage of embryo development is the best for cryopreservation.
If an embryo is frozen immediately after it has been fertilized (pronuclear stage), the survival of the embryo after thawing appears to be high. However, since the embryo was not cultured in the laboratory first, its potential viability is unknown. Therefore, after the embryo is thawed, it must then be cultured in the laboratory in the same way it would have been if it had not been frozen. It is impossible to predict how many of the thawed embryos will reach the stage of development desired by the physician for transfer. Therefore, a higher number of embryos must be thawed. If a large number of embryos does reach that stage of development, then there is a dilemma. Either a larger number of embryos must be transferred (which increases the risk of multiple pregnancy) or the extra embryos must be discarded or refrozen. There is very little data about the safety or success of refreezing embryos so it is not recommended.
An embryo can also be frozen after two to three days of embryo development. This is called the cleavage stage. Cleavage stage cryopreservation allows for some limited assessment of the development of the embryos. Some embryos, for example, will not have developed or look abnormal and thus would not be frozen. On the downside, the survival of cleavage stage embryos is lower. As with the case of embryos frozen at the pronuclear stage, cleavage stage embryos can also be cultured after thawing to further help determine the best embryos for transfer.
An embryo frozen after 5 days is at the blastocyst stage. Since the embryos have been cultured for five to six days, this enables the best assessment for viability and thus fewer non-viable embryos will be frozen at this stage. In the past, survival of the embryo after thawing has not been very good. In recent years, however, techniques for freezing blastocysts have improved and in selected centers the survival rate is very good. Blastocyst cryopreservation allows for the thaw and transfer of embryos on the same day.
Frozen Embryo Transfer Success
There is much confusion about the ability of frozen embryos to produce pregnancy. On initial inspection, the chance for pregnancy using frozen embryos appears to be lower than the transfer of fresh embryos. On closer analysis, however, this may not be true.
Typically, when a frozen embryos transfer is performed, the embryos that were frozen were those that were not chosen for the initial fresh embryo transfer. Why not? Often, the embryologist chose the “best” embryos for the initial transfer. The embryos that remained were frozen. Some programs are very strict about the quality of the embryos they will freeze, other programs will freeze any and all remaining embryos. As in the case of fresh embryo transfer, embryo quality has a profound effect on the chance for pregnancy. If poor quality embryos were frozen, the survival rate after thawing as well as the pregnancy rate would be expected to be lower.
A second important factor is the number of embryos that are transferred. Take the example of a couple who produce four good quality embryos. Two are transferred in the fresh in vitro fertilization cycle and two are frozen. A pregnancy results and the couple delivers a baby. Later, the couple decides to attempt pregnancy again using the frozen embryos. Upon thawing, however, only one embryo survives. The frozen transfer is of a single embryo. Pregnancy rates of a single embryo are going to be lower than that seen with a multiple embryo transfer.
Studies have been performed in women who had a very vigorous stimulation of their ovaries and were considered to be at high risk for ovarian hyperstimulation syndrome (OHSS). Their physicians decided to skip the embryo transfer and instead freeze all of the embryos for later use. This significantly decreases the risk of serious or complicated OHSS. In other cases, the physicians decided to go ahead with a fresh embryo transfer anyway, despite the risk of OHSS. In this experiment, the couples in both groups have a large number of embryos and the selection of embryos for transfer was for the best embryos in each case. These studies show no difference in the pregnancy rates between fresh or frozen embryos.