PGS – aneuploidy screening
Previously referred to as preimplantation genetic screening (PGS), Preimplantation Genetic Testing of Aneuploidy (PGT-A) is a method that analyses a small number of cells taken (biopsied) from each embryo before they are selected for transfer. It enables us to find out whether the embryos from assisted reproductive treatments such as in vitro fertilization (IVF) or ICSI show randomly developed changes in their chromosome number that could be caused by the age of the egg and sperm provider, or the external environment. PGT-A is therefore able to determine whether the embryo has a normal (euploid) or abnormal (aneuploid) number of chromosomes within its cells before pregnancy is attempted in a subsequent frozen embryo transfer (FET) cycle.
In theory, by excluding abnormal embryos, shortens the journey to the right embryo which in turn should increase the chance of a successful pregnancy and live birth. It also increases the chances of having no embryos to transfer in a treatment cycle however, if all the embryos are found to be chromosomally abnormal.
Historically, evidence supporting PGT-A as beneficial was poor as earlier forms of chromosomal screening such as fluorescent in-situ hybridisation (FISH) may have shown little benefit. The newer, more comprehensive screening approaches such as next-generation sequencing (NGS) are seen to benefit patients undergoing PGT-A, and the latest evidence from several clinics/studies have been very encouraging.
The assumption is that at least half of all embryos that reach the blastocyst stage have a chromosome abnormality which could lead to their failure to implant, early miscarriage or a birth affected by congenital abnormality, although early miscarriage could also be due to other hormonal or implantation factors. The frequency of chromosome aberrations in recognized pregnancies is at the beginning are much higher than at the time of live birth. This means that the majority of chromosome aberrations are miscarried in the course of pregnancy. The spectrum of chromosomal defects detected in new-borns is dependent on whether the defect is compatible with intrauterine development.
A common chromosomal defect diagnosed during pregnancy and at childbirth is Down syndrome – when three copies of chromosome 21 instead of two are found in each cell, known as Trisomy 21. Any chromosome can be affected by aneuploidy however, and the majority of embryos with chromosome aberrations are miscarried at an early stage of pregnancy.
PGT-A is offered to patients with a higher risk of aneuploidy within their eggs/embryos:
• Couples with recurrent miscarriages up to week 12 of pregnancy
• Older women (over 40 years)
• Patients with recurrent failures of IVF cycles
It should be noted here that the efficiency of PGT-A expressed by an increase in live births compared to live births without PGT-A has not been reliably proved yet. The current aim of PGT-A therefore is to decrease the time to pregnancy by further refining the selection of embryos for transfer, only transferring embryos that are classed as chromosomally normal from the cell biopsy results.
PGT-A is performed during a cycle of in vitro fertilisation (IVF). The egg provider will complete hormonal treatment for controlled ovarian stimulation to produce a number of mature oocytes (eggs). The oocytes are removed during a simple operative procedure and fertilised using the partner's or donor sperm in the laboratory. The embryos are cultured in the lab for up to 7 days and using micromanipulation, a portion of the embryo’s outer cells (trophectoderm) are removed at the blastocyst stage on days 5 to 7 of development. At City Fertility, embryos that are classed as chromosomally abnormal following PGT cannot be transferred.
Biopsying embryos at the blastocyst stage does not practically present any additional risk for the embryo, has a higher diagnostic value and is economically more advantageous for both the patients and the clinic. Only embryos with the highest chance of forming a pregnancy are biopsied and frozen for potential future treatment therefore. The embryos are frozen using the modern vitrification method and the replacement of any chromosomally normal embryo can take place in a future Frozen Embryo Transfer (FET) cycle after the endometrial lining has been optimally prepared.
Success rate of PGT-A
Below are City Fertility's success rates comparing our success from PGT-A vs. untested FET cycles. The stats are covering Clinical Pregnancy Rates (CPR) as well as Live Birth Rates (LBR) per Embryo Transfer procedure (ET) as well as per Embryo Transferred (ET'd). These include data up until 6th May 2022 and although we have only performed 19 PGT-A embryo transfers for 16 patients in the years 2018-2022, our Live Birth Rate (Take Home Baby) per Embryo Transferred following PGT-A testing is 57.9% (11/19) compared to 23.9% (38/159) for untested FET embryos.
The most interesting statistic is in patients aged 40 and over, the PGT-A Live Birth Rate per Embryo Transferred was 50% (4/8) while in untested embryos it was 10% (4/40). As we have found only 15% of embryos to be chromosomally normal in patients 40-42, PGT-A does reduce the number of patients ending up with a transfer, but greatly improves the chances of live birth / reduces the number of miscarriages if a normal embryo is identified and transferred.
PGT-A can identify embryos suitable for transfer with greater than 97% accuracy, but it cannot detect abnormalities caused by random mutations and other developmental defects that have no clear genetic cause (these occur even in 3–5% of non-IVF pregnancies). Therefore, for PGT-A pregnancies the same prenatal care and screening is recommended as for any other pregnancy.
