Staggered IVF with PGT – Selection  of “Competent” Embryos Greatly Enhances the Utility & Efficiency of IVF

Staggered-IVF involves the use of Preimplantation Genetic Testing of advanced embryos (blastocysts) to identify those that are euploid (“competent”) and thereupon  the subsequent transfer to the uterus of embryos identified as being chromosomally “competent” in later cycle(s) of hormone replacement. 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 undeniable 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%). Even in young women, an advanced embryo (blastocyst) that “looks good” under a microscope will at best, will have a 30% chance of implanting successfully and this statistic becomes progressively attenuated with advancing age such that by 40 years of age the chance would at best be 15% and at 45 years, only  4-5%. There is a profound lack of correlation between the microscopic appearance (grading) of an embryo and its subsequent ability to propagate a viable pregnancy (“competency”). 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 the ploidy of the mature egg (rather than the sperm) that largely determines the post-fertilization chromosome configuration of the embryo and thus its “competence” to propagate a viable pregnancy. We and others have reported on the fact that it is primarily the numerical chromosomal make-up (karyotype) of the egg, (rather than the sperm) which is the main determinant of an embryo’s chromosomal integrity and its “competence”. An egg with an abnormal karyotype (aneuploid) cannot propagate a “competent” embryo while one with all its chromosomes intact (euploid) is highly likely to do so. The fact is that most human eggs are aneuploid. In fact, even in young women >50% of all mature eggs (MII) are likely to be aneuploid and thus incapable of propagating “competent” embryos. And, egg aneuploidy increases progressively with advancing age such that by the mid-forties the incidence of egg aneuploidy is > 90%. The transfer of 1-2 euploid, (“competent”) embryos to a receptive uterine environment has better than a 50% chance of resulting in pregnancy. Since the vast majority of IVF failures and early miscarriages are attributable to embryo aneuploidy, it follows that transferring euploid, “competent” embryos, can significantly reduce this risk. Staggered in Vitro Fertilization (St-IVF): As stated above, St-IVF involves using PG testing of advanced embryos (blastocyst) to identify those that are euploid (“competent”). Since PGT requires several days to perform, it precludes transferring fresh embryos to the uterus. Instead they need to be cryobanked (vitrified) and stored for subsequent transfer in a later cycle.  Thus a St- IVF cycle involves 2 stages: The first involves ovarian stimulation, egg retrieval, fertilization of the eggs and subsequent blastocyst biopsy 5-6 days later, to remove a few cells for karyotyping. This is followed by ultra-rapidly freezing (vitrifying) and storing them.  The second stage (embryo transfer of euploid embryos) is performed later. It involves hormonal preparation of the recipient’s uterus, thawing/warming of one or two pre-vitrified euploid blastocysts and then transferring these to the uterus. St-IVF improves the efficiency of the IVF process by:

• Markedly improving the birth rate per embryo transferred
• Avoiding the need to transfer several embryos at a time thereby reducing the likelihood of high order multiple pregnancies (triplets or greater) and
• Reducing the incidence aneuploidy-related miscarriages and birth defects such as Down and Edwards’s syndromes.
• Making it possible for older women and those who have diminished ovarian reserve, to stockpile PGT-normal embryos over a number of cycles (Embryo Banking), test them and then selectively transfer one or two PGT-“competent” embryos in a subsequent cycle for a much improved pregnancy rate per embryo transferred and a significant reduction in the risk of miscarriage.

A few words of caution: While PGT with full embryo karyotyping indeed represents a major break-through in the IVF arena, is not a panacea.  First, even euploid embryos will in about 20% of cases, not be fully “competent”. Confounding genetic and metabolic factors that are not detectable through karyotyping, as well as variations in technical skill and laboratory errors can all compromise outcome. In addition, not all PGT-aneuploid embryos are incompetent. In some cases embryo aneuploidy may be initiated following fertilization of a euploid egg with a euploid sperm when mitotic cell replication goes wrong. In such cases some (but not all) of the embryo’s cells may be aneuploid). This is referred to as “mosaicism” which in most cases autocorrects during subsequent development. The problem lies in the fact that it is currently not possible to reliably differentiate between egg-related (meiotic) aneuploidy and mitotic aneuploidy mosaicism. Finally, a totally “competent” embryo might fail to develop due to anatomical (uterine lining thickness) and immunologic implantation dysfunction rather than aneuploidy. This all serves to explain why only about half of euploid embryos/blastocysts transferred will propagate viable pregnancies.