PGS by NGS
Improve the chances of reproductive success with Next-Generation Sequencing for PGS
1.What is PGS for aneuploidy screening?
Preimplantation genetic screening (PGS) for aneuploidy is a powerful genetic test that may be performed on embryos during IVF treatment to screen for numerical chromosomal abnormalities. PGS is performed on a small embryo biopsy prior to transfer and identifies which embryos are chromosomally normal. Chromosomally normal embryos are the most likely to develop to term and to be born as a healthy baby. PGS testing helps IVF physicians and patients decide which embryos to transfer.
PGS offers comprehensive analysis of all 24 chromosome types: the two sex chromosomes (X and Y) and the 22 other non-sex chromosomes. Normally there are 23 pairs of chromosomes in each human cell. A numerical change in the number of chromosomes is called aneuploidy. Aneuploidy is responsible for the vast majority of spontaneous miscarriages and can result in birth defects and mental retardation in live born babies. Most types of aneuploidy are not compatible with life. The most common syndromes caused by non-sex chromosome aneuploidies are Down syndrome, Edwards syndrome, and Patau syndrome. Aneuploidy is usually not inherited and can involve any chromosome; however, the likelihood of embryos being aneuploid increases with the age of the mother.
Igenomix uses Next Generation Sequencing (NGS) as an effective technique for the analysis of copy number variation in single cells. This technology is specially developed for analysis of only a few cells or even a single cell as is required for preimplantation genetic testing. Validation studies with cell lines of known karyotype have been performed in our laboratory to optimize library preparation, timing and diagnosis accuracy. PGS testing with NGS is 99% accurate.
2. What are the benefits of PGS?
The majority of abnormal embryos are indistinguishable from normal embryos when studied using a microscope. Therefore, normal embryo appearance cannot be used to evaluate for chromosome abnormalities. For women in their mid-thirties and older, the risk of chromosome abnormalities is significantly higher than for younger women. Women with a history of recurrent miscarriage or recurrent implantation failure, or who have had a prior pregnancy with a chromosome abnormality, or men with abnormal sperm analysis may also create a higher percentage of abnormal embryos.
Increase in implantation rate: Some embryos that are chromosomally abnormal will fail to implant into a woman’s uterus. Therefore, by transferring chromosomally normal embryos, PGS by NGS can increase the implantation rate.
Reduction in miscarriage rate: In the general population, 20% of all clinical pregnancies miscarry and about half are chromosomally abnormal. Since PGS evaluates numerical changes in chromosome numbers and large chromosome imbalances, embryos with chromosome abnormalities will not be transferred. Therefore, especially, in high-risk groups, PGS reduces the risk of miscarriage.
Increase in the chance of delivering a healthy baby: Some pregnancies with chromosome abnormalities will result in the birth of a child with multiple serious anomalies. Therefore, PGS can increase the chance of delivering a healthy baby by assisting physicians in identifying chromosomally healthy embryos for transfer. These conditions can also be detected by chorionic villus sampling (CVS) or amniocentesis later during the pregnancy.
Decrease in time to achieve a pregnancy: With this approach, the time to achieve a healthy live-born decreases compared to a regular IVF cycle, avoiding multiple frozen embryo transfers before the transfer of the implanting embryo.
NGS provides a new approach to PGS with advantages including:
- Validated NGS protocol vs Arrays CGH:
Igenomix has validated NGS comparing the results with Array CGH technology. Array CGH will remain as a back-up technology in our labs.
- Sample throughput flexibility and scalability:
NGS enables the cost-effective screening of 2 to 24 samples per analysis, minimizing the need to batch embryos.
- Best Cost-Efficiency:
NGS enables more samples per chip, significantly driving down the cost per sample.
- New diagnostic possibilities:
NGS technology allows for embryo screening together with mitochondrial DNA screening (MitoScore).
3. Who should use PGS testing?
Over 50% of spontaneous miscarriages are caused by chromosomal abnormalities. Some birth defects are caused by chromosome abnormalities, and the risks of having a child with a chromosome abnormality increases with maternal age. Couples who are at increased risk of having aneuploidy embryos should consider using PGS testing. These groups of individuals include:
- Women over 35 years of age
- Couples who have experienced several spontaneous miscarriages of unknown cause
- Couples with several cycles of IVF that have not achieved pregnancy
- Men with low sperm concentration
- Couples with a previous pregnancy with chromosomal abnormality
The selection of chromosomally normal embryos in these couples greatly reduces the risk of miscarriage and increases reproductive success.
Delayed Maternity (Advanced Maternal Age)
The rhythm of life has caused more and more women to decide to become mothers later in life when their fertility has been reduced. A woman is born with a certain number of eggs, and her ability have children decreases over her lifetime, in part because the chance of chromosome abnormalities also increases as she ages. Most embryos with an incorrect number of chromosomes fail to implant or miscarry during the first trimester of pregnancy. The decline in fertility is gradual, but many medical providers consider the risks of chromosome abnormalities to be significant at age 35 or older. Chromosome abnormalities in live borns can cause conditions such as Down syndrome (three copies of chromosome 21 instead of two), Edwards syndrome, and Patau syndrome.
