The selection of one or more “competent” embryos for transfer is thus central to IVF success.Unfortunately, most methods currently used to select the best embryos for transfer are relatively unreliable – yielding at best a 25% pregnancy rate per embryo transferred. This serves to explain why so many IVF practitioners, hoping to improve the odds of securing a pregnancy choose to transfer several embryos at a time. Unfortunately, such practice is fraught with risk because it can lead to high-order multiple pregnancies (triplets or greater) which carries with it a substantial danger to both mother and the babies.
Methods currently used to select the best embryo(s) for transfer include:
1. Microscopic Embryo Grading: Currently, most IVF centers culture embryos in groups and then perform a single microscopic evaluation (at 2, 3 or 5-6 days) prior to transferring one or more to the uterus. This approach is limited in scope and in its ability to reliably discriminate between "competent" and "incompetent" embryos, since chromosomally abnormal embryos are often identical in appearance to those that are normal.
2. Blastocyst Embryo Transfer: Following fertilization, the cells of the embryo divide progressively over several days until after 4 days the embryo reaches an advanced (100 cell or more) stage known as a morula. One or two days later the morula will have differentiated further, developing a defined fluid filled cavity within its substance. Only about 40% of embryos make it to this highly advanced or blastocyst stage of development. With few exceptions, embryos that fail to progress to the blastocyst stage are in fact aneuploid and therefore “incompetent”. By waiting five or six days post fertilization to select and transfer only blastocysts to the uterus, many abnormal embryos are in effect culled out prior to transfer, thereby improving the likelihood that those being transferred are more likely to be the 'competent" ones.
3. Embryo sHLA-G Expression: Soluble Human Leukocyte Antigen-G (sHLA-G) is a compound released by early embryos into the media in which they are cultured. Recent studies have shown that its presence in sufficient concentration is an indication that the embryo is more likely to implant and develop into a healthy baby. We recently published data on the use of this method in more than 1,000 women undergoing IVF. The findings revealed that women under 39 had a 45%-50% viable pregnancy rate when sHLA-G concentrations were above a defined threshold level. Although not a “silver bullet”, this is definitely a helpful tool.
4. PGD Using Fluorescence In-Situ Hybridization (FISH): This method involves the extraction of a cell from the embryo, followed by a test (FISH) to evaluate up to 12 of the 23 chromosome pairs in the embryo for abnormalities. Unfortunately, the remaining chromosome pairs cannot be accessed by this method. Thus while PGD/FISH accurately in evaluates several chromosome pairs for abnormalities, there remains about a 45% likelihood of an aneuploidy involving one or more of the remaining chromosomes - even when the FISH results are reported as “normal”.
5. Comparative Genomic Hybridization (CGH): This very promising method of embryo selection, developed and introduced by physicians at the Sher Institutes for Reproductive Medicine (SIRM), represents a real break through in the IVF arena. Unlike FISH, CGH allows identification of all chromosomes. CGH performed on the egg and/or the embryo overcomes the inadequacies associated with all other methods of embryo selection.
A recent SIRM study published in Fertility & Sterility (May, 2007) demonstrated a birth rate of more than 70% in women who received just one or two CGH-selected embryos. It appears that for the first time, there is finally a highly reliable method for differentiating between “competent” and “incompetent” embryos. Now, with CGH, the goal of “one embryo/one baby” is closer than ever to becoming a reality. CGH-based embryo selection also eliminates the current incentive to transfer multiple embryos at a time in order to improve the chance of success.
Embryo selection by CGH holds the potential to decrease the cost per IVF baby and lead to a reduction in overall reproductive health care costs. Staggered -IVF (St-IVF): With St-IVF, the IVF cycle is separated into two segments to allow for identification of “competent” embryos. “CGH-normal” embryos/blastocysts are frozen and stored for subsequent transfer to a hormonally prepared uterus, several weeks or months later. Cryostoring blastocysts allows sufficient time for the CGH testing to be completed.
Until recently cryopreservation of human embryos was problematic because it often caused ice crystals to form inside the embryo, damaging or destroying it. The recent introduction of ultra-rapid freezing or vitrification (see the post on vitrification) has changed all that. With vitrification, embryos are so rapidly frozen that no ice forms, yielding a post-thaw embryo survival rate of more than 90%. Impressively, the birth rates hardly differ from those using fresh embryos.
NOTE: Results reported using PGD with FISH and/or CGH can be erroneous. FISH has an error rate of around 10% and trisomy 21 conceptions have occurred after normal PGD/FISH. And, while the transfer of blastocysts derived from fertilization of CGH” normal” embryos minimizes the occurrence of aneuploidy related birth defects such as Down’s syndrome, it does not eliminate the risk completely. Accordingly, I strongly advocate that Prenatal Genetic Testing including (but not necessarily limited) to 1st trimester chorionic villus sampling (CVS) and/or 2nd trimester amniocentesis be carried out in all cases where pregnancy occurs following the transfer of “CGH-and/or FISH normal” embryos
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