Some embryos contain a proportion of both normal and abnormal cells. These are known as “mosaic” aneuploid embryos and in some circumstances their transfer is permitted in the absence of any normal embryos and after the patients have had further genetics counselling on the implications of transferring a mosaic embryo.
Sex selection for X-linked diseases
Preimplantation genetic testing with sex selection may be offered to couples with a genetic disease that is linked to the sex chromosome X, if the condition cannot be identified using the more specific PCR method.
Sex selection is uniquely performed for genetic reasons as sex selection for family balancing is not permitted under UK law. Diseases for which sex selection can be performed as opposed to identifying the specific mutation must be verified with the HFEA by the treating centre prior to embarking on the treatment cycle.
Procedure and risks
PGT for X-linked diseases is performed in a similar way as PGT-A.
If the genetic disease is linked to the maternal X chromosome (mother is an unaffected carrier), theoretically 50% of the boys could be affected by the disease and 50% of the boys could carry the „healthy“ X chromosome. Therefore, the biggest hindrance of the sex selection method when performing PGT of X-linked diseases is the fact that by sex selection, healthy boys would not be considered for the transfer either. Therefore, this method is only used in cases when it is not possible to perform a targeted PGT via PCR.
New screening method – Next Generation Sequencing
Screening of aneuploidy is now performed using the Next Generation Sequencing (NGS) method. As with Array CGH, this technique enables us to assess all 24 chromosomes however studies have shown the NGS screening method to be more sensitive and therefore more accurate when compared to Array CGH. Both methods replace the now obsolete FISH method for PGT-A.
PGT-A is outlined as an additional treatment option by the Human Fertilisation and Embryology Authority (HFEA) and has currently been deemed as red in the HFEA traffic light system for additional treatment options as there is no evidence from randomised controlled trials to show that it is effective at improving the changes of having a baby for most fertility patients. For more information on this HFEA add-on, please follow the link provided.
As per HFEA “PGT-A does not carry any additional known risks for the person undergoing fertility treatment. However, PGT-A is known to carry some risks for the embryo:
- Although current PGT-A techniques are mostly very accurate, the test may give the wrong result (it may miss an abnormality or detect one that isn’t there).
- Using PGT-A may mean you have fewer embryos to use in treatment, or for freezing to use in treatment later. If any healthy embryos are erroneously discarded in this process, you may have fewer chances to transfer an embryo which could develop into a healthy baby.
- Removing a cell from the embryo may damage it and prevent it from successfully developing once it’s been transferred to the womb.
- Removing part of the embryo may cause changes in later growth in the womb, which may cause problems in later life.
- In some cases, cells within the same embryo are not chromosomally identical (known as ‘mosaic’), which means that PGT-A may show that the embryo has chromosome abnormalities when in fact it’s capable of producing a normal pregnancy or vice versa. In some clinics, mosaic embryos are considered for transfer, even though they show some chromosomal abnormality.”
As per HFEA “PGT-A is traditionally offered to women over 37, patients who have had several miscarriages or failed IVF cycles, people with a family history of chromosome problems, and men whose sperm may carry abnormal chromosomes.
PGT-A is now mostly carried out at the blastocyst stage on day five or six. There is no evidence from RCTs that PGT-A carried out at this stage is effective at improving your chances of having a baby for most patients undergoing IVF. It appears possible that reduced availability of embryos for transfer following PGT-A may counter any benefit of embryo selection.
There have been no RCTs conducted where the main objective of the study was to assess the effect of PGT-A on the rate of miscarriage. There is some evidence that suggests PGT-A may be beneficial for certain categories of women, particularly older women, in relation to a potential reduction in miscarriage. It is important to keep in mind that this reduction in the rate of miscarriage does not increase the chances of having a baby. It is likely that, with PGT-A, embryos that express a chromosomal abnormality that could lead to a miscarriage are not selected for embryo transfer. This means that although the patient does not have a miscarriage, she also does not become pregnant because the embryo transfer did not take place.”
It is also important to keep in mind that the evidence that PGT-A can reduce the rate of miscarriage in certain groups of women are secondary outcomes, that is, they were not the main aim of this research. This means that the study was not designed to investigate the effect of PGT-A on miscarriage rate, which may make these secondary results less reliable. For this reason, it is important to discuss your individual circumstances with your doctor.
At the October 2019 Scientific and Clinical Advances Advisory Committee (SCAAC) meeting the Committee evaluated the evidence base for PGT-A. Minutes of this discussion and the evidence used to inform this discussion are available on the SCAAC webpage.
This Cochrane review has further information on the evidence for PGT-A.”
For more information on this HFEA add-on, please follow this link.
This link will provide the costed treatment plan for PGT-A treatment (PGT-A CTP).