Preimplantation Genetic Testing

Preimplantation genetic testing at a glance

• Preimplantation genetic testing (PGT) is a biopsy and lab analysis process that evaluates embryos for genetic abnormalities prior to implantation into the uterus during in vitro fertilization (IVF).
• PGT is an option for any patient undergoing IVF and is most commonly used for patients with known genetic diseases, a history of recurrent miscarriages, previous IVF failures, and/or patients over age 35.
• PGT is the term fertility specialists now use that covers the analysis done in preimplantation genetic screening (PGS) and preimplantation genetic diagnosis (PGD).
• The benefits of using PGT during IVF include fewer failed IVF cycles, lower incidence of congenital disease and lower risk of miscarriage.
• New developments in genetic testing technology, including next generation sequencing (NGS) that makes DNA genome evaluation more accessible, raise difficult but important questions in how we select embryos for transfer following PGT.

Preimplantation genetic testing guide

What is preimplantation genetic testing?
Identifying chromosomal abnormalities with PGT
When should PGT be used?
Risks and considerations of PGT
Next generation sequencing (NGS) and mosaicism

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What is preimplantation genetic testing?

Preimplantation genetic testing (PGT) is the process of testing embryos created during in vitro fertilization (IVF) to determine the presence of genetic abnormalities that can lead to pregnancy complications, birth defects, congenital disease and/or miscarriage. IVF with PGT can improve the chances of having a healthy child in situations where a parent has a risk of passing on a genetic problem. Risk factors include the age of the woman and the presence of an inheritable genetic disorder in one or both parents.

Many genetic disorders can be diagnosed with PGT of embryos. During testing, 5-6 cells from blastocyst embryos are removed and sent to a genetics lab. The embryonic blastocyst stage, which is usually reached around five days after fertilization, means two types of cell masses have formed (one for the fetus and one for the placenta).

After cells are removed from the blastocyst embryo for testing, all of the embryos are frozen. Once the genetic report of the embryos is completed, the embryos that do not have genetic disease or chromosomal abnormalities can be identified. Healthy embryos are then selected preferentially for an embryo transfer. This greatly increases the chance of having a healthy child.

Preimplantation genetic screening (PGS) is a term used when PGT is testing the embryos for the total number of chromosomes. This type of testing is now also referred to as PGT for aneuploidies (PGT-A) and PGT for chromosomal structure rearrangements (PGT-SR). It is a tool to help select the highest quality and healthiest embryo and avoid transferring those with genetic markers for congenital diseases such as Down syndrome and cystic fibrosis.

Preimplantation genetic diagnosis (PGD) is a term used when PGT is testing embryos of known genetic risk. PGD is also referred to as PGT for monogenic/single gene defects (PGT-M). This is used in cases in which testing of the parents prior to an IVF cycle has identified a genetic problem and the embryos are tested for that specific abnormality as well as the total number of chromosomes.

Identifying chromosomal abnormalities with PGT

The likelihood that an embryo has a normal number of chromosomes depends on a woman’s age, as illustrated in the following table. The below data on PGT for chromosomal abnormalities effectively illustrates the effect of a woman’s age on pregnancy outcomes with PGT.

When PGT is done to screen for chromosome numbers (PGT-A), there is a chance that there will be no normal embryos. Using PGT gives more confidence with the frozen embryo transfer that there will be a live birth of a healthy baby, but there is no guarantee that there will be a normal embryo.

Pregnancy rates with IVF using PGT are dependent on a number of variables: the IVF program, the biopsy technique, the freezing technique and the genetic testing lab. At RSC, we have had a consistent, reliable and high performance with PGT.

When should PGT be used?

A fertility doctor can help patients make the decision that is best for their unique situation. Generally speaking, one of the above forms of PGT should be considered for the following circumstances.

• • Patients with a known genetic disease or carriers of a genetic disease who wish to avoid having a child born with that disease.
  • Patients that have had prior recurrent miscarriages (2 or more), especially if the miscarriages were due to a chromosomal abnormality.
  • Patients that have not conceived in a previous IVF cycle.

