Success stories & clinical value of PGT-A

Dr Manuel Izquierdo
Director of Medical Quality & Consultant Gynaecologist, IVF Life Group

Category:
Genetics PGS / PGT-A, Success Stories

From this video you will find out:

What is PGT-A, and when is it indicated?
Why is it worth performing PGT-A?
Who can benefit from PGT-A?
How is PGT-A testing done?
What is the clinical value of PGT-A?

Success stories & clinical value of PGT-A

During this webinar, Dr Manuel Izquierdo, Director of Medical Quality & Consultant Gynaecologist at IVF Life Madrid, discussed the indications for Pre-implantation Genetic Testing (PGT-A) and shared some of his real-life patient cases, showing all the steps that allowed the couples to achieve pregnancy. Chromosomes are essential structures containing DNA information that determine our genetic makeup. They are arranged in pairs, with 22 pairs known as autosomes and one pair determining the sexual characteristics (X and Y chromosomes). During fertilization, the egg and sperm each contribute half of the chromosomes, forming a complete set in the embryo. Errors can occur during the division of chromosomes in gametes, resulting in abnormal karyotypes. These abnormalities may lead to conditions like Turner Syndrome (X chromosome deficiency) or Down Syndrome (extra chromosome 21). Many chromosomal abnormalities are not compatible with life, leading to failed implantation or early miscarriages.

Prevalence of Aneuploid Embryos and Maternal Age

A significant percentage of embryos are found to be aneuploid, with around 30% detected in women under 36 years old undergoing IVF. The rate of aneuploidy increases with maternal age, with 90% of day 5 blastocysts being aneuploid in women around 44 years old. The prevalence of aneuploid embryos negatively affects pregnancy rates in older women. Patients may struggle to conceive, even with regular periods and normal sperm parameters, due to chromosomal abnormalities in their eggs.

The Role of PGT-A in improving pregnancy chances

PGT-A (Preimplantation Genetic Testing for Aneuploidy) is a valuable tool to identify chromosomally normal embryos for transfer. In cases where a woman has a good ovarian reserve and produces multiple embryos, PGT-A can increase the chances of identifying a euploid embryo that has the potential to lead to a successful pregnancy. As women age, the quality of their eggs and embryos is affected, leading to an increased likelihood of chromosomal abnormalities. PGT-A can be a helpful option for those undergoing fertility treatments, as it allows the identification of chromosomally normal embryos, improving the chances of a successful pregnancy. Though pregnancy rates may decrease with age, the presence of euploid embryos offers hope and the possibility of starting a family.

Defining Repeated Implantation Failure

Dr Izquierdo addressed the concept of repeated implantation failure, where embryos fail to implant after several attempts. While embryo quality and morphological grading are considered, they do not provide perfect information about the embryos’ chromosomal constitution. Hence, it is vital to define repeated implantation failure carefully and consider chromosomal analysis as an option to improve success rates in such cases. The biopsy procedure for chromosomal analysis is a safe technique. Dr Izquierdo explained that the process is minimally invasive and does not pose a significant risk to the embryos. Additionally, the embryos are frozen while awaiting the analysis results, ensuring their well-being during the process.

Conclusion

In conclusion, factors such as age, previous attempts, and medical history should be carefully evaluated to determine if this option is suitable for each patient. Ultimately, chromosomal analysis can significantly improve the chances of successful implantation, pregnancy, and the birth of healthy babies, making it a valuable tool in fertility treatment.

Could sperm collected from procedure (mTESE) create a higher risk of chromosome errors?

This is a very good question. Back in the 90s, when ICSI was introduced, there were concerns about whether selecting one sperm for injection into the egg could introduce chromosomal abnormalities. However, we soon discovered that nature has built-in barriers to prevent non-selected, unhealthy sperm from fertilizing the egg. Today, the main concern is not about introducing more chromosome errors through this selection process.

I’m 50 and have undergone three IVF cycles with a Gonal F protocol of 300 units for 9 to 10 days. I got 7 to 22 follicles, but many of them were immature, especially in the first cycle with only nine days of stimulation. They froze the embryos on day three and tested them together, with two out of nine showing normal chromosomes. Is it too much to take 375 units of Gonal F for the first four days, followed by 150 units of Menopur and 300 units of Gonal F? My AMH is 4.05 nanograms per millimeter, FSH is 7, and AFC last month was 14. My other question is about freezing and unfreezing day three embryos. Can you biopsy a frozen embryo? My first clinic tested the embryos from day three, and some were frozen and some fresh. I’m now doing NGS and hoping for a euploid embryo.

At 50 years old, with an AMH of 4.05 nanograms per millimetre and FSH of 7, it is indeed surprising to still have an AFC of 14. Normally, by age 44, 90% of the embryos would have been aneuploid (chromosomally abnormal). However, it’s important to note that the initial test mentioned in the question refers to the FISH (Fluorescence In Situ Hybridization) method, which only tested five chromosomes. Today, with Next Generation Sequencing (NGS), it’s possible to test the full chromosome number, providing more accurate results. Testing and biopsying frozen day 3 embryos is possible, but the success rates for obtaining euploid embryos are generally lower compared to testing on day 5. Today, the standard approach is to allow embryos to develop to day 5 blastocysts before performing the biopsy. This allows for more accurate results and increases the chances of finding euploid embryos suitable for transfer. Embryo biopsy can be performed if the embryos reach day 5 and have enough cells for testing. However, it’s essential to manage expectations and be prepared for potential challenges in obtaining euploid embryos.

