Embryo Selection – Some Thoughts
Selection of the best embryo for transfer has always been an important objective of IVF treatment. The earliest attempts at selection relied heavily on cell number and detailed microscopic appearance of the embryo (morphology). For example, an eight-cell embryo on day three with minimal fragmentation was generally felt to have better prospects for implantation compared to a six-cell embryo with 20% fragmentation. The ability of the embryologist to select the best embryo clearly has limitations as we have learned through preimplantation genetic screening (PGS) has demonstrated in recent years. It is not uncommon to find through PGS that an embryo with poor morphology is actually a genetically normal embryo (euploid).
BLASTOCYST (DAY 5) VS. CLEAVAGE STAGE (DAY 3) TRANSFER
The goal of infertility treatment is for each patient to achieve a healthy singleton pregnancy. Toward this end our profession has made great strides by reducing the number of embryos transferred in general, and encouraging single embryo transfer when appropriate. As we have become more focused on transferring fewer embryos, transferring the “best” embryo takes on added significance. During the past fifteen years there has been a significant trend toward extended culture, allowing embryos to remain in culture past the third day of embryonic life. Extended culture implies fortification of culture media to handle the increased metabolic needs of the rapidly growing embryo. If an embryo fails to make a blastocyst by the 5th or 6th day in culture, the conventional wisdom held by many, is that the embryo would not have progressed to a live birth. In this way, extended culture has been perceived as helping with the embryo selection process, allowing for higher implantation rates. Large studies comparing day 3 embryo transfer (cleavage stage transfer) to blastocyst transfer have shown that blastocyst transfer improves pregnancy rates primarily in “good prognosis” patients. Pregnancies in these good prognosis patients occur more quickly because extended culture helps select the best embryo for transfer. For all but the best prognosis patients, investigators have found that cumulative pregnancy rates are better for cleavage stage embryos. The implication is that transferring fresh embryos on day 3, and freezing any additional embryos, results in a greater number of ongoing pregnancies per egg retrieval. It may be that the conventional wisdom that any embryo that does not make it to the blastocyst stage cannot result in a live birth may be flawed. Some viable embryos that do not progress in culture conditions may be capable of successful implantation and live birth if placed in the uterus. Stated another way, we may be losing viable embryos by maintaining them in culture for two additional days. This concept may be especially important to the poor prognosis patient who has only a limited number embryos. Extended culture in this sub-group may actually be decreasing their chances for success.
Another method of embryo selection gaining popularity at this time is through pre-implantation genetic screening (PGS). The initial application of PGS for embryo selection involved day 3 embryo biopsy. However this approach has been largely abandoned for because of inaccuracy and lack of reproducible results across different laboratories. More recently, platforms for performance of PGS have become more comprehensive and more reliable. At present, it appears that the best time to biopsy the embryo is on day 5 or 6 when it has reached the blastocyst stage, trophectoderm biopsy. Some clinics are recommending that all embryos be biopsied so that only embryos with normal chromosomal makeup (euploid) embryos are transferred to the uterus. Recent data has indicated that even when a chromosomally normal embryo is transferred, this does not guarantee successful pregnancy. It seems quite likely that the complex process of implantation may be faulty and result in failed implantation even when the embryo is known to be genetically normal. Attempting to grow embryos to the blastocyst stage of development so that it may be biopsied for chromosomal screening, may be decreasing the patients overall chances for success. Based on the earlier discussion, it may be that some normal (euploid) embryos do not do well in extended culture, and therefore never achieve blastocyst development. These embryos are not biopsied or offered for transfer.
Embryo selection holds great promise going forward. We do need to learn more about which group of patients is most likely to benefit from which technology. While we gather this essential information we should be cautious about assimilating technologies too quickly. The ideal embryo selection technology would be non-invasive, inexpensive, harmless to the embryo, highly accurate, and simple to use. While we search for this technology and await the necessary clinical trials, we must exercise some restraint in offering or recommending new technologies to our patients.
Source: Gleicher, N. Kushnir, V. Barad, D. Is it time for a paradigm shift in understanding embryo selection? Reproductive Biology and Endocrinology Vol.13