PGT-A vs embryo grading: results of a 2021 clinical trial.

Researchers in a 2021 study found that women with three or more good quality blastocysts (by conventional grading), had a cumulative live birth rate that was similar to those that transferred up to three euploids.

PGT-A is a technique used to select the best embryos for transfer. It does this by evaluating the number of chromosomes present in a biopsy sample of the embryo. If there are 46 chromosomes (2 pairs of each of our 23 chromosomes), then the embryo is euploid and any number besides this is aneuploid. Aneuploid embryos are avoided for transfer because they are believed to the major cause of miscarriage with advancing female age.

There is controversy over whether or not PGT-A fundamentally works. It’s ability to decrease miscarriage isn’t clear, and a recent large RCT by Munne et al. (2019) (reviewed here) demonstrated that there was no advantage in using PGT-A over conventional grading for women <35, but there was an improvement in live birth rates for those aged 35-40.

Check my complete guide to PGT-A to get more background on PGT-A (aka PGS testing).

Adding to this, Yan et al. (2021) in their multicenter non-inferiority RCT between 2017-2018 compared conventionally graded embryos and PGT-A tested euploid embryos. Women had a good prognosis (20-37 years old).

The trial was designed to compare women with at least 3 good quality blastocysts: either these 3 embryos were tested and the resulting euploids were transferred consecutively up to 3 times, or these 3 weren’t tested and the embryos were transferred consecutively up to 3 times.

On Day 5, patients with 3 good quality blastocysts (grade 4BC or higher) were randomly assigned to the PGT-A group or the conventional grading group. In the PGT-A group, these 3 embryos were biopsied.

A single embryo was transferred (a euploid from the PGT-A group, or one of the three good quality embryos from the conventional grading group), and if it failed, then another embryo was transferred. In some cases, women had fewer than 3 euploids to transfer and they only transferred what they could.

In total, 1212 women were split into the two groups (606 in each).

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In the intention-to-treat analysis, the cumulative live birth rate after 3 transfers was 77.2% in the PGT-A group and 81.8% in the conventional grading group (rate ratio [95% CI]: 0.94 [0.89-1.00]).

They also reported the rates for each transfer:

• Transfer 1: 66.3% (PGT-A) vs 62.1% (conventional grading) – not statistically different
• Transfer 2: 62.2% vs 55.2% – not statistically different
• Transfer 3: 40.0% vs 38.8% – not statistically different

This data is important here, because it shows that there are no difference in each of the transfers when they’re head to head. In other words, PGT-A doesn’t select embryos that have a higher chance of working compared to traditional grading (at least for women <37).

The miscarriage rate was 8.7% in the PGT-A group and 12.6% in the conventional grading group which was statistically significant (rate ratio [95% CI]: 0.69 [0.49-0.98]). So a benefit of PGT-A might be selecting embryos that are less likely to miscarry. Remember, not all of the 3 embryos that were selected were euploid, so there’s some embryos that the PGT-A group didn’t transfer. Compare this to the group with conventional grading where most of the three embryos were transferred, and there was a slight increase in miscarriage rates.

The number of embryos transferred to obtain a live birth was lower with the PGT-A group (1.2 vs 1.3, absolute difference [95% CI]: -0.2 [-0.2 to -0.1]). The number of embryo transfer procedures was also lower with PGT-A (1.1 vs 1.3, absolute difference [95% CI]: -0.1 [-0.2 to -0.1]). This is another benefit of PGT-A we can see in this study, although the differences (though significant) are relatively minor.

They also did an awesome job reporting on obstetric and neonatal outcomes, much more thorough than I’ve seen before.

Adverse obstetric events:

• No difference in ectopic pregnancies (first trimester)
• No difference in vaginal bleeding (first trimester)
• No difference in gestational diabetes (second/third trimester)
• No difference in preeclampsia (second/third trimester)
• No difference in gestational hypertension (second/third trimester)
• No difference in premature rupture of membranes (second/third trimester)
• No difference in preterm delivery (second/third trimester)
• No difference in placenta previa (second/third trimester)
• No difference in placental abruption (second/third trimester)
• No difference in cervical incompetence (second/third trimester)
• No difference in anemia (second/third trimester)
• No difference in postpartum hemorrhage (after delivery)
• No difference in puerperal infection (after delivery)
• No difference in postpartum anemia (after delivery)

They also looked at adverse neonatal events:

• No difference in still birth
• No difference in neonatal hospitalization
• No difference in neonatal respiratory distress syndrome
• No difference in neonatal jaundice
• No difference in neonatal infection
• No difference in congenital anomaly
• No difference in low birth weight
• No difference in very low birth weight
• No difference in macrosomia

So conventional grading had a higher cumulative birth (81.8%) compared to PGT-A (77.2%). Slightly higher anyway – why is this?

Embryo biopsy was only performed on the PGT-A group, so it’s possible that the biopsy itself damaged the embryos and lowered their potential for live birth. Future studies that perform the biopsy on both groups (but only do PGT-A testing on one group) might prove if this is the case or not.

Another possibility is that only euploids were transferred, and not mosaics. Approximately 10% of the embryos tested were mosaic but were not transferred in this study.

This was a non-inferiority trial. This means that they designed it to answer a simple question: is PGT-A no worse (non-inferior) than conventional grading? It wasn’t designed to see if PGT-A is better (they would use a “superiority trial” design for that), but is it more or less the same as conventional grading? Non-inferiority trials are common in the drug industry, where generic drugs are tested against brand name drugs to show they have a similar performance. The margin of noninferiority in this study was 7%, so this was their cutoff (which was met).

The study compared women with 3 good quality blastocysts: one group tests them by PGT-A and transfers only the euploids they get, the other group transfers their 3 good quality embryos. Some women didn’t have enough euploids to make it to 3 euploid transfers. This wasn’t how the study was designed. The cumulative rate we’re looking at in this study is bearing this in mind – it is not comparing 3 consecutive euploid transfers to 3 consecutive untested embryo transfers.

So the real conclusion from all this is that for women less than 37, who have 3 good quality blastocysts, PGT-A doesn’t perform any better than conventional grading (in terms of cumulative live birth rate).

Even though conventional grading may select an embryo just as well as PGT-A in some cases, a benefit of PGT-A is identifying which embryos are aneuploid. Aneuploid embryos have a very low chance of producing a live birth, so even in younger women PGT-A may be desirable.

It’s interesting to compare this study to the Pierta et al. (2020) study (reviewed here), who found that women who transferred 3 euploid embryos consecutively had a 92% cumulative live birth. That study was retrospective. They were able to pick out data from their clinical databases to see how these women performed. This current study isn’t negating what Pierta et al. found because 3 euploids weren’t consecutively transferred across all the women, because this wasn’t the design of the current study.

Reference

Yan J, Qin Y, Zhao H, Sun Y, Gong F, Li R, Sun X, Ling X, Li H, Hao C, Tan J, Yang J, Zhu Y, Liu F, Chen D, Wei D, Lu J, Ni T, Zhou W, Wu K, Gao Y, Shi Y, Lu Y, Zhang T, Wu W, Ma X, Ma H, Fu J, Zhang J, Meng Q, Zhang H, Legro RS, Chen ZJ. Live Birth with or without Preimplantation Genetic Testing for Aneuploidy. N Engl J Med. 2021 Nov 25;385(22):2047-2058. doi: 10.1056/NEJMoa2103613. PMID: 34818479.

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About Embryoman

Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.

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