If you’re in the IVF world and haven’t come across PGT-A testing, its likely only a matter of time before you do.

Where does PGT-A fit in?

PGT-A is classified as an IVF add-on, meaning it’s not part of a standard IVF protocol. A protocol is generally stimulation, egg retrieval, embryo development and embryo transfer. Add-ons are processes, procedures or pharmaceuticals sometimes referred to as ‘supplementary add-ons’, ‘adjuvants’ or ‘supplementary treatments’ that have little or no evidence to support their efficacy and may carry an ethical burden.

What is PGT-A?

PGT-A stands for Pre-implantation Genetic Testing for Aneuploidies. It can be simply described as an investigation to determine how many chromosomes are in each cell of an embryo.

Why would this information be useful?

To understand why it’s being used, we need a tiny highschool biology refresher.

1 egg has 23 chromosomes
1 sperm cell also has 23 chromosomes

When PGT-A technology was developed back in 1990, a fundamental belief of healthy or viable conception was that a sperm fertilises an egg to create one embryo containing 46 chromosomes - 23 from each parent. That embryo cell multiplies creating more cells, each with 46 chromosomes.

We are considered to be chromosomally normal if each of our cells carries 46 chromosomes.

Counting chromosomes

During PGT-A testing, the embryo is biopsied and the number of chromosomes within each cell is counted.

PGT-A testing will give your embryo one of three classifications:

The cells have 46 chromosomes - the embryo is euploid, or normal
The cells have more or less than 46 chromosomes - the embryo is aneuploid, or abnormal.
Some cells have 46, and some don’t - the embryo is classified as mosaic

Using the information

When this technology was first being developed, researchers hypothesised that PGT-A testing will make IVF conception more likely based on the assumption that aneuploid embryos (“abnormal embryos”) are rarely destined for implantation, pregnancy and a healthy child. PGT-A would give doctors the ability to select normal euploid embryos, improving outcomes and success rates.

Sounds great. What’s the problem?

The problem is that the hypothesis was disproved - the highest quality research in the form of randomised controlled trials showed that PGT-A testing actually reduced the probability of pregnancy compared with the transfer of untested embryos.

What has current research found?

The last 20 years of research in this area has tried without much success to demonstrate the efficacy of PGT-A and it’s predecessor PGS.

The most recent research is the STAR trial - Single Embryo Transfer of Eupoid Embryo Trial, published in 2018. It looked at:

34 clinics and 9 genetic testing labs
Across four countries - the US, UK, Australia and Canada
Randomised 661 women.

STAR trial findings

The premise of this study was that half the group would have untested Day 5 embryos transferred, and the other half would have a PGT-A euploid (normal) embryo transferred.

The main finding - the ongoing pregnancy rates were statistically the same at 50% and 46% . PGT-A did not increase the likelihood of IVF conception.

Commentary on the STAR trial by Dr Glenn Schattman, an MD in the US specialising in reproductive endocrinology and fertility preservation and the past chairman the Society of Assisted Reproductive Technology, points out that if 50% of the embryos are truly abnormal, mathematically PGT-A should have had a higher implantation rate than the non tested group. So, either

The biopsy of the embryo is detrimental to the embryo, or
The tests are not accurate

What about mosaics?

If you opt to use PGT-A to investigate your embryos, theres a good chance you’ll be faced with a decision regarding a mosaic. Historically, mosaic embryos have been discarded, or put in the freezer with a big question mark. However, research shows this may be problematic.

Dr Schattman referring to a 2017 study;

“the additional problem of mosaic embryos still haunts us. There have been several studies recently published that refute the notion that mosaic embryos are abnormal and in fact, embryos with low rates of mosaicism have nearly identical outcomes compared with ‘euploid’ embryos”.

A Castle Built On Sand

In 2021, research review ‘PGT-A; A Castle Built On Sand"‘ was published. This study looked at all the research from the inception of PGT-A up to and including the STAR trial. Researchers outlined how PGT-A was fundamentally flawed due to it being developed on a lack of understanding and appreciation for the way chromosomes can change and develop at pre-implantation stage. PGT-A is based on the principle that how an embryo tests at day 5, is how it will continue to develop, however 20 years of research strongly implies that this is simply not true, embryos have an innate ability to self correct aneuploidy.

Thus, the concept of

Euploid - normal
Aneuploid - abnormal
Mosaic - a mix

Is simply, just not reliable.

Are you a good prognosis patient? PGT-A at 35 and over

The STAR trial did show that women over 35 were found to have statistically more chance of abnormal embryos, however, ongoing pregnancy rate in the randomised groups were statistically the same in both the control group (untested embryos) and the group that had PGT-A ‘normal’ embryos.

Something else very important to consider from the STAR trial; patients who didn’t get at least 2 good quality blastocysts were excluded from the data. This group was made up of predominantly women over 35 years.

Concern 1: The uterus is potentially more hospitable than the lab
Dr Schattman is of the mindset that the uterus is potentially more hospitable than the lab, and outlines that this exclusion of data is problematic because some of these women may have benefited from a day 3 transfer.

Concern 2: A targeted demographic?
A study from the University of Auckland on NZ and Australian IVF clinic websites found that PGT-A is being advertised in a way that suggests it is potentially most effective for women 35 years or older.
Remember - this is the group with the biggest exclusion rate, so have the most impacted data. If the Sydney marathon calculated the average time of all the professional marathoners to be 2 hours, and then advertised that time as being the average for all the participants, every amateur runner would expect to be able to run the race in about 2 hours. This is total nonsense. The data that is relevant the amateur, has been excluded. This group of women is most likely to have low numbers of embryos, and stand to lose the most from incorrect results, damage to the embryo during testing or the thaw process.

First do no harm

We have to take PGT-A seriously. Research clearly shows that PGT-A decreases the likelihood of IVF conception by virtue of discarding or ruling out potentially healthy embryos.

“Primum non nocere: First do no harm. To maximize pregnancy rates and micromanage the selection of preimplantation embryos, patients are getting hurt. Our infertile patients come to us with a single goal: to achieve a pregnancy and deliver a healthy child. Performing genetic testing on preimplantation embryos appears to run counter to that goal.”
Dr Glenn Schattman

Want to read about PGT-A testing from another perspective? Read embryologist Kristen Jones’s break down on PGT-A testing here

A simple explanation of how PGT-A decreases your chance of IVF conception