A convenient and applicable parallel that we often draw to illustrate the relative importance of embryo competence and uterine environment in the IVF equation is that of a “seed/soil relationship.” The ability of an embryo (the “seed”), upon reaching a receptive uterine environment (the “soil”) to successfully implant and develop into a healthy baby (the “plant”), is no different than what takes place in a regular agricultural setting. In simple terms, it is determined by establishing an ideal seed/soil relationship. It follows that it is no more possible to achieve a viable healthy pregnancy when a “competent” embryo is transferred to a “non-receptive” uterus than when an “incompetent” embryo is transferred to a receptive uterus.
In human reproduction, the establishment of an ideal seed/soil relationship is pivotal, since both embryo competence and uterine receptivity are indispensable to the development of a healthy baby. It is, however, an undeniable fact that reproductive failure (i.e. failed implantation, miscarriages and major birth anomalies) are far more likely to be due to embryo incompetence (70-75%) than to a lack of uterine receptivity (25-30%).
It is mostly (but not exclusively) the embryo’s chromosomal configuration that will determine its “competence”. The number of chromosomes in a cell is referred to as its ploidy. A cell with a normal number of chromosomes is referred to as euploid while one with an irregular chromosome number is aneuploid. It appears that it is the ploidy of the mature egg (rather than the sperm) that determines the post-fertilization chromosome configuration of the embryo. The embryo’s ploidy, in turn, determines its competence.
While advances both in methods and drugs used for ovarian stimulation as well as improvements in embryo culture techniques have undoubtedly had a positive influence, IVF success rates have been relatively stagnant over the last 10 years. This is largely due to an inability to reliably identify the most competent embryos. Even in young women, an embryo that “looks good” under a microscope is not necessarily competent. At best, it has a 25% chance of implanting. Furthermore, this statistic shrinks drastically with advancing age beyond 35 years. Even the use of preimplantation genetic diagnosis (PGD) via fluorescence in-situ hybridization (FISH) to identify chromosomes does not significantly improve this capability. As a result, many IVF specialists still transfer multiple embryos at a time to increase the odds that at least one competent embryo will reach the uterus and produce a pregnancy. The problem is that while this improves the chance of a pregnancy occurring, it also markedly increases the risk of high-order multiples (triplets or more).
The enormous short and long term financial costs associated with IVF multiple births (many of which are related to prematurity) represents one of the main reasons why health insurance providers in this country are reluctant to cover the procedure.
Though most programs use some form of visual (morphologic) grading system, our research has shown that the appearance of an embryo is not an accurate indicator of its ability to produce a baby. Moreover ,Preimplantation Genetic Diagnosis/Sampling (PGD/S) of human eggs and embryos for their chromosomal integrity using fluorescence in-situ hybridization (FISH) is only fractionally more reliable. The reason is that FISH cannot fully access all the chromosomes - in fact, only about 1/2 of them. Thus, even when FISH reveals that all the assessed chromosomes are normal, there still remains more than a 40% chance of chromosomal aneuploidy involving those chromosomes not targeted by the test. The incidence increases to above 50% by the time the woman reaches her forties.
We reported on studies involving the performance of Comparative Genomic Hybridization (CGH) on a fragment of nuclear material (the first polar body or PB-1) that is routinely discharged from the egg during the chromosomal rearrangement that takes place following the “hCG trigger”. The PB-1 has a chromosomal makeup which is a mirror image of the chromosomes in the egg’s nucleus. This biopsy can be achieved without damaging the egg itself.
The study referred to above was performed on eggs extracted from women aged 25-42 years who underwent ovarian stimulation with fertility agents. It revealed the following remarkable information:
The chromosomal make-up of the egg, rather than the sperm, is the main determinant of an embryo’s chromosomal integrity and its ability to develop into a baby. (i.e., its “competence”).
Even in young women, >60% of all mature eggs are likely to be aneuploid and thus incapable of propagating “competent” embryos.
The incidence of egg aneuploidy increases progressively with advancing age such that by the mid-forties it is probably above 90%.
Eggs that have abnormal quotas of chromosomes (i.e. are aneuploid) will, upon fertilization, invariably propagate aneuploid, “incompetent” embryos. Such embryos will either fail to attach to the uterine lining, attach and then subsequently miscarry, or be manifest as a birth defect if carried to term.
Approximately 85% of eggs that have a normal number of chromosomes (i.e euploid) fertilized with normal sperm will subsequently develop into “competent” embryos.
The transfer of 1-2 euploid, (CGH-tested) embryos to a receptive uterine environment has better than a 60% chance of resulting in a live birth.
Embryos that fail to progress to the blastocyst stage will almost always develop into aneuploid, “incompetent” embryos. This finding all but dispels the erroneous contention that embryos might be better off being transferred to the uterus prior to reaching the blastocyst stage.
Most IVF failures and early miscarriages are almost always attributable to embryo aneuploidy. It follows that only by transferring euploid, “competent” embryos, will this risk be significantly reduced.
Fertilization of an egg by dysfunctional sperm significantly increases sperm contribution to the development of aneuploid embryos. Given that male infertility is responsible for more than 50% of infertility, it follows that it would be preferable to perform CGH analysis on the embryo (rather than the egg). This would improve the accuracy of CGH-diagnosis in diagnosing embryo competence. Accordingly when predicting embryo “competence” we shifted from egg to embryo CGH testing. A study recently published using embryo (rather than egg) CGH testing has demonstrated the accuracy of this approach and illustrates that regardless of the age of the embryo recipient, the transfer of one or two CGH-normal embryos should result in better than a 60% live birth rate and a marked reduction in the miscarriage rate.
This being the case, there is no question in my mind that this should become standard practice for embryo selection in IVF treatment. Given the fact that there are very few labs in the world that can perform CGH testing currently, it will be some time before most practices are able to offer CGH embryo selection. SIRM has been offering CGH embryo selection for our IVF patients for more than 2 years and we are proud to have helped achieve nearly 200 births through this technique to date.
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