The numerical chromosomal configuration of a cell is referred to as its karyotype or ploidy. A cell with an irregular chromosome number is referred to as aneuploid while one with a normal karyotype, as euploid. It is predominantly (but not exclusively) the ploidy of the embryo that determines its subsequent ability, upon reaching a receptive uterine environment, to propagate a normal pregnancy, also referred to as its “competence.” A “euploid (“competent”) embryo transferred to a receptive uterine environment (free of anatomical, molecular or immunologic impediments to implantation” is the most likely to propagate a viable pregnancy.
Embryo transfer (ET) is undoubtedly one of the most important variables that determine IVF outcome. The procedure itself requires gentle placement of one or more embryo(s) near the roof of the uterine cavity under direct ultrasound guidance. Central to successful IVF outcome is the selection of high-quality embryos that upon being transferred to a receptive uterine environment are capable of propagating a normal pregnancy (i.e. “competent embryos”). The following methods currently in use for differentiating between “competent” and “incompetent” embryos all to a lesser or greater degree lack both sensitivity and specificity in evaluating “embryo quality/”competence”:
- Microscopic Embryo Grading which evaluates and grades embryos based upon their structural appearance (morphology).
- Prolonged embryo culture to the Blastocyst stage, an approach aