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The promise of preimplantation genetic screening (PGS) from the very beginning was to improve IVF live birth rates and decrease miscarriage rates. The first clinical use of PGS involved embryo biopsy on the third day after fertilization. The biopsied cell was then analyzed using fluorescent in-situ hybridization (FISH), which allowed for the evaluation of several chromosomes for signs of chromosomal abnormalities. When this technology became clinically available, physicians and patients were enthusiastic about applying this technology to improve IVF success rates and decrease miscarriage rates. PGS was offered in the majority of IVF clinics, and the number of patients opting for this technology increased significantly. Unfortunately, in time it became apparent that while miscarriage rates seemed to consistently decrease through the application of this technology, achieving improved IVF success rates did not follow. It was especially concerning that those patients who stood to benefit the most from proper embryo selection, the older patients, were not experiencing improved pregnancy rates. In 2007 Mastenbroek et al. published a study showing that PGS in women of advanced age resulted in decreased ongoing IVF pregnancy and live birth rates. This study captured worldwide attention and resulted in significant reduction in the use of PGD. Other studies have suggested that embryo biopsies performed on day 3 after fertilization may identify chromosomal abnormalities that are destined to self-correct later in embryonic development.
In recent years new technologies have become available including comparative genomic hybridization (CGH), and comprehensive chromosomal screening (CCS). These technologies enable comprehensive analysis of 24 pairs of chromosomes. In addition, there is a trend toward performing embryo biopsies on the 5th day of embryonic life when the embryo is at the blastocyst stage of development. The benefits of performing biopsies at this more advanced stage of development include the capability of removing a greater number of cells for analysis, and reduced potential to inflict harm on the embryo. In addition, removing cells at the blastocyst stage of development should reduce the prospects of falsely identifying an embryo as genetically abnormal, since self- correction of chromosomal abnormalities should theoretically have occurred by this stage of development.
At present enthusiasm is growing for performing blastocyst biopsies on day 5 of embryonic development followed by freezing of all biopsied embryos. Twenty-four chromosome analyses by either CGH or CCS is performed and chromosomally normal embryos are eligible to be transferred in a standard frozen embryo replacement cycle the following month. A recent review of the literature by Gleicher et al. Reproductive Biology and Endocrinology 2014, 12:22 suggests fundamental flaws in two important studies that suggested improved ongoing pregnancy rates following blastocyst biopsy with 24-chromosome analysis. Concern has been raised that we need to be cautious in adopting these new approaches to PGS to avoid the problems that were ultimately seen with day 3 post fertilization biopsies and fluorescent in-situ hybridization. It would seem prudent to learn from our experience with PGS and delay widespread implementation of day 5 biopsy with CGH or CCS until several large randomized well constructed studies have been published showing a clear benefit and identifying which patients are most likely to benefit from this technology. At this time it would be reasonable to offer PGS only in experimental protocols designed to answer the question, “Does PGS increase IVF pregnancy rates?”
Dr. Norbert Gleicher, in a systematic review of PGS published inReproductive Biology and Endocrinology 2014, 12:22 had the following comments pertaining to two recent publications on this subject:
“Considering that these authors, despite utilization of trophectoderm biopsy and state-of-the-arts aneuploidy testing, still, in even highly favorable patient populations were unable to improve pregnancy rates suggests a quickly shrinking population base in which PGS may be ineffective. Indeed one has to accept the increasing likelihood that the underlying paradigm for PGS, simply may not work. The procedure just seems to increase costs and complexities of IVF.”