PGT categories

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PGT falls into two main categories: a genetic test that may be widely offered to anyone undergoing IVF, and genetic testing offered only to people with known risks for passing on specific single-gene or structural chromosomal abnormalities.  

For anyone doing IVF, preimplantation genetic testing for aneuploidy (PGT-A) — formerly 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 (aneuploidy) 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 both complicated to assess and highly debated. For those with pre-existing reproductive genetic risks, 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, which happens when part of a chromosome is missing, extra, or has switched places with another part.  

The clinical usefulness of these tests for people with these known risks — formerly called preimplantation genetic diagnosis (PGD) — is firmly established, according to the American College of Obstetricians and Gynecologists.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, the European Society of Human Reproduction, and over 20 other international participating organizations.ⁱⁱ

Table 1. Types of prenatal genetic testing*

^{*Zegers-Hochschild, F., Adamson, G. D., Dyer, S., Racowsky, C., De Mouzon, J., Sokol, R., ... & Van Der Poel, S. (2017). The international glossary on infertility and fertility care, 2017. Human reproduction, 32(9), 1786-1801.  https://doi.org/10.1093/humrep/dex234}

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Advances in PGT methods

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PGT is usually performed when an embryo is at the blastocyst stage. Testing is performed on a sample of five to 10 cells 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 preimplantation genetic testing of embryos because it is more accurate and faster than previous methods.^iv NGS, which is widely available across North America, can screen all 23 pairs of chromosomes in cells removed from the embryo before implantation, doing so more comprehensively and at higher resolution than previous techniques.  

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

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PGT-A 

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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: euploid, aneuploid, or mosaic.^vi Euploid embryos have the typical number of 46 chromosomes in the samples of cells (biopsy) that were genetically tested. Therefore, euploid embryos are predicted to result in a fetus with the expected number of chromosomes. Aneuploid embryos have an abnormal number of chromosomes in the embryo biopsy and, as a result, a higher risk of not implanting or miscarriage, if transferred. Mosaic embryos have the correct number of chromosomes in some of the biopsied cells and an incorrect number in other cells. Embryos reported as mosaic 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.

Table 2. Classification of PGT-A results**

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

**Clinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: A committee opinion. (2020). Fertility and Sterility, 114(2), 246-254. https://doi.org/10.1016/j.fertnstert.2020.05.014

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PGT-A benefits

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While PGT-A cannot fix chromosomal anomalies in an embryo, it does screen for them, which increases the success rate per embryo transfer if an euploid embryo is available and transferred.^vii This is because individuals can prioritize which embryos to transfer based on the PGT-A results.

Increased chances of successful implantation  

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 those with repeated implantation failure (RIF) or recurrent pregnancy loss (RPL).^ix 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.  

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 women with only mosaic embryos showed a difference in live birth rates of 44.5 percent in low-level mosaics and 36 percent in high-level mosaics.^xii  

The risk of aneuploidy increases with maternal age, and PGT-A allows people to select euploid embryos for transfer, if euploid embryos are produced. For women 26 to 35 years old, over 65 percent of embryos tested euploid, based on PGT-A in over 10,000 embryo biopsies.^xiii This 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 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 differ, the evidence consistently shows that increasing maternal age is significantly correlated with increasing chances of producing aneuploid embryos.

Shorter IVF treatment time

For women with a significant number of embryos, PGT-A can shorten the treatment time and subsequent time to live birth. A 2018 study published in Fertility & Sterility reported that the average time in IVF treatment was reduced by over three months for women with more than two embryos.^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 woman spends 56 days away from treatment after a failed embryo transfer and 134 days away from treatment after a pregnancy loss.^xvi PGT-A genetic screening also shortens the time to live birth for women 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 can 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 they fail to implant after embryo transfer or result in a loss, some may still lead to a live birth of a child with a genetic condition. PGT-A may be able to identify aneuploidies compatible with life, which include two basic types: monosomies such as Turner’s syndrome (which affects only females and is a result of having only one X chromosome), and trisomies such as Down syndrome (also referred to as trisomy 21), characterized by an extra chromosome.^xx Some other trisomy conditions compatible with life are Patau syndrome (trisomy 13), Edwards syndrome (trisomy 18), and Klinefelter syndrome (male with an extra X chromosome).  Screening embryos for chromosomal abnormalities before transfer can 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 These conditions can also be detected by non-invasive prenatal testing (NIPT), chorionic villus sampling (CVS), or amniocentesis later in the pregnancy.  

