PGT-A & its use with Frozen Donor Eggs

Fairfax EggBank Roundtable Series

The Fairfax EggBank Roundtable Series Launched in Q3 2023 with the goal of engaging industry leaders in dialogue aimed at addressing practice patterns in emerging and non-standardized areas of practice. 

Our first topic was on Preimplantation Genetic Testing for Aneuploidy (PGT-A) & its Use with Frozen Donor Eggs. 

PGT-A is a technology that has traditionally been used to prioritize the transfer of euploid embryos. While aneuploidy has been detected in embryos and pregnancies regardless of the egg source age, it is well documented that the rate of aneuploidy increases with advancing age. Given that most anonymous egg donors are below the age of 30, the question remains: is PGT-A indicated for embryos conceived using donor eggs?

To help us explore this topic, we invited several experts in the field for a roundtable discussion. Their expertise spanned specialties including embryology, reproductive endocrinology, genetic counseling, and nursing. We were curious to understand, based on their experiences, how they manage discussions on PGT-A with patients.  There are clear benefits to the use of PGT-A such as reducing the miscarriage rate and shortening the time to achieve a pregnancy. However, there are also challenges associated with it such as the implications of mosaic results and the cost-benefit to patients with a low number of blastocysts.  We started our discussion on the indications for PGT-A. Typically, a cohort of donor eggs contains ~6 total eggs. The blastocyst rate varies but it’s usually between 1-3 blastocysts (days 5-6). With that in mind and given the typical young age of anonymous egg donors, the roundtable participants concurred that the cost-benefit of PGT-A for recipients in these scenarios does not warrant recommending it for their embryos. Dr. Eric J. Forman, MD, HCLD, the Medical and Laboratory Director at Columbia University Fertility Center, summarized his stance by saying:  

“I think the terminology is important; “offer” versus “recommend.” PGT-A should be offered to anyone doing IVF as part of comprehensive genetic counseling. I do not necessarily recommend it to patients using donor eggs, fresh or frozen, because the expected aneuploidy rate is very low.” 

Eric J. Forman, MD, HCLD

While recommending PGT-A for all egg donor-conceived embryos may not be the standard of care, there was agreement that recommending it would be warranted based on patient-specific factors including: 

• Patients planning to use a gestational carrier where reducing the risk of pregnancy loss is preferred/required.
• Male with an autosomal dominant condition, chromosomal structural rearrangement, or other male factor infertility requiring PGT-M and/or PGT-SR, where PGT-A is usually performed concurrently with PGT-M or inherently as part of PGT-SR analysis.
• Clients with a history of unexplained recurrent pregnancy loss who desire minimizing the recurrence of loss.
• Requests for sex selection, although the purchase of more than one cohort of frozen eggs may be encouraged in these cases to increase the number of available blastocysts.
• Patients from states with an abortion ban in order to minimize the risk of needing to consider a medical abortion.

It is not possible to discuss indications for PGT-A without considering the implications of results on transfer decisions. In particular, mosaic (or intermediate copy number) reporting has become an integral component of PGT-A results. It creates a challenge in discussions with patients considering transfer of donor egg-conceived embryos, especially given the relatively low yield of blastocysts per cohort and the young age of donors. In addition, patients have higher expectations for PGT-A results in these scenarios because they have invested a lot into the process. Receiving mosaic results can be confusing and frustrating, and patients generally feel less inclined to transfer these embryos than if they were autologous embryos.

So, is there a need for mosaic results to be part of PGT-A results reporting? Dr. Claudio Benadiva, MD, HCLD, the Medical Director of The Center for Advanced Reproductive Services in Connecticut explained his view on this issue:  

“If we’re doing PGT-A then I want mosaic results reported by the lab. However, for patients using donor eggs, it adds another layer of complexity to the discussion. What if they get only one embryo that is a mosaic? This is one of the reasons why I don’t routinely recommend PGT-A when using donor eggs.” 

