Single Embryo Transfer: Standard of the Future
Single-embryo transfer (SET) is a procedure involving the selective transfer of a single embryo to the uterus. Here, the embryo transferred might be fresh, or it may be a frozen/cryostored embryo from a prior IVF attempt. Recent research has revealed that younger women undergoing IVF who elect to have one or repeated SET’s (over as many cycles as the number of available embryos would allow), can anticipate cumulatively (over several cycles of fresh or frozen SET’s), having a similar number of live-birth deliveries as would be the case for women who have multiple embryos transferred at the same time. The only difference is that pregnancy resulting from a SET would virtually always result in a singleton birth while with the transfer of multiple embryos, there is an ever present risk of multiple births with its incumbent life endangering complications attributable to premature delivery. SET is, in my opinion, destined to become the treatment of choice in women under 35 years of age who have good quality embryos available for transfer.
Selecting embryos that have the best chance of implanting and propagating a healthy baby is one of the most important remaining challenges in the field of Assisted Reproduction. However, the use of morphologic (microscopic) criteria onday2-3 post-fertilization as well as conventional preimplantation genetic testing such as fluorescence in-situ hybridization (FISH), lack both sensitivity and specificity and accordingly are seriously flawed when it comes to identifying those embryos that are most likely to develop into healthy babies (what we refer to as “competent” embryos). Because of this, many IVF physicians still transfer multiple embryos at a time in an attempt to maximize the chance of a successful outcome. Unfortunately, such practice often results in an unacceptably high rate of multiple gestations with the associated, prematurity-related neonatal complications that often exact devastating short and long term consequences on the very quality of life after birth.
The presumption that it is better to transfer healthy embryos into the uterus sooner rather than later (cleaved on day 2-3 following fertilization, rather than as blastocysts on day 5 or 6), has been shown to be flawed. In fact, we now know that the vast majority of embryos that fail to develop into blastocysts in the lab are chromosomally abnormal and would not have resulted in a healthy baby anyway. Thus by culturing all embryos to the blastocyst stage, we can effectively weed out many of the non-viable ones. We have found that the baby rate per transferred blastocyst is about twice as high as is the transfer of day 2 or day 3 cleaved embryos, at any maternal age. Thus transferring the most “competent” blastocyst(s) increases the chances of a healthy fetus and normal baby.
It follows that if we could reliably identify and then cryostore the “competent” embryos without compromising their survival and post-thaw viability, it would be far better for all concerned to conduct SET’s, especially in younger women (under 35 years) who have normal ovarian reserve.
Three (3) relatively recent developments in the IVF arena now make it possible to conduct single embryo transfers in good candidates, with a strong expectation of success. Implementation of the first two (numbers 1&2 below) are regarded as standard. The third (no. 3 below) offers promise of greatly enhancing the potential for success but is not as yet regarded as a standard requirement. It is especially helpful in older women, or women with diminished ovarian reserve (DOR) who are considering embryo banking, and for women with alloimmune implantation dysfunction (DQalpha/HLA matching). These three developments are:
- Emergence of new extended embryo culturing methods: The development of advanced extended embryo culture techniques over the last decade now makes it possible to successfully grow embryos to the blastocyst stage of development without prejudicing those that are “competent” in the processes.
- Ultrarapid embryo freezing (Vitrification): Vitrification, by allowing for freezing to take place 600 times faster than when conventional (slow) embryo freezing is conducted, keeps ice from forming in the cells and so protects the embryo from damage. Thus it allows us to safely bank and store embryos without them being severely damaged by the freeze-thaw process and at the same time, ensures the same potential to propagate a baby as with freshly transferred embryos.
- Introduction of reliable full embryo karyotyping using CGH: It has long been recognized that it is the numerical chromosomal integrity of the embryo that represents the “rate limiting factor” in human reproduction. Those embryos that have more or less than the normal human genome of 46 chromosomes in their cells (i.e., are aneuploid), either will not attach to the uterine wall (failed implantation), attach for a brief period of time and then miscarry, or (albeit infrequently) will result in the birth of a chromosomally abnormal baby (e.g., Down syndrome).It was against this background that the use of preimplantation genetic diagnostic testing (PGD) to evaluate embryo chromosomal integrity was contemplated as a method by which to selectively identify and transfer only those embryos that had all 46 chromosomes intact (i.e., euploid). But alas, standard PGD tests such as fluorescence in-situ-hybridization (FISH), because of its inability to identify all 46 chromosomes in the embryo’s cells, are unreliable and thus not helpful in this regard.Almost a decade ago, we at SIRM introduced a chromosomal testing method that could identify all 46 chromosomes in the human embryo’s cells. The test, comparative genomic hybridization (CGH), thereby enabled identification of the most “competent” embryos for selective IVF embryo transfer. It was our hope and expectation that by selectively transferring only euploid embryos to the uterus, we might improve the baby rate per embryo, reduce the risk of miscarriage and all but eliminate chromosomal birth defects. A few years later we were the first to report that the transfer of a single CGH-normal embryo produced about a 60% chance of a live birth.
The journey from infertility to family is an arduous one, and deciding upon IVF can be somewhat overwhelming. One of the serious risks associated with doing IVF is that with the transfer of multiple embryos comes the serious risks associated with multiple births. With the introduction of technology that makes SET a successful process, there is no longer a need to transfer multiple embryos at one time in order to improve the chance of having a healthy baby. The human price to pay, i.e., multiple births, makes this a dangerous gamble.