Reduced risk of multiple pregnancy

In the early days of assisted reproductive technology (ART), multiple pregnancies were 20 times higher than in natural conception.^xxi Multiple pregnancies are associated with a higher risk of complications for the mother and babies than giving birth to a single baby. PGT-A helps promote the use of elective single embryo transfer (eSET)^xxii in women undergoing IVF by increasing the chances that a single euploid embryo will be implanted successfully and lead to a healthy live birth of a single baby, according to a 2021 study.^xxiii This reduces incidence of multiple pregnancies and the associated health risks for the mother, as well as problems such as preterm birth and low baby birthweight. Single embryo transfer also eliminates the potential need to undergo fetal reduction during pregnancy in order to save the healthiest fetus, suggests a Reproductive Biomedicine commentary.^xxiv

Help with IVF decisions

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

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PGT-A Risks

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Discarding viable embryos  

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

A 2019 study reported 106 successful pregnancies and live births.^xxix Similarly, a 2018 report published in Fertility & Sterility found similar outcomes with transfer of euploid embryos and low-level mosaic embryos.^xxx

Misdiagnosis, where a false positive result indicates an embryo is aneuploid when it is actually euploid, represents another risk for discarding viable embryos. Although the exact frequency of these technical errors is debated, estimates from several studies suggest a false positive rate of 2-5 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. A University of California Irvine School of Law study strongly recommends that clinics create or adopt detailed policies setting out their preferences and practices. regarding transfers of embryos showing chromosomal abnormalities following PGT-A.^xxxiii The study also looks at different arguments both for and against a physician’s decision to support or decline a patient’s request to assist in the transfer of a chromosomally abnormal embryo.  

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 have an impact on the viability of the embryo or affect pregnancy outcomes. A 2020 study reported that the risk of preeclampsia increased almost threefold to over 10 percent following trophectoderm biopsy,^xxxiv while a 2019 study also found an elevated risk of preeclampsia after this procedure.^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, for example, 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 Society.^xxxvii Estimates of PGT-A diagnostic error rates vary considerably, ranging between two^xxxviii and 10 percent.^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 women from 34 IVF centers in the U.S., Canada, U.K. and Australia,^xli and the ESTEEM trial, which focused on women 36 to 40^xlii — found no overall improvement in live birth rates after use of PGT-A. 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, 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  

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 technique, shipping conditions, or human error. About 2.5 percent of biopsies in PGT-A testing will produce an inconclusive result, according to a 2019 study.^xliv Re-biopsy of a no-result blastocyst may be offered and give a conclusive result, but it is not known whether this would have an impact on pregnancy outcome, a 2018 study reported.^xlv Meanwhile, another study found re-biopsied frozen and re-thawed embryos had a lower pregnancy rate.^xlvi    

Complexities of mosaic embryos

PGT-A testing can produce a mosaic embryo result, indicating that some cells may have the correct number of chromosomes and others an incorrect number. At the blastocyst stage, between two and 13 percent of embryos are mosaic, according to a 2021 literature review.^xlvii For mosaic results, false positives and negatives are possible or can 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.^xlviii 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.^xlix  

Mosaic embryos with aneuploidy percentages of less than 50 percent had a 48.9 percent implantation rate and 42 percent birth rate, compared to a 24.2 percent implantation rate and a 15.2 percent live birth rate for mosaic embryos with aneuploidy percentages of over 50 percent, a Duke study reported.^l  

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 (which have more than half aneuploid cells) and just 30.4 percent for high-level mosaics.^li  

No fresh embryo transfers  

PGT-A usually requires that if an embryo biopsy is done on day five of embryo development, the embryos will need to be frozen to allow enough time for testing to be completed. Some women undergoing IVF want fresh embryo transfers rather than frozen embryo transfers, often due to timing or costs involved. 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 with 44 percent for frozen embryos.^lii  

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 the costs of embryo biopsy, storage fees, and frozen embryos transfer are included. Costs will also vary between clinics and based on the number of embryos tested.

A 2018 study of 8 998 patients from 74 US 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.^liii 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.  

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PGT-M and PGT-SR

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PGT-M is useful for people known to be at high risk for passing on an inherited condition caused by a single-gene abnormality. A few cells from the early embryo, usually at the blastocyst stage,^liv are biopsied to test for the familial condition. 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.  

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

A few cells from the early embryo are biopsied to test for structural chromosome rearrangements, which are changes from the normal size or arrangement of chromosomes.^lv 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 correct amount and arrangement of genetic material are selected for transfer.  

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Conclusion

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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 both about the necessity of the testing 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.