Approximately 50% of spontaneous miscarriages occur in the first trimester because of random (de novo) chromosome abnormalities. PGS studies in these couples have revealed that 65% of embryos are chromosomally abnormal, and in 15% of couples, all embryos are chromosomally abnormal. PGS evaluates all 24 chromosomes to detect any numerical chromosome abnormality. (Rubio et al., 2013).
Clinical studies show that the application of this technique doubles pregnancy rates obtained compared to 30% obtained without performing PGS*.
(*)Based on clinical studies performed by the IVI group up to 2012
Recurrent Implantation Failure
Sometimes, even when the egg is successfully fertilized and developing normally, it will not be able to implant into the uterus. This is called implantation failure and may occur because of abnormalities of either the uterus or the embryo itself. If chromosomal abnormalities are impacting embryo viability, the selection of chromosomally normal embryos will improve the chances of implantation and ongoing pregnancy. For couples who experience recurrent implantation failure, about 65% of embryos are expected to be abnormal. (Garcia-Herrero et al., 2015).
Igenomix offers different techniques for couples experiencing implantation failure to increase their reproductive success.
Male reproduction requires good sperm quality and quantity. In cases of severe male infertility, Igenomix can perform sperm chromosome studies (see Sperm Aneuploidy Test). We know that low sperm count increases the percentage of chromosomally abnormal sperm and therefore increases the risk of producing aneuploid embryos. PGS for aneuploidy screening to identify chromosomally normal embryos may increase pregnancy success for couples where the man has an abnormal sperm analysis. For couples who experience male-factor infertility, approximately 55-65% of embryos may be chromosomally abnormal, depending on the severity of the male factor. (Rodrigo et al., 2014).
4. What are the advantages of PGS testing with IGENOMIX?
- Robust and reliable technology using NGS with internal validation
- Comprehensive analysis of all 24 chromosomes
- Experienced genetic counselors
- Senior team who analyzes results for every embryo
- Banking/batching program for low responders
- 12-hour protocol allowing results to be provided the morning after the biopsy
- Double signature on all result reports
- Training of embryologists
- Guaranteed outstanding customer service
5. Genetic counseling
It is recommended that you have a consultation with a genetic counselor. The genetic counselor will describe the benefits and risks of PGS as well as answer any additional questions. This consultation can be arranged by calling customer service at +34 963 905 310, or can be arranged by your IVF clinic. Please call at least 3 business days prior to your biopsy date to schedule the appointment. You may also request a consultation to review the results after the testing has been completed.
1. What is embryo biopsy? Is the embryo damaged during the biopsy?
Embryo biopsy is the removal of one or just a few cells from the embryo (depending on the stage of development). If the embryo is handled correctly by a skillful embryologist, the embryo develops normally after embryo biopsy. Published studies demonstrate that there is no increased rate of birth defects in IVF babies that are born after biopsy compared to IVF babies that are born without embryo biopsy.
2. Can biopsy be done on day 3 or blastocyst stage (day 5)?
Igenomix can perform PGS testing on embryos that are biopsied at either day 3 or day 5. A 3-day-old embryo has approximately 8 cells, and so only a single cell is removed for a biopsy done at day 3. A 5-day-old embryo has a few hundred cells, and so several cells can be safely removed during the biopsy. There are several good reasons to do either a day-3 or a day-5 biopsy. The number of cells that can be safely removed, rates of mosaicism, expertise of the embryologist, and embryo quality are all important factors in deciding when to do embryo biopsy. Patients should discuss with their IVF doctor the best time to do the biopsy. (Mir et al., 2016).
3. Does PGS include all genetic diseases?
No genetic test can detect all potential genetic abnormalities. PGS testing for aneuploidy can only assess numerical changes in chromosome number and other imbalances in genetic material including deletions and duplications. PGS will identify any missing or extra chromosomes, deletions, duplications, and unbalanced rearrangements that are larger than our detection limit of 6 Mb. PGS for aneuploidy screening cannot rule out single gene disorders, balanced structural abnormalities, uniparental disomy, and genetic imbalances including deletions and duplications smaller than our detection limit of 6 Mb. PGS can detect some types of polyploidy but cannot detect polyploidy in which the sex chromosomes are found as a multiple of normal (triploidy 69,XXX and tetraploidy 92,XXXX or 92,XXYY).
4. What is the effectiveness of NGS for different indications?
When an embryo is identified as normal after PGS testing, the likelihood of a pregnancy is higher than 60% in women younger than 40 years. In women over 40 years, there is a higher percentage of cycles in which all embryos are abnormal, but when normal embryos are found, the likelihood of pregnancy is about 50%.
5. How many embryos are expected to be normal when using PGS?
The likelihood that embryos will be chromosomally normal decreases as women get older. According to data generated at Igenomix, the average percentages of normal embryos are:
|Maternal Age (years)||%Normal Embryos|
These estimates are based off of a large data set from many combined PGS cases and may not apply to small numbers of embryos from a single PGS case. Igenomix cannot guarantee that there will be normal embryos for any PGS test.
6. If PGS testing is done, is prenatal testing recommended?
Although PGS for aneuploidy screening is highly accurate, there is still a chance of misdiagnosis. PGS cannot detect mosaicism in the embryo because only a single cell or just a few cells are analyzed. Prenatal testing is recommended to confirm the results of PGS testing and may detect other abnormalities not tested for by PGS. Pregnant mothers should discuss options for prenatal testing with their obstetrician. Non invasive prenatal testing could be also an alternative.