Claudio Benadiva, MD, HCLD

Recent literature indicates that while mosaic embryos overall have less reproductive potential compared to euploid embryos, low mosaic embryos have a comparable reproductive outcome. Some of the larger studies enabled ranking of mosaic findings by likelihood for positive clinical outcome, with mosaic segmental mosaicism of any level performing best, and high-level whole chromosome mosaicism performing least. The studies differed in their design and sample size (e.g. retrospective versus prospective) and there may have been selection bias for a few. As such, the roundtable participants noted that additional research is needed to better under the clinical significance and outcomes of transferring mosaic embryos. Nonetheless, given the benefit of facilitating decision-making on embryo transfer, a lot of clinicians still desire mosaic reporting to be part of PGT-A results reporting.  Andria Besser, MS, CGC, the Director of Reproductive Genetics at the NYU Langone Fertility Center, noted that her center was receiving more mosaic results on donor egg created embryos than fully aneuploid results, which eventually prompted her team to discourage the use of PGT-A in these cases. She explained:  

“It is important to define what is meant by not reporting mosaicism. If [masked] mosaic results are grouped together with euploids, then mosaic reporting [instead of masking] can do more harm than good, particularly in embryos created from donor eggs. The main purpose of PGT-A is to exclude [the transfer of] fully aneuploid embryos; mosaic results are not as clinically significant.” 

Andria Besser, MS, CGC

There are arbitrary cut offs for when laboratories consider mosaic results low, intermediate, and high. There are also arbitrary cut offs for when mosaic results can be reported as euploid, with cut offs ranging between <20-40%. Dr. Cihan Halicigil PhD, HCLD, the laboratory director at Yale Fertility and Greenwich Fertility in CT, noticed that switching from one PGT-A laboratory to another affected the number of mosaic cases at his center. He added:  

“The fundamental differences between laboratory PGT-A results are associated with the [technology] platforms used. More focus should be made on validating these methods.”

Cihan Halicigil, PhD, HCLD

The roundtable participants indicated that embryo morphological grading does not always correlate with euploid results. However, there is a tendency in the field to prioritize the transfer of euploid embryos with lower grading than mosaic or aneuploid embryos with higher grading. As such, clinicians try not to place so much emphasis on morphological grading of embryos when PGT-A results are available.

When it comes to biopsy procedures, other than making sure enough cells are biopsied and the washing is done properly, there is currently no sufficient evidence to correlate biopsy procedures with rates of PGT-A euploidy/aneuploidy. More data would be needed to arrive at any conclusions.  Given the crucial role that labs play in PGT-A results analysis and reporting, the roundtable participants shared the criteria they evaluate for choosing a lab. They place their preferences on:

• The type of validation studies and clinical outcomes assessment performed on aneuploid and mosaic results, not just euploid results.
• The criteria used to determine cut offs for euploidy and aneuploidy.
• Hours of operation and days of the week when they can accept samples.
• Ease of ordering.
• Ability to work with most insurance plans.
• The availability of pre- and post-test genetics counseling services.
• Transparency in results reporting.
• A “no results” reporting of <2-3%, and clear reasons for this type of results in order for the clinic to trouble shoot.
• The ability to store DNA from embryo biopsies for additional testing, if needed.
• Kit size and storage.
• PGT-A technology used. For example, SNP-based PGT-A which can be useful for some cases.
• The use of AI in reporting and having a portal for accessing PGT-A results.

One aspect of PGT-A to note is that it is not a covered benefit for most insurance plans. However, more recently, there have been a few plans on the market that cover part or all of the cost. That said, coverage does not necessarily affect the clinician’s standpoint on the indication (or lack thereof) for PGT-A. It is an overall easier discussion when there is coverage, but it does not alter the clinician’s decision on the recommendation of PGT-A based on the case and all factors involved.  Lastly, it is important to acknowledge the existence and benefits of support groups for patients on social media platforms. Patients may have higher trust towards their support peers relative to their clinicians and may take the information discussed back to their groups for weigh in. While patients who belong to these groups often come into clinical consultations with certain preconceptions, they often are very well educated on topics like mosaicism and discussions with them can be efficient given the knowledge base they come in with. Jill Chisholm, APN, WHNP, Founder and President of GeneScreen, added:  

“I welcome anyone who has educated themselves on the topic [of PGT-A]. It can be challenging when patients come in with a lot of information, but it can also be beneficial when they have sufficient background and good questions.”

Jill Chisholm, APN, WHNP

 Clinicians can play a huge role in facilitating the discussion on PGT-A, clarifying some of the misconceptions, and closing potential knowledge gaps. As such, while there is a lot of useful information shared on PGT-A in support groups, clinicians can play a huge role in distilling the complexity to suit the needs of each patient.  

In conclusion, PGT-A is a technology that has proven to be useful but may not be indicated for all cases, especially in cases of embryos created using donor eggs. The decision to offer it should always be patient-centered and based on various clinical factors.