Balancing the clinical benefits in miscarriage risk against the non-benefits in cumulative live birth rate.
Chromosomal screening of polar bodies for embryo selection in assisted reproduction makes no difference to live birth rates, according to results from the much anticipated ESTEEM trial, the largest published study of its kind. Results from this multicentre randomised controlled trial designed and supported by ESHRE, have now been reported in Human Reproduction (1) and, say the authors, confirm the "widely accepted" view that preimplantation genetic testing for chromosome abnormality (PGT-A) will not increase live birth rates in IVF.
The study, which recruited its first patients in 2012, was performed in 396 women of "advanced maternal age" (aged between 36 and 40), a patient group considered likely to benefit from PGT-A. The women, treated in nine centres in seven countries, were randomly allocated to PGT-A (205 subjects) or no PGT-A (thus, a control group of 191 subjects).
Results of the study showed that up to one year after randomisation and after a first cycle of treatment 24% of the PGT-A group had had a baby, and 24% of the control group. This - measured as cumulative live birth rate - was the study's primary endpoint.
There was, however, a marked difference in the miscarriage rate (a secondary endpoint) between the two groups: significantly fewer subjects with a miscarriage in the PGT-A group than in the control group (7% versus 14%).
The similarity in live birth rates was not only achieved with fewer miscarriages in the PGT-A group, but also with fewer embryo transfers (and fewer double embryo transfers, as the protocol allowed). This, say the authors, would point to "a greater efficiency of transfers with PGT-A". However, they add, "it remains to be seen" whether this benefit of efficiency and reduced miscarriage risk are sufficient to outweigh the drawbacks of cost and an invasive procedure in PGT-A. This question of reduced miscarriage as a clinical benefit is discussed by the trial's first author, Willem Verpoest, in a Focus on Reproduction filmed interview
It is now 20 years since first reports suggested an increased pregnancy rate from embryos screened for chromosomal abnormality, and since then the practice has continued to prove controversial. The early forms of PGS were limited by the small number of chromosomes in the analysis. This problem was later resolved by comprehensive chromosome screening, and thus the detection of abnormality in any of the full complement of 23 chromosomes.
The study reporting today also analysed a full complement of chromosomes, as found in the two polar bodies of recently collected oocytes. Polar bodies are the first non-functional "by-product" cells found in the egg as it prepares for its first division after fertilisation. Although the two extruded polar bodies contain only genetic material of maternal origin, they do reflect the chromosomal content of the egg, which accounts for 90% of all chromosomal errors found in fetuses and live births.
The study's principal investigator, Professor Karen Sermon from the Research Group Reproduction and Genetics of the Vrije Universiteit Brussel (VUB) in Belgium, explained that embryo biopsy for embryo selection was not allowed in two of the study countries at the time (Germany and Italy) and that anyway polar body biopsy was perceived as less invasive.
She described the results as "extremely robust", noting the large number of subjects and rigorous multicentre study design. She added that the results, although derived from polar body analysis, could confidently be extrapolated to other techniques of PGT-A in this patient population (women of advanced maternal age). "There is now a growing consensus that the most important chromosomal abnormalities interfering with implantation are of meiotic origin - that is, they are derived from the egg or the sperm," she explained.
Commenting on the trial's findings, Professor Sermon "saw no benefit" of now offering PGT-A to the patient population of this study, especially in cases where only few eggs have been retrieved. She advised that similarly rigorous trials should now be performed in other patient groups.
Otherwise, the benefits of PGT from this trial are confined to fewer miscarriages and fewer treatment cycles, which, said Professor Sermon, "may still tip the controversy scale in favour of PGT-A". But these benefits, she added, must still be balanced by the cost of PGT-A and the invasive nature of the procedure.
1. Verpoest W, Staessen C, Bossuyt P, et al. Preimplantation genetic testing for aneuploidy by microarray analysis of polar bodies in advanced maternal age: a randomized clinical trial. Hum Reprod 2018; doi:10.1093/humrep/dey262.