Embryo Selection: The Critical Factor in IVF Success

Geoffrey Sher MD
No other factor in the IVF process influences success as directly as choosing the “right” embryo for transfer to the uterus. This is due mainly to the fact that Aneuploidy, an irregular numerical chromosomal configuration of the embryo, is responsible for the majority of IVF failures. Aneuploidy generally results in either: 1) the failure of the embryo to develop to a stage capable of attaching to the uterine wall, 2) miscarriage after implantation, or 3) a chromosomal birth defect such as Down syndrome. 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 inconsistent – yielding on average less than a 20% pregnancy rate per embryo transferred. This fact is responsible for the tendency to transfer a large number of embryos during an IVF cycle in hopes of attaining a pregnancy. Unfortunately, this can lead to high-order multiple pregnancies which carry substantial risks to both the 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 of the developing embryos to the uterus. This approach is limited in its ability to identify competent embryos, since chromosomally abnormal embryos are often identical in appearance to those that are normal.
2. Blastocyst Embryo Transfer: Following fertilization, the cells in an embryo divide progressively over several days until reaching what is known as the Blastocyst stage on day 5-6 (only about 40% of embryos make it this far). With few exceptions, embryos that fail to progress to the blastocyst stage are in fact chromosomally abnormal and therefore “incompetent”. By waiting until the blastocyst stage to select and transfer the embryo(s) to the uterus, they are in effect “self-selecting” by culling out many of the abnormal embryos prior to transfer.
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 much more likely to implant and develop into a healthy baby. Recently published data on this method tested in more than 1,000 women undergoing IVF demonstrated that women under 39 had a 50% viable pregnancy rate when sHLA-G concentrations were above a 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 to evaluate 8 to 12 of the 23 chromosome pairs in the embryo for abnormalities. Unfortunately, the remaining chromosome pairs cannot be examined for numerical chromosome abnormalities (aneuploidy) using this method. While very accurate in evaluating those particular chromosome pairs for abnormalities, there remains about a 45% chance that an abnormality exists in one or more of the remaining chromosomes - even when the results are reported as “normal”.
THE BREAKTHROUGH! Comparative Genomic Hybridization (CGH)
This very promising method of selection, currently in use exclusively by physicians at the Sher Institutes for Reproductive Medicine (SIRM), allows identification of all chromosomes, providing a much more complete analysis than FISH. CGH performed on the egg/embryo overcomes the inadequacies of previous 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 from ongoing data that for the first time, there is 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.
Introducing 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. The cryostorage allows sufficient time for the CGH procedure to be thoroughly executed. 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 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: PGD by way of FISH and CGH can be wrong.

  1. With Fluorescence in-situ hybridization: Preimplantation genetic diagnosis (PGD) of numerical chromosome abnormalities significantly reduces spontaneous abortions and may increase pregnancy rates in women of advanced maternal age undergoing in vitro fertilization. However, the technique has an error rate of around 10% and trisomy 21 conceptions have occurred after normal PGD/FISH.
  2. With Comparative genomic Hybridization: While the transfer of blastocysts derived from fertilization of CGH” normal” eggs/embryos minimizes the occurrence of aneuploidy related birth defects such as Down’s syndrome, it does not definitively preclude their occurrence.

We strongly recommended that Prenatal Genetic Diagnosis, including (but not necessarily limed to) 1st trimester chorionic villus sampling (CVS) and/or2nd trimester amniocentesis be carried out in all cases where pregnancy occurs following the transfer of “CGH-normal” embryos.