• Patients that are 35 years and older who wish to decrease their miscarriage risk and decrease the risk of having a chromosomal abnormality detected in pregnancy.
• For patients who want to have chromosomal screening performed to reduce their risk of having a pregnancy complicated by miscarriage or a chromosomal abnormality.

Risks and considerations of PGT

Any time there is handling or manipulation of an embryo, there will be some risk of harm or loss. However, in our experience at RSC it is very rare to see any direct damage of the embryo with the biopsy.

The embryo does need to be frozen after the biopsy, and the risk of losing an embryo with the biopsy, freeze and thaw is about 5 percent. RSC has evaluated the survival of embryos that are frozen with and without a biopsy and there is no increased risk of loss with the biopsy. Pregnancy rates with embryos that have undergone a biopsy and freeze/thaw are as high as or higher than in un-biopsied embryos.

Additionally, while PGT greatly increases the chances of implanting a healthy embryo, it is not perfectly accurate. Though statistically unlikely, testing could falsely indicate that a healthy embryo is abnormal, or that an abnormal embryo is healthy.

Is there an increased risk of birth defects with PGT?

The risk of birth defects with PGT appears to be no higher than the risk of them in IVF without PGT. But the birth defect risk is 1 to 2 percent higher than the risk with natural conception.

What is the risk of miscarriage with PGT?

With PGT, the risk of miscarriage is between 7 and 10 percent. This is lower than the miscarriage rate of naturally conceived pregnancies, which is between 10 and 25 percent.

What is the pregnancy rate with PGT?

The pregnancy rate for embryo transfers following PGT is 70 to 75 percent in women under the age of 40. For women over 40 years old, the pregnancy rate decreases to 55 percent. In these women, it is thought that other genetic factors other than chromosome number also affect the embryo and hence pregnancy as the egg cell ages.

Next generation sequencing (NGS) and mosaicism

In the past few years, a new DNA technology called next generation sequencing (NGS) was introduced that is faster and less expensive than previous methods used to analyze DNA. It allows scientists to quickly obtain huge amounts of genetic information. How to interpret the genetic data obtained from embryos is an area of active research and debate in reproductive medicine.

At present, pregnancy rates using NGS technology are not higher than other DNA technologies, and it has not been shown to be more accurate than previously existing technologies. Much of the confusion about mosaicism in embryos (discussed below) originated with the introduction of NGS.

What is mosaicism?

Mosaicism is when not all the cells in an embryo have the same genetic composition. For example, some cells may have 46 chromosomes and some may have 47 or 45. This may occur with regular cell division, where a normal cell with 46 chromosomes splits into two daughter cells but does not split the chromosomes equally.

Studies show that errors in regular cell division do occur. It is thought that the normal cells grow better than the abnormal ones and that if most of the embryos cells are normal, then the small number of abnormal cells will die off as the embryo grows and develops. Since PGT involves testing just 5-6 cells of an embryo that has 150 cells, there is a chance that the cells removed for the biopsy are not representing the majority of the embryo cells.

Scientists disagree on how much mosaicism exists in an embryo. Estimates range from 7 to 20 percent. This can be one explanation for why PGT testing is not always accurate.

A PGT result may be reported as mosaic when the genetic test shows an ambiguous result for one chromosome. One interpretation is that of the 5-6 cells biopsied, perhaps just 1 or 2 cells are abnormal and the other 3-5 cells are normal. Each individual cell is not tested separately.

Mosaicism is a theoretical interpretation of why the results may be slightly abnormal. Possible explanations of an uncertain result can also be: only part of a cell was included in the biopsy, the DNA was not amplified (copied) properly, inaccuracies in the DNA testing, and limitations of the statistical analysis of the results.

What happens if a mosaic embryo is transferred?

The benefit of PGT is to transfer the best quality embryo to ensure the highest chance of having a healthy baby. If a mosaic embryo is transferred that has a low chance of being normal, the pregnancy rates are much lower and the miscarriage risks are higher. There is also a higher risk of having a child born with an abnormality. The benefits of PGT are lost.

RSC will not transfer embryos that are determined with high certainty to be abnormal. For those in which we would have low confidence, each individual case is considered. The risks of poor outcome depend on which specific chromosome is involved. In these cases, counseling is sought from a genetic counselor and a physician specializing in prenatal genetic testing.