A recent large randomised trial published in the New England Journal of Medicine is receiving significant attention with clinicians who are critical of preimplantation genetic testing for aneuploidy (PGT-A) claiming it provides evidence that PGT-A does not improve IVF outcomes and should not be used outside of research settings (see BioNews 1123).
Previous smaller trials had shown that PGT-A can improve live birth rate per transfer and improve selection for single embryo transfer, but typically limited analysis to the first embryo transfer procedure, as this meta-analysis published in Fertility and Sterility shows. The trial in the New England Journal of Medicine differs from other PGT-A trials by focusing on cumulative live birth, the chance that a couple will take home a baby after a year of treatment using the embryos created in a single IVF cycle using ICSI, with up to three transfer procedures.
It is important to realise that PGT-A was developed as a selection tool to eliminate the transfer of aneuploid embryos. Since aneuploidy of embryos increases significantly with advancing maternal age, those who promote PGT-A generally recommend it for IVF patients over the age of 35. Now more than a third of IVF cycles in the USA include PGT-A.
PGT-A is a complex procedure that involves biopsying cells from the outer layer (trophectoderm) of a blastocyst-stage embryo, carefully loading those cells into tiny PCR tubes, then amplifying the DNA for next-generation sequencing and analysis of chromosome copy number of the biopsied cells using bioinformatics algorithms. The purpose of PGT-A is to detect whole-chromosome aneuploidy, which occurs when an embryo originates from an egg and/or sperm that had an error in meiosis, and thus every daughter cell has an incorrect chromosome copy number. Using validated methods for PGT-A, embryos predicted to be aneuploid have essentially no chance at healthy live birth, but may result in miscarriage and ongoing aneuploidy syndromes, one multicentre, non-selection study published in the journal Fertility and Sterility showed.
This is different from embryos with a 'mosaic' result. These type of embryos were excluded from transfer in this recent trial, although mounting evidence supports the safety of transfer of 'mosaic' embryos, which perform similarly to euploid embryos (those with the correct number of chromosomes in all cells), a recent paper in the American Journal of Human Genetics showed (see BioNews 1122).
Since PGT-A is a selection tool, it would be mathematically impossible for PGT-A to improve cumulative live birth rates if all embryos are eventually transferred. It cannot produce more babies from the same cohort of embryos. However, PGT-A can reduce the treatment burden faced by IVF patients by reducing the risk that a transferred embryo does not implant or that an ensuing pregnancy results in miscarriage. A failed transfer can be devastating and after a failed transfer many patients are tempted to transfer more embryos in successive cycles with the additional risk that brings with it of multiple pregnancy and birth.
Since it was shown that transfer of a tested euploid embryo results in the same live birth rate as transferring two untested embryos in research published in the American Journal of Obstetrics and Gynecology in 2013 when PGT-A is employed, it has become standard care to transfer only one embryo at a time, even after prior failure, as outlined in American Society for Reproductive Medicine guidance.
The study design of this trial included a young, good prognosis population with average age 29 and an average of seven high-quality blastocyst embryos. The trial limited the PGT-A group to biopsy only three embryos, yet this is not how PGT-A is generally practised. In practice, all good-quality blastocysts are typically biopsied before cryopreservation. While the conventional IVF group had an opportunity to have up to three embryo transfer procedures, the PGT-A group would only have that opportunity if all three embryos tested normal. PGT-A resulted in a higher live birth rate per transfer (458/700 = 65.4 percent vs 494/835 = 59.2 percent, P<0.01). There were also more terminations and twins in the conventional IVF group though this was not statistically significant.
Embryos with a mosaic result were not permitted for transfer in the PGT-A groups, despite a large body of data suggesting it is safe to transfer these embryos, as was outlined in a multi-centre study published earlier this year in Fertility and Sterility. So even with a smaller pool of embryos to choose from, a similar cumulative live birth rate (85.3 percent with PGT-A and 82.5 percent without) was achieved with fewer transfer procedures and reduced miscarriage risk (8.7 percent compared to 12.6 percent).
IVF is a stressful and expensive process. Cumulative live birth rates may be maximised by successively transferring untested embryos in a trial and error fashion. Outside of a trial setting, some fertility patients drop out of care before achieving live birth. The ability to reduce the stress and financial burden of fertility treatment by achieving live birth with fewer failed attempts at IVF should not be undervalued.
Despite the headlines in the popular press, this trial supports the practice of offering PGT-A even to young patients at low risk of aneuploidy who want to minimise their risk of facing an unsuccessful embryo transfer or a miscarriage before achieving a live birth from IVF.