Embryo Banking With PGS: Puts the Biological Clock on-hold and for Many, Provides an Attractive Alternative to IVF with Egg Donation
Until recently, for many infertile older women and those with diminished ovarian reserve (DOR) who wanted to have a baby, IVF using donated eggs provided the only realistic choice. Many who were unwilling to use donor eggs and who despite of this reality nevertheless attempted IVF (often repeatedly) with their own eggs, only rarely succeed in achieving their dream. The recent introduction of Embryo Banking where (preimplantation genetic screening (PGS)-tested, “competent” embryos are selectively preserved over several IVF cycles and then transferred in a later cycle, now provides the opportunity for many such women/couples to have their own genetic offspring without having to resort to egg donation.
It is mainly the chromosomal integrity of the egg, rather than the sperm that determines whether the embryo will be “competent” (i.e. have the potential to develop into a normal baby). It is the age of the woman that most profoundly impacts the likelihood that the mature egg will have a full contingent of chromosomes (euploid), necessary to achieve embryo “competency”. By way of example, up to about 35 years of age, fewer than 50% of a woman’s mature eggs will be euploid and thus upon fertilization more than half will have an irregular chromosome component (i.e. aneuploid) and thus be “incompetent”. Incompetent embryos either will fail to develop normally, fail to attach (implant) in the uterine lining, miscarry or even result in a chromosomally abnormal baby (e.g. Down syndrome. As a woman ages beyond her mid-30’s the incidence of egg/embryo aneuploidy increases such that by the time she reaches her mid-forties, more than 90% of her eggs/embryos will be aneuploid and incompetent.
To make matters worse, the older the woman, the closer she gets to the time that her ovaries run out of eggs and she stops ovulating and menstruating (i.e. menopause). The 6-8 years prior to menopause (i.e. the climacteric or pre-menopause) which is characterized by diminishing ovarian reserve (DOR) with an associated progressive reduction in the number of available e # of mature eggs at the time of egg retrieval along with building resistance to fertility drugs. To complicate matters further, it becomes ever more difficult in the face of DOR, to protect developing eggs during stimulation with fertility drugs in the hope of minimizing the incidence of egg/embryo aneuploidy. This is why, unless a very customized and individualized approach to ovarian stimulation is used in older women and those with DOR the incidence of egg/embryo aneuploidy may even approach 100%. It also serves to explain why IVF success rates plummet with diminishing ovarian reserve and with advancing age and why the relentlessly ticking biological clock often creates in them a profound sense of urgency and even desperation to have a baby before their time runs out. Confronted with the reality that advancing age and diminishing ovarian reserve will inevitably reduce the likelihood of an IVF pregnancy, increase the risk of miscarriage and would in all probability come at considerable emotional and financial cost, many such women often choose to undergo IVF using the eggs derived from a younger egg donor.
In 2005 Levent Keskintepe PHD and I introduced full embryo karyotyping into the clinical IVF arena. Using a method of full chromosomal karyotyping known as comparative genomic hybridization CGH) technology to select those embryos that had all 46 chromosomes intact (euploid), and selectively transferring such embryos to the uterus, we demonstrated that pregnancy rates could be markedly enhanced, miscarriages reduced dramatically and the occurrence of aneuploid birth defects such as Down syndrome minimized in the IVF setting. More recently, with the introduction of next generation gene sequencing (NGS), the sensitivity and specificity of PGS karyotyping was enhanced. This method now is the mainstay of PGS testing.
The combination of PGS with ultra-rapid embryo freezing (vitrification) made it possible to bank/stockpile euploid blastocysts for subsequent dispensation. Vitrification) virtually avoids damaging “competent”: embryos during the freezing and thawing process. In fact, in most IVF centers of excellence, the post-vitrification FET process now yields the same (and perhaps even better) IVF success rates as when fresh embryos are transferred. The combination of PGS and se vitrification has not only made embryo banking/stockpiling feasible but has rendered the approach a most appealing option for older women and women with DOR who seek to undergo IVF using their own eggs. This having been said, PGS is not an indispensable part of embryo banking. The process can be can done without it. The only problem is that given the inevitability of an age-related increase in the incidence of egg/embryo aneuploidy “incompetence”, the inability to select only “competent” embryos for banking would make it impossible for patients to know that they ultimately will have a good chance of success.
Embryo banking involves a process whereby several blastocysts are accumulated (stockpiled) over two or more IVF cycles. After each such cycle, the embryos are taken to the blastocyst stage of development biopsied for PGS analysis and are then vitrified (ultra-rapidly frozen and banked). All biopsy specimens accumulated over several such cycles are held for as long as it takes to complete the scheduled IVF cycles, whereupon they are collectively dispatched (for cost containment purposes) for a single PGS analysis. When the results return, the “incompetent (PGS-abnormal) embryos are selectively discarded while the “competent” ones are stored (cryobanked) for subsequent dispensation by FET to the uterus of the embryo recipient. In this way, the subsequent transfer of even a single “competent” embryo is capable of achieving almost a 50% chance of a viable pregnancy.
Most women/couples would like to have more than one child. This desire is no less prevalent in older women. However, by the time the older woman decides to do IVF, goes through the process successfully, has a baby, completes breastfeeding and thereupon re-establishes regular menstruation in order to try for another IVF baby, a period of 2-3 years will have elapsed. While such a hiatus would usually be of little consequence to a young woman, for an older woman such a delay could seriously impact her “biological clock” so as to drastically reduce her chance of having another baby with her own eggs. Embryo banking/stockpiling would also have appeal to younger women who plan on postponing having children until later in life. Even some fertile women for whom IVF would otherwise not be necessary could fall into this category.
The concept of embryo banking/stockpiling would not have been feasible 15-20 years ago, since it was not until quite recently that we became able to reliably identify chromosomally normal (“competent”) embryos for selective banking. Nor was it possible to prevent freezing from severely damaging up to 50% of frozen embryos. But that was then…