Types of PGT

There are different types of preimplantation genetic testing (PGT). In general, PGT falls into two main categories: a genetic test that may be widely offered to anyone undergoing in vitro fertilization (IVF), or genetic testing offered only to people with known risk for passing on specific single-gene or structural chromosomal abnormalities.

For anyone doing IVF, PGT for aneuploidy (PGT-A) — formally known as preimplantation genetic screening (PGS) — is a test performed to determine whether an embryo’s cells have the correct number of chromosomes (46), versus too few or too many. Having an atypical number of chromosomes is called aneuploidy and can result in a fetus with a chromosome disorder, such as trisomy 21 (Down syndrome) or monosomy X (Turner syndrome). While PGT-A is offered routinely by many clinics and physicians to individuals or couples undergoing IVF, the benefits, risks, and limitations are complicated to assess and highly debated.

For patients with a known risk of passing down a certain genetic condition, there are two types of tests. Preimplantation genetic testing for monogenic disorders (PGT-M) is intended for people who are at higher risk of passing on an inherited condition caused by a defect in a single gene. Preimplantation genetic testing for structural rearrangements (PGT-SR) is intended for people known to have a structural chromosomal abnormality, such as a translocation or inversion, which results in extra or missing genetic material. The clinical usefulness of these preimplantation diagnostic tests for people with known risks — formerly called preimplantation genetic diagnosis (PGD) — is firmly established, according to the American College of Obstetricians and Gynecologists (ACOG).ⁱ

The new names for these three types of PGT were introduced in 2017 to improve consistency and communication between fertility professionals, researchers, and patients. These were published in a standardized glossary of fertility-related terms developed by the American Society for Reproductive Medicine (ASRM), the European Society of Human Reproduction and Embryology (ESHRE), and over 20 other international participating organizations.ⁱⁱ

Advances in PGT methods

Preimplantation genetic testing is usually performed when an embryo is at the blastocyst stage. Testing is performed on a sample of five to 10 cells taken from the trophectoderm, a layer of cells on the outer edge of a blastocyst that becomes a part of the placenta.ⁱⁱⁱ

Next generation sequencing (NGS) is the current gold standard for PGT of embryos because it is more accurate and faster than previous methods.^iv Widely available across North America, NGS can screen all 23 pairs of chromosomes in cells removed from the embryo before transfer, doing so more comprehensively and at a higher resolution than previous techniques.

Non-invasive chromosome screening (NICS) is a new technology for screening embryos for genetic abnormalities. It analyses DNA in the nutrient-rich solution around the embryo, instead of removing cells from the embryo. A 2019 pilot study suggests that this non-invasive technique could be a clinically viable alternative to NGS for PGT testing, but the researchers recommend that larger clinical trials be done to verify the findings.^v

Preimplantation genetic testing for aneuploidy (PGT-A) 

PGT-A screens for an abnormal number of chromosomes in embryos before transfer to the uterus. For each embryo tested, PGT-A results will fall into one of three categories:^vi

• ‍Euploid: These embryos have the typical number of 46 chromosomes in the samples of cells (called a biopsy) that were genetically tested. Therefore, euploid embryos are predicted to result in a fetus with the expected number of chromosomes.
• ‍Aneuploid: Aneuploid embryos have an abnormal number of chromosomes in the embryo biopsy and, as a result, a higher risk of failure to implant or miscarriage if transferred.
• ‍Mosaic: These embryos have the typical number of chromosomes in some of the biopsied cells and an abnormal number in other cells. Embryos reported as mosaics are at risk of producing a fetus with a mixture of cell lines — some with the typical number of 46 chromosomes and others with an atypical number.

PGT-A results can identify a risk of having both missing and extra chromosomes, which can also provide information about possible outcomes for the embryo. This information can help people make a more informed decision about which embryos to select for transfer to improve the chances of having a successful pregnancy and a baby without a chromosomal aneuploidy.

*Biopsy sample of cells taken from trophectoderm of the blastocyst (embryo)

PGT-A benefits

Research has shown that euploid embryos identified by PGT-A are more likely to successfully implant in the uterus and lead to a live birth compared to untested embryos.^viii Knowing whether embryos are chromosomally normal before transfer may be particularly useful for females with recurrent implantation failure (RIF) or recurrent pregnancy loss (RPL). It is also generally accepted that euploid embryos are much more likely to implant than aneuploid embryos and have more implantation potential than mosaic embryos.^ix

A study published in Fertility and Sterility found that after being identified by PGT-A, euploid embryos had a 70 percent implantation rate compared with 53 percent for mosaic embryos.^x Another study found a difference in implantation rates of 57.2 percent versus 46.5 percent in euploid and mosaic embryos, respectively.^xi The extent of mosaicism also has an impact; a recent study of 108 females with only mosaic embryos showed a live birth rate of 44.5 percent in low-level mosaics (embryos in which fewer than half of the biopsied cells are aneuploid) compared to 36 percent in high-level mosaics (embryos in which half or more of the biopsied cells are aneuploid).^xii