Would you recommend testing a frozen embryo for PGT-A, or is it too risky?

That’s a good question. We generally prefer testing embryos that have not been frozen. However, in some cases, we do test frozen embryos. The risk of not surviving the thawing procedure is not very high, but it is essential to consider the potential risks associated with freezing and thawing the embryo twice. While it is not the ideal scenario, there is some risk involved in the process.

Wouldn’t it be better to always offer PGT testing of all embryos, regardless of quantity, so that only euploid embryos are transferred? Considering the client’s situation, extra cost, and the potential emotional toll of multiple transfers and failures.

Yes, that’s a very realistic approach. While it’s not mandatory to test all embryos, it can be important to consider the chances of obtaining euploid embryos. If you have a high expected rate of euploid embryos, starting with a larger number to be tested may increase your chances of finding suitable embryos for transfer. Additionally, you can consider accumulating embryos for testing if needed. However, it’s essential to weigh the emotional and financial costs involved in multiple transfers and potential failures. Each patient’s situation is unique, and personalized treatment plans can help you make the right decision based on your specific circumstances.

Do you think that AI supports and affects the discussion of embryo transfer?

Yes, that’s a very good approach. Recently, I attended a scientific meeting where the topic of artificial intelligence (AI) was present in various fields, including fertility treatments. AI is being introduced and applied in fertility discussions, not only for embryo transfer but also for ovarian stimulation and other aspects of the treatment process. In summary, my conclusion after attending this conference was that AI is emerging as an ongoing helping tool in the field of fertility treatment. While it may not entirely take over decision-making in the next few years, it is starting to demonstrate its ability to assist us in making better choices regarding embryo transfer. AI can use morphological approaches and analyze the evolution of embryos inside incubators, providing information that may not be easily appreciated by humans. This information can lead to insights about which embryos are most likely to successfully implant. However, it’s important to note that AI’s role in fertility clinics is still in its early stages and not yet a daily basis approach. As AI technology continues to advance, it may play a more significant role in fertility treatments in the future. For now, it offers promising potential as an additional tool to support decision-making in embryo transfer discussions.

Do you detect only aneuploid embryos with any whole chromosome missing or any extra chromosome?

When we perform chromosomal analysis in embryos, we not only look for the number of chromosomes (aneuploidy) but also for chromosome structure. Some patients may have translocations, which are rearrangements of genetic material between different chromosomes. These translocations may have no impact on the health of the individual carrying them, but they can affect the embryos during cell division. For instance, in cases of minor translocations, where a segment of a chromosome is misplaced in another chromosome, the embryos may have an unbalanced chromosomal constitution. This imbalance could potentially lead to developmental issues. Therefore, in such situations, we not only examine the number of chromosomes but also the structure of the chromosomes in the embryos. Regarding the technical aspect, with the use of Next Generation sequencing (NGS) technology, we primarily focus on the chromosome constitution, i.e., whether the embryo has the correct number of chromosomes and their structure. This technology allows us to analyze the amount of DNA in each chromosome, determining whether the embryo has the appropriate balance of DNA in its chromosomes. This information is crucial in deciding whether an embryo is suitable for transfer. So, to answer your question, during chromosomal analysis, we consider not only the number of chromosomes but also any minor defects like translocations or inversions, and we carefully evaluate the DNA levels in each chromosome. This comprehensive assessment ensures that we select embryos with the best chances of a successful pregnancy.

I’m very worried about the concordance of Mosaic and aneuploid results in PGT-A. What is your opinion on this?

With the increasing amount of information available, we sometimes face challenges in determining whether embryos with Mosaic or aneuploid results should be transferred. In the past, when we performed a single-cell biopsy on day three embryos, we assumed that all the cells in the embryo, being 6 to 8 cells at that stage, had the same chromosomal constitution. However, with the current practice of embryo biopsy in the blastocyst stage, we often find that not all cells in the biopsy contain the same number of chromosomes. This situation is known as mosaicism. Regarding Mosaic embryos, the guidelines have evolved, and today, we consider transferring them if they are the only viable embryos available for transfer. Depending on the degree of mosaicism and after informing the patient about the potential risks, these embryos may be considered for transfer. In some cases, Mosaic embryos can self-correct during development, leading to a healthier chromosomal constitution in the final embryo. However, it’s essential to carefully assess the degree of mosaicism and the number of cells containing the incorrect chromosome number to make an informed decision about whether the embryo is suitable for transfer. Today, we are moving towards a more nuanced approach, taking into account the degree of mosaicism and the specific chromosomal abnormalities present in the embryo. It’s not just a black-and-white decision; rather, we use a greyscale approach, considering the various factors to determine the chances of implantation and the likelihood of a successful pregnancy with each embryo. In summary, while the concordance of Mosaic and aneuploid results in PGT-A can be a complex matter, our goal is to make the best possible decision based on the specific characteristics of each embryo and to provide our patients with all the necessary information to make informed choices about their fertility treatment.

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Authors

Dr Manuel Izquierdo

Dr Manuel Izquierdo is part of the IVF-Life group as Director of Medical Quality & Consultant Gynaecologist at IVF Life Madrid. Graduated in Medicine and Surgery from the University of Salamanca, specialising in Gynaecology and Obstetrics, from the Hospital Universitario Fundación Jiménez Díaz. Dr Izquierdo also holds an MSc in Human Reproduction from the Complutense University of Madrid. Dedicated to the field of fertility for more than 25 years, he has developed his profession in different centres, always projecting his vocation of help and service to patients until today.

Event Moderator

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.

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