PGD/PGS: 23 Chromosome Microarray The Future of IVF?
23-Chromosome microarray is a technique to scan the genome for gains and losses of chromosomal material. This method has significantly high resolution and clinical yield. This new analytical technology, microarray analysis, allows for the evaluation of all 23 pairs of human chromosomes on a single cell, which includes the sex chromosomes, X and Y.
Arizona Center for Fertility Studies believes that 23-chromosome microarray could change the future of In-Vitro Fertilization (IVF).
We feel so strongly about this technology and how it could significantly improve our In-Vitro Fertilization (IVF) success rates, that Arizona Center for Fertility Studies has decided not to charge for the PGD/PGS procedure, other than what the PGD laboratory charges us.
Successful treatment of reproductive failure demands full prior identification and treatment of those factors that adversely influence both embryo "competence" (the ability of an embryo to develop to a normal pregnancy) and uterine "receptivity" (i.e., thickness of the uterine lining, immunologic modalities, anatomical integrity of the uterus, as well as infective and biochemical factors.
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, In-Vitro Fertilization (IVF) success rates have lagged and even stagnated over the last 10 years. This is largely due to an inability to reliably identify and selectively transfer only "competent" embryos (those that are capable of producing a healthy baby) to the uterus. 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/screening (PGD/PGS) using fluorescence in-situ hybridization (FISH) to identify chromosomes does not significantly improve this capability. As a result, many In-Vitro Fertilization (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 multiple gestations/pregnancies.
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.
The relatively lax and unregulated In-Vitro Fertilization (IVF) setting in the United States has provided a safety net for those wishing to transfer multiple embryos, and this in turn has led to a virtual explosion in the incidence of multiple births in this country. The enormous short and long term financial costs associated with In-Vitro Fertilization (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.
There is a profound lack of correlation between the microscopic appearance (grading) of embryos and embryo "competence". Moreover, preimplantation genetic diagnosis/screening (PGD/PGS) of human eggs and embryos for their chromosomal integrity, using traditional fluorescence in-situ hybridization (FISH) is only fractionally more reliable. The reason is that conventional FISH cannot fully access all the chromosomes - in fact, only about 12 of them. Thus, even when FISH reveals that all the accessed chromosomes are normal, there still remains more than a 40% chance of chromosomal aneuploidy involving those chromosomes not targeted by the test?and the incidence increases to above 50% by the time the woman reaches 40 years of age. This constitutes a serious drawback when it comes to attempting to select the most "competent" eggs or embryos for dispensation in ART.
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 producing "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 or will attach and then subsequently miscarry early on in pregnancy.
- 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 (23-chromosome microarray tested) embryos to a receptive uterine environment (free of immunologic and anatomical irregularities) 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 (day 3 transfer).
- Most In-Vitro Fertilization (IVF) failures and early miscarriages are almost always attributable to embryo aneuploidy. It follows that only transferring euploid, "competent" embryos will significantly reduce this risk.
Fertilization of an egg by a dysfunctional spermatozoon significantly increases sperm contribution to the development of aneuploid embryos. This is more likely to occur in cases of moderate to severe male factor infertility. Given that male infertility is responsible for more than 50% of infertility, it follows that it would be preferable to perform 23-chromosome microarray analysis on the embryo (rather than the egg). This would improve the accuracy of microarray diagnosis in diagnosing embryo competence. Accordingly when predicting embryo "competence" we shifted from egg to embryo 23-chromosome microarray testing.