It is also known that the risk of aneuploidy increases with maternal age. Therefore, PGT-A might be particularly beneficial for patients at increased risk, allowing for the selection of euploid embryos for transfer, if euploid embryos are produced. For females 26 to 35 years old, over 65 percent of embryos tested euploid, based on PGT-A in over 10,000 embryo biopsies.^xiii This number declined steeply to less than 20 percent euploid after age 42. Another study showed that the likelihood of having at least one euploid embryo per IVF cycle is over 80 percent up until age 35, but decreases rapidly to less than 40 percent after age 44.^xiv While statistics from different studies vary, the evidence consistently shows that increasing maternal age is significantly correlated with increasing chances of producing aneuploid embryos.

Shorter IVF treatment time

For females with a significant number of embryos, PGT-A can shorten the treatment time and subsequent time to live birth. A 2018 study reported that PGT-A decreases the average time in IVF for patients with more than two embryos by more than three months.^xv The shorter time in treatment was mainly due to fewer unsuccessful transfers after genetic testing, although fewer miscarriages also shortened treatment time. That same study also determined the average female spends 56 days away from treatment after a failed embryo transfer and 134 days away from treatment after a pregnancy.^xvi PGT-A also shortens the time to live birth for individuals of advanced maternal age.^xvii

Reduced risk of miscarriage

Aneuploidy is the most common cause of miscarriage in the first trimester, accounting for an estimated 50 to 70 percent of miscarriages.^xviii Screening embryos for chromosomal abnormalities before transfer may help to identify embryos at higher risk of miscarrying due to embryo aneuploidy. A 2021 review study in the Journal of Assisted Reproduction and Genetics found a 45 percent lower miscarriage rate per clinical pregnancy after PGT-A.^xix

Lower risk of aneuploidy disorders  

Although most aneuploidies are incompatible with life, either because the embryos fail to implant after transfer or result in a pregnancy loss, some abnormal embryos may still implant and lead to a live birth of a child with a genetic condition. PGT-A may be able to identify aneuploidies that are compatible with life, such as Turner syndrome (which affects only females and is a result of the embryo having only one X chromosome instead of two) and Down syndrome (also referred to as trisomy 21, characterized by an extra chromosome).^xx

Some other trisomy conditions (in which there is an extra chromosome) that are compatible with life are Patau syndrome (trisomy 13), Edwards syndrome (trisomy 18), and Kleinfelter syndrome (affecting males with an extra X chromosome). These conditions can also be detected by non-invasive prenatal testing (NIPT), chorionic villus sampling (CVS), or amniocentesis later in pregnancy.

Reduced risk of multiple pregnancy

In the early days of assisted reproductive technology (ART), the chances of pregnancies with twins or other multiples were 20 times higher when ART was used than with natural conception.^xxi Multiple pregnancies are associated with a higher risk of complications for the mother and fetuses when compared to carrying a single fetus.

PGT-A helps promote the use of elective single embryo transfer (eSET) in females undergoing IVF by increasing the chances that a single euploid embryo will implant successfully and lead to a healthy live birth of a single baby.^xxii,xxiii This type of transfer reduces the incidence of multiple pregnancies and the associated health risks for the mother, as well as problems such as preterm birth and low baby birthweight. Ogilvie (2013) also suggests that single embryo transfer eliminates the potential need to undergo fetal reduction during pregnancy to save the healthiest fetus.^xxiv

Help with IVF decisions

Getting additional genetic information that indicates whether an embryo has a normal or abnormal number of chromosomes can help people make informed decisions about prioritizing which embryos to transfer.

PGT-A risks

PTA-A testing is not perfect and involves several risks:

Discarding viable embryos

For females who only produce a few embryos, disposing of mosaic or aneuploid embryos that could potentially lead to a healthy pregnancy may reduce these patients’ already limited chances of a live birth, according to recent evidence.^xxv,xxvi For example, a 2022 study observed that patients over 40 years old with fewer than four embryos created had a 99.7 percent chance of having no euploid embryos to transfer after PGT-A.^xxvii

Some embryos diagnosed as mosaic or aneuploid by PGT-A have the ability to produce healthy live births, according to a 2021 study from Nature Cell Biology.^xxviii Additionally, a 2019 study reported 106 successful live births after the transfer of embryos found to be abnormal by PGT-A, accounting for 49.3 percent of the cycles with “abnormal” embryos transferred.^xxix Likewise, a 2018 report found similar outcomes with the transfer of euploid embryos and low-level mosaic embryos (embryos in which fewer than half of the biopsied cells are abnormal).^xxx

