Preimplantation Genetic Testing (PGT-A)
Preimplantation Genetic Testing for Aneuploidy & In Vitro Fertilization
PFC offers preimplantation genetic testing for aneuploidy (PGT-A, previously called Comprehensive Chromosome Screening or CCS) as an option for patients undergoing in vitro fertilization (IVF). PGT-A is a treatment for patients who wish to improve implantation rates, reduce miscarriage rates, and reduce the risk of multiples after IVF. This is one of the truly exciting technologies that sets apart modern fertility programs such as Pacific Fertility Center, and we are pleased to be able to offer PGT-A to our patients.
Providing high pregnancy rates with minimum risk after in vitro fertilization requires high quality embryos. But a problem remains in the IVF lab – which embryos are high quality? Embryos that look good under the microscope don't always have what it takes to produce a pregnancy. Selecting high quality embryos, those with the highest pregnancy potential, can reduce the numbers of embryos transferred, significantly reduce the chance of miscarriage, increase pregnancy rates and live birth rates per embryo transferred, and reduce the chance of a child born with a chromosome abnormality such as Down syndrome.
Patients who can benefit from PGT-A include those who have:
- Experienced recurrent miscarriage for unknown reasons or due to prior aneuploidy
- Increased risk for aneuploidy (such as Down syndrome) due to maternal age
- Additional medical risks associated with the possibility of twin pregnancy
- Risk for sex-linked disease in offspring or other reasons for sex selection
- Plans to use a gestational carrier
PGT-A – Choosing the best embryo
PGT-A is a technique that allows selection of embryos with normal chromosomes from a group of embryos. After in vitro fertilization, a few cells from each embryo are sent to the genetics lab and chromosomes are counted. The embryos with a normal number of chromosomes are selected from the group for transfer. Embryo selection by conventional imaging techniques is not very selective. Abnormal embryos often look just like normal embryos under the microscope. Early cell division is to some extent independent of the number of chromosomes in the embryo, so an embryo with an abnormal number of chromosomes can look just like any other. To compensate, IVF programs may transfer more than one embryo, risking multiple pregnancy. When an abnormal embryo results in pregnancy, miscarriage is possible. PGT-A refines embryo selection, offering a means of choosing the embryos most likely to result in successful pregnancy out of a group.
The biology behind PGT-A
An embryo that contains a normal number of chromosomes is a 'euploid' embryo. An embryo that carries an abnormal number of chromosomes is 'aneuploid'. Examples of aneuploid embryos include trisomy 18 and trisomy 21, otherwise known as Edward syndrome and Down Syndrome respectively. Embryos can also be affected by complex combinations of abnormal chromosomes, and even contain an extra entire set of chromosomes (triploidy).
Aneuploidy is quite common and, more often than not, PGT-A testing will show that an embryo is aneuploid. Half or more (sometimes all) embryos in a particular IVF treatment cycle are aneuploid, and while we can't prove this, we suspect that the majority of natural conceptions are affected by aneuploidy as well. The common clinical scenarios of age-related infertility, miscarriage, and Down syndrome are all expressions of aneuploidy.
In the early days of embryo development, most of these aneuploid embryos don't grow, and are never seen clinically. A few aneuploid embryos continue development and result in clinical problems. Miscarriage occurs in about a fourth of pregnancies – most of these are aneuploid. The rate of aneuploid embryos resulting in miscarriage increases dramatically with maternal age such that 50% or more of pregnancies after age 40 will miscarry. In milder forms of aneuploidy, embryos can survive longer, with a few continuing on into pregnancy, accounting for common problems like Down syndrome.
Most eggs and their resulting embryos do not have the ability to produce a viable pregnancy. On average, about 10 eggs are required to produce a euploid embryo. It works like this: approximately two-thirds of eggs fertilize and form an embryo. Roughly half of the embryos develop to the blastocyst stage at day 5-7, and about half or less of the day 5-7 embryos will be euploid. In other words, 10 eggs can produce 1-2 euploid embryos (created from eggs of a woman in her 30s). About 3 out of 4 of these euploid embryos will implant on average (75 percent implantation rate), with high pregnancy rates per transfer.
Age is the best predictor of aneuploidy and a major factor to consider when thinking about aneuploidy. In a woman under age 30, about half of embryos are aneuploid. At age 42, around 80% of embryos are aneuploid. On occasion, especially in older age groups, all embryos from a cycle are aneuploid.
It is difficult to predict for an individual how many of the embryos will be aneuploid. In the extremes, we have seen circumstances where every embryo is euploid. Unfortunately somewhat more common is the opposite, all embryos aneuploid. Aneuploidy in all embryos from a cycle is unusual under age 30, but afflicts a third of cycles over age 40. The only way to tell if an embryo is aneuploid is to test.
The technology of PGT-A
For PGT-A, a few cells are sampled from the embryo and chromosomes counted. Those that test normal can be transferred back to the uterus for pregnancy. PGT-A allows for selection of the embryos most likely to result in successful pregnancy.
The technique of PGT-A requires IVF and growing embryos to the blastocyst stage (day 5 to 7). The embryo is "hatched” in the IVF lab, and a few cells sampled from the outer trophectoderm layer of cells (which later goes on to form the placenta and membranes of a pregnancy). The embryo is then vitrified (an advanced technique of embryo freezing), and stored for later transfer back to the uterus if euploid. The biopsied cell samples are sent to a PGT lab for a count of the chromosomes.
Embryos are stored after sampling, since genetic testing takes about a week. We are finding that almost all embryos do well with the freezing-thawing process, with >97% of embryos surviving vitrification and thaw. It appears that implantation rates actually improve with a delayed transfer in a cycle after the retrieval cycle. This is likely due to the effects of ovarian stimulation on the endometrial lining, making it a bit resistant to implantation in a fresh cycle. In a later natural cycle, the normal endometrial lining is restored with normal implantation rates.
Pacific Fertility Center uses Natera as its primary PGT laboratory. Natera uses a SNP microarray from Ilumina with a proprietary technology called Parental Support™, which tests all 24 chromosomes (22 numbered chromosomes plus the X and Y) and delivers results that are typically >99% accurate. There are certain patient-specific circumstances in which a different lab would be preferable and your genetic counselor will help determine if this indicated for you. Expectations are that on average about 1/10 eggs produces a chromosomally normal embryo, for example, starting with 10 eggs yields on average 7 embryos that on CCS testing will yield 1-3 with normal chromosomes.
The rate of chromosomally normal embryos varies between women especially with age. As women age, the chance of a chromosomally normal embryo declines. Under age 30, roughly half of embryos will be normal, and most young women find multiple euploid embryos after testing. Over age 40, 1/3 to 1/2 of all women will not find a viable embryo after PGT-A.
PGT-A Pros and Cons
Pros of PGT-A include:
- Improved selection of embryos most likely to result in pregnancy and birth
- Reduction in aneuploidy
- Reduction in miscarriage rate
- Improved implantation rate
- Reduced multiple (twin or more) pregnancy risk
- Identification of sex of embryo
- Rare errors in test results, assumed to be mostly due to mosaicism (mixture of euploid and aneuploid cells in an embryo) that is not detected
- Few randomized prospective trials
- Data on safety incomplete, but reassuring
- Data on delivered child outcomes is under continued study
Despite the fact that there are few randomized trials and data on outcomes is limited, we have enough experience with pre-implantation genetic testing to feel confident that this is a safe and highly accurate procedure.