Frozen Embryo Preimplantation Genetic Testing (PGT)
What is PGT of frozen embryos & who might consider it?
There has been a huge surge in patients desiring to do preimplantation genetic testing (PGT) of their embryos created through in vitro fertilization (IVF) to improve pregnancy rate per embryo transfer. Since the field of fertility medicine and RSC in particular have been freezing embryos for a couple of decades, many couples and individuals have frozen embryos in storage that are now candidates for this testing prior to embryo transfer.
PGT is the term fertility specialists now use for the analyses done in preimplantation genetic screening (PGS) and preimplantation genetic diagnosis (PGD). Preimplantation genetic testing is an option for any patient undergoing IVF and is most often used for patients with known genetic diseases, a history of recurrent miscarriages, previous IVF failures and female patients over age 35.
PGT can identify many genetic disorders. It can test for total number of chromosomes to identify aneuploidies such as Trisomy 21, also known as Down syndrome, as well as detecting chromosomal structure rearrangements. PGT can also test embryos for single gene defects, which is done when testing of the parents before IVF has identified a genetic problem for which the embryos are specifically tested. PGT can also determine the sex of the baby, since the X and Y chromosomes are part of routine testing of the complete set of chromosomes.
PGT of frozen embryos is primarily an option for patients who did IVF without PGT in the fresh cycle and had embryos left over that were then frozen and stored (cryopreservation). They may not have gotten pregnant, had a miscarriage or had a baby with a chromosomal abnormality resulting in a birth defect. These patients could later wish to have more children and want to test the other embryos they froze to make sure a genetically flawed embryo will not cause an unsuccessful cycle or a child with a birth defect in their next attempt at implantation.
Another scenario for PGT of a frozen embryo is for patients who had a successful birth, perhaps of a girl, but now they want a boy, or vice-versa. PGT of their frozen embryos can identify a healthy embryo of the desired sex for implantation, a procedure often referred to as family balancing.
The possibility of PGT of frozen embryos can also occur when a couple or individual has a new diagnosis of a genetic condition that runs in their family, such as BRCA gene mutation for breast cancer, and they want to screen the embryos for this genetic mutation.
Steps in PGT of frozen embryos
During preimplantation genetic testing of a frozen embryo, several steps take place. The embryos must be retrieved from cryopreservation and successfully thawed. At Reproductive Science Center (RSC), 98 percent of our embryos survive the thawing. However, embryos actually have to do better than just survive to be able to make it to the biopsy of PGT. The unfrozen embryos must have enough cells that they can withstand giving up some for the testing. So a patient may have four embryos thawed, but we are only able to biopsy three of them due to not having enough cells.
The cells that will be biopsied must come from the trophectoderm, or the cells destined to become the placenta, rather from those cells that will become the fetus. So the trophectoderm cells must be hearty and numerous.
Embryos are surrounded by an outer coating called the zona pellucida (shell) that holds together the individual cells of an embryo. One of the most common barriers to becoming pregnant with IVF is improper implantation of the embryo because it hasn’t “hatched” through the zona pellucida enabling it to implant in the uterus. A process called assisted hatching that involves a laser can be used with IVF to help embryos implant and increase the chances of pregnancy success.
In frozen embryo PGT, if the embryo has not already been hatched with the laser, the zona pellucida must be hatched. Then as the embryo re-expands, 5-6 cells are taken from the trophectoderm and sent for preimplantation genetic testing.
Each embryo is numbered and the sample of cells is numbered to correspond to the embryo. The testing can be done on several different platforms (see above), but most all forms of PGT will tell us if there is a normal chromosome count and what the sex is. If there is a specific gene mutation we are looking for, then we can also tell if the embryo is affected with the mutation.
After PGT, when should embryo transfer occur?
For most patients, it is easiest and perhaps best to thaw the embryos a month or more before they are ready to proceed with the transfer. In this scenario, the lab will choose a day to thaw the embryos, biopsy all that they are able to, and re-vitrify (re-freeze) the embryos while we wait for the results.
Usually the turnaround time for the results is one week. At that time the physician can sit down with the patient and review the results and then decide which embryo to transfer next. If there are no normal embryos, then the patient has not had to take any medicines unnecessarily in preparation for implantation and can then decide if she wants to undergo a fresh egg harvest.
If there are embryos that the patient wants to transfer, a typical frozen embryo transfer can then begin. This usually takes one month to complete before the patient knows she is pregnant. Typically, we use estrogen pills, progesterone shots and vaginal suppositories.
We conduct one (maybe two) ultrasounds and need one visit for the embryo transfer. We would thaw the chosen embryo (98 percent survival rate) on the day of transfer. We do recommend testing at the end of the first trimester of pregnancy to confirm the results of the embryo PGT.
Another option is to do a frozen embryo transfer at the same time as the PGT biopsy of the frozen embryos. This may be considered if the patient has lots of frozen embryos, as there is a smaller chance that there would be none to transfer. In this scenario, there is a one day turnaround on the biopsy results, and the patient starts estrogen and progesterone to time the transfer with the results.
Patients and physicians must make a quick decision about which embryo to transfer on the morning the results come back. If there are no normal embryos or none of the desired sex, then the cycle would be cancelled.
Success rates for frozen embryo transfer after PGT
For a fresh cycle with PGT to identify chromosome number abnormalities, the pregnancy rate is 68 percent. But for the same PGT testing on a thawed frozen embryo, the success rate is 55-65 percent. The variation depends on why someone wants to do the biopsy and whether they had a baby from the batch, as well as morphological and kinetic characteristics of the embryos (how the embryo looks and divides.)
Live birth rates of PGT to identify chromosome number abnormalities are about 50 percent. Miscarriage rates are 8-10 percent, which is less than age-related rates (25 percent for a 35 year old and 50 percent for a 40 year old).
Considerations & risks of PGT of frozen embryos
All patients want to reduce their miscarriage rate and increase the chance of having a healthy pregnancy. However, doing the PGT biopsy is invasive and is a newer procedure on which we do not have long term health data. For this reason, patients need to have a strong indication for wanting it done.
For a young patient with a high chance of having a normal embryo, then it may be best not to pursue PGT and subject the embryo to the wear and tear of multiple freezes and thaws. On the other hand, if a patient has been through miscarriages or has a high chance that most of her embryos are not chromosomally normal, then the patient may be willing to take the risk associated with PGT. By talking with a reproductive embryologist, hopefully patients will get the information and guidance they need to make the best decision.
We have not seen an increase in birth defects or abnormalities when frozen embryos undergo PGT. There is also no increase in miscarriage, but actually a decrease in miscarriage and almost no chromosomal abnormalities. Frozen embryo PGT is about 95 percent accurate.
We have been doing PGT for 10-15 years so we have data on children up to age 10-15, but not on adults. Data about thawing embryos only to do the PGT biopsy and then re-vitrifying them are sparse and very limited, as this is a newer technique and most patients do the PGT biopsy in the fresh cycle with nonfrozen embryos.
The biopsy has an “impact” on the embryos but likely only reduces success rates by about 5 percent at most, according to the newest data. A certain percentage of a couple’s or individual’s embryos are projected to be normal based on their age at the time they created the embryos (60 percent if younger than 35 years old, 35 percent if 40 years old). By avoiding transferring the abnormal embryos, patients can achieve a healthy pregnancy in fewer embryo transfers in the event that the next best embryo without testing might have been an abnormal one.