Another risk for discarding viable embryos is misdiagnosis. For example, when the PGT result concludes that an embryo is aneuploid when it is actually euploid. Although the exact frequency of these technical errors is debated, estimates from several studies suggest a false positive rate of 2 to 5 percent in PGT-A.^xxxi,xxxii

In advance of working with a clinic, patients should ask whether they automatically discard aneuploid and mosaic embryos after PGT-A, or if the clinic allows transfers of either or both embryo types. Most clinics will have detailed policies setting out their preferences and practices regarding transfers of aneuploid and/or mosaic embryos following PGT-A, and it is worth learning more about these policies before doing PGT.^xxxiii

Biopsy harm

Removing five to 10 cells from the trophectoderm of an embryo with only 200 to 300 cells for PGT-A testing is an invasive procedure and may impact the embryo's viability or affect pregnancy outcomes. A 2020 study reported that the risk of pre-eclampsia (a serious high blood pressure complication of pregnancy) increased almost threefold to over 10 percent following trophectoderm biopsy, and a 2019 study also found an elevated risk of pre-eclampsia after the procedure.^xxxiv,xxxv Embryo biopsy was also associated with a small increase in preterm births, warranting further investigation, according to a 2021 study in the American Journal of Obstetrics and Gynecology.^xxxvi

Possible misdiagnosis

No genetic screening test is 100 percent accurate; false positives and false negatives can occur due to technical or human errors. Diagnostic errors with PGT-A are also possible because a few cells from the trophectoderm that are aneuploid may not be representative of the entire embryo or those of the inner cell mass that will become the fetus, according to guidelines from the Canadian Society of Fertility and Andrology.^xxxvii

Estimates of PGT-A diagnostic error rates vary considerably, ranging between 2 and 10 percent.^{xxxviii,xxxix} Diagnostic errors may be more common with mosaic embryos. A 2020 review study found that when mosaics were retested, they showed the same result just 42 percent of the time.^xl

Lack of high-quality evidence

Some IVF clinics claim that PGT-A increases live birth rates or the overall chances of having a baby. However, two recent randomized controlled trials — the STAR trial that involved over 600 females from 34 IVF centers in the U.S., Canada, U.K., and Australia, and the ESTEEM trial that involved 396 females from nine centers in seven European countries and Israel — found no overall improvement in live birth rates after the use of PGT-A.^xli,xlii

The Human Fertilisation and Embryology Authority (HFEA), the U.K.’s independent regulator of fertility treatment, has developed a red-amber-green rating system for treatment add-ons such as PGT-A. The HFEA gives PGT-A a red rating for improving chances of having a baby, saying that for most fertility patients, there is insufficient evidence from high-quality trials that PGT-A increases the chances of having a baby.^xliii Similarly, the most up-to-date guidelines by the European Society of Human Reproduction and Embryology (ESHRE) on the use of add-on treatments during IVF do not recommend the routine use of PGT-A.^xliv

Inconclusive results

PGT-A can produce an inconclusive result, which fails to indicate whether the embryo is euploid, aneuploid, or mosaic. Inconclusive results may be due to poor DNA quality, problems with biopsy techniques, shipping conditions of the biopsied sample, or human error. About 2.5 percent of biopsies in PGT-A will produce an inconclusive result, according to a 2019 study.^xlv A re-biopsy of a no-result blastocyst may be offered and give a conclusive result, but it is not known whether this additional testing would have an impact on pregnancy outcome, a 2018 study reported.^xlvi Meanwhile, another study found that embryos that had been re-biopsied, frozen, and re-thawed resulted in a lower pregnancy rate.^xlvii

Complexities of mosaic embryos

PGT-A can produce a mosaic embryo result, indicating that some cells may have the normal number of chromosomes and others an abnormal number. At the blastocyst stage, between 2 and 13 percent of embryos are mosaic, according to a 2021 literature review.^xlviii For mosaic results, false positives and false negatives are possible, or the results could be misleading because a biopsy of five to 10 cells from the trophectoderm may not represent the true proportion of normal and abnormal cells in the embryo.^xlix Although mosaic embryos are less likely to implant and more likely to result in miscarriage than euploid embryos, many live births of babies without chromosomal abnormalities have been reported after mosaic transfer.^l

A Duke study reported that mosaic embryos in which fewer than half of the biopsied cells were aneuploid had a 48.9 percent implantation rate and a 42 percent live birth rate, compared to a 24.2 percent implantation rate and a 15.2 percent liver birth rate for mosaic embryos with aneuploidy percentages of over 50 percent.^li

A 2020 study that looked at several thousand embryo transfers found that euploid embryos had a 57.2 percent rate of resulting in a live birth compared to 44.5 percent for low-level mosaics (in which fewer than half of the biopsied cells are aneuploid) and 30.4 percent for high-level mosaics (in which half or more of the biopsied cells are aneuploid).^lii

In addition, a 2024 study examined the prevalence of mosaicism in high-quality donated embryos and found that 82 percent had chromosomal abnormalities. The study concluded that in most cases, low levels of mosaicism may not impact the developmental potential of embryos, highlighting the need for further research into the potential of PGT-A to enhance clinical outcomes.^liii

No fresh embryo transfers

PGT-A usually requires the embryos to be frozen to allow enough time for testing to be completed. One large 2021 study showed that patients who received fresh embryo transfers at 370 IVF clinics in the U.S. had live birth rates of 56.6 percent, compared to 44 percent for frozen embryos.^liv

Additional cost

The cost of PGT-A is an issue to be considered along with the potential benefits, limitations, and risks. Costs in North America range from $5,000 to 10,000 USD and vary as to whether embryo biopsy, storage, and frozen embryo transfer fees are included. Costs also vary between clinics and based on the number of embryos tested.

A 2018 study of 8,998 patients from 74 U.S. clinics looked at the cost effectiveness of PGT-A and found that it can reduce the treatment time and risk of failed transfers or miscarriage.^lv While PGT-A did not impact the overall success rates per cycle, it did reduce the total costs associated with treatment in this group of patients.

Preimplantation genetic testing for monogenic disorders (PGT-M)

PGT-M is useful for people known to be at high risk for passing on an inherited condition caused by a single-gene abnormality. Similarly to PGT-A, a few cells from the early embryo, usually at the blastocyst stage, are biopsied to test for the familial condition.^lvi PGT-M has been successfully performed for conditions such as cystic fibrosis, hemophilia, Huntington’s disease, Duchenne muscular dystrophy, Fragile X syndrome, sickle-cell disease, thalassemia, and hereditary breast or ovarian cancer associated with a mutation in the BRCA1 or BRCA2 genes. PGT-M identifies embryos affected by these single-gene conditions and allows embryos not affected to be selected for embryo transfer, which significantly lowers the risk of the condition being passed on to a future child.

Preimplantation genetic testing for structural rearrangements (PGT-SR)

PGT-SR helps people known to have chromosomal rearrangements, such as a balanced translocation, or individuals who have had a child with a chromosomal rearrangement. Some people first find out they have such a chromosomal condition when they get testing during fertility treatments.

In PGT-SR, a few cells from the early embryo are biopsied to test for structural chromosomal rearrangements, which are changes from the normal size or arrangement of chromosomes.^lvii A person with a chromosomal rearrangement such as a translocation (segments of two chromosomes break off and switch places) or inversion (a chromosome segment is flipped and reinserted upside down) is at increased risk of producing embryos with missing (deletions) or extra (duplications) pieces of chromosomes.

These deletions and duplications reduce the chances of having a successful pregnancy and a healthy baby. PGT-SR can help identify large deletions and duplications in embryos, so that only embryos with the normal amount and arrangement of genetic material are selected for transfer.

Preimplantation genetic testing for polygenic disease risk (PGT-P)

A new type of PGT is preimplantation genetic testing for polygenic disease risk (PGT-P).^lviii Unlike PGT-M, which assesses the presence of a single-gene abnormality in the embryo, PGT-P is meant to identify complex genetic patterns that contribute to the risk of developing certain conditions such as cancer, heart conditions, type 1 diabetes, or schizophrenia.^lix A 2020 study tested this technology in a family with a case of type 1 diabetes and found PGT-P was able to identify embryos at an increased risk for the disease.^lx

Nonetheless, this technology is highly controversial, mainly due to the lack of conclusive evidence that PGT-P can significantly reduce the risk of genetic disease development. The complexity of polygenic diseases adds to the uncertainty, as the clinical significance of certain variants often remains unknown.

Significant ethical concerns should be addressed before the widespread adoption of this technology, such as the potential misuse of PGT-P for non-medical reasons (for example, selecting for traits like height, eye color, or IQ) and issues surrounding the accessibility of the technique due to its high cost.^lxi

Conclusion

Preimplantation genetic testing (PGT) refers to several types of genetic tests performed to evaluate embryos before transfer to the uterus. PGT is complex and expensive but aimed at improving reproductive outcomes. The benefits of PGT-M and PGT-SR are well-established for people with known risks of passing on single-gene disorders or structural chromosome abnormalities. PGT-A is more controversial because of questions around both the necessity of the test and the certainty of the results. Understanding the potential benefits, risks, and limitations allows each person undertaking IVF to make an informed decision about whether PGT-A may be a useful tool to help achieve a successful pregnancy.