More than 25 years ago, it was found that human embryos of about three days old cultured in the lab, showed chromosomal abnormalities in more than half of them. Many of these abnormalities did not come from the sperm or the egg, but occurred after the embryo has cleaved two times, creating four cells, or three times, reaching the eight-cell stage. The – not unreasonable – hypothesis arose that these chromosomal abnormalities were responsible for the low efficiency of human in vitro fertilisation (IVF), and a new addition to the assisted reproductive technologies (ART) was born: preimplantation genetic screening, or PGS. The idea was to not transfer embryos with chromosomal abnormalities.
PGS is achieved by removing one or two cells from the total of eight cells the embryo normally has on the third day of development, and by analysing these biopsied cells by a method called fluorescent in situ hybridisation or FISH. As only embryos with a normal number of chromosomes would be transferred to the uterus, this would increase the number of pregnancies after IVF, right? Wrong: after the results of a number of clinical trials were published about ten years ago, it appeared that the idea was clever but too simple. It turned out that FISH could not fully represent all the chromosomal abnormalities present in the embryo, as a maximum of nine of the total 23 chromosomes could be counted, and moreover, the eight-cell stage was particularly prone to chromosomal errors and so the timing of the biopsy was wrong. Of considerable concern was the finding that many embryos were so-called “mosaics”: some of their cells could be completely normal, while other cells of the same embryo would show chromosomal abnormalities usually found in cancer cells. One or even two cells taken from an embryo would, in many cases, misrepresent its genetic content, and therefore add nothing to the selection done by embryologists on the morphology of the embryo alone.
In comes what has been dubbed PGS 2.0: genetic analysis technologies took a giant leap in the last decade, and it became possible to screen the whole chromosomal content of a single cell. The biopsy at day three was replaced by biopsy at day five, when the embryo has more than 100 cells and has already developed into an inner cell mass which will become the foetus, and an outer layer of cells destined to become the placenta. It is generally believed that embryos at this stage, called blastocysts, have fewer cells with chromosomal abnormalities, and up to ten cells can be taken from the embryo causing presumably less harm than a one-cell biopsy at day three.
But still not all is well: this so called PGS 2.0 is advocated even more strongly than the first generation, although the scientific community is still waiting for evidence to support its usage. In the absence of this, this topic is heavily debated. Advocates of PGS 2.0 deem that sufficient proof is available that PGS 2.0 increases the chances of their patients becoming pregnant. Others are adamant that the only way to introduce a new treatment – and that includes IVF treatments – is after its usefulness was shown in solid randomized controlled trials.
In June 2015 we started to collect the opinions of all the leaders in the field. During the process of opinion collection it became clear that consensus is lacking regarding all major aspects of PGS 2.0. This starts with the question which patient groups, if any at all, can benefit from PGS 2.0. Recently, a new and highly efficient method for freezing of human embryos, called vitrification, was introduced. Recent reports state that over 80% of embryos frozen with vitrification will survive the thawing procedure, and retain the same likelihood of establishing a viable pregnancy as an embryo that is transferred a few days after fertilisation. The high efficiency of vitrification of blastocysts has added a layer of complexity to the discussion, and it is not clear whether the best strategy to follow would be PGS in combination with vitrification, or PGS alone, or vitrification alone, followed by thawing and transferring embryos one by one. The opinions range from favouring the introduction of PGS 2.0 for all IVF patients rather than using PGS as a tool to rank embryos according to their implantation potential, to scepticism towards PGS pending a positive outcome of robust, reliable, and large-scale randomized controlled trials in distinct patient groups.
We were confronted with difficulties and inconsistencies regarding the costs of PGS for the patients, which ranges from 350 € to approximately 9000 €. Our colleagues rightly commented that details of what the costs include needed to be clear. Only biopsy and analysis? Or the complete cycle? However, frozen embryo transfer also carries its own costs, such as ultrasound examinations, medication, embryo thaw and culture, and embryo transfer, as well as indirect costs such as lost wages or cost for childcare. Some of our colleagues argued that this aspect should not be included in the article and the discussion, as it was not part of the “scientific” discussion. We felt that this is urgently needed, especially for a procedure where the debate of its usefulness is still raging, but it is hard to get these data. However, the future of PGS not only depends on clinical or scientific evidence but also on a cost-benefit analysis at two levels. First, the costs of the whole selection procedure in terms of dollars or euros should be considered. Second, the costs of PGS 2.0 should be balanced with transferring untested embryos one by one in terms of time to pregnancy. As long as both these costs are unknown the future of PGS use will remain based only on opinion.
Featured image credit: Blastocyst. Author’s own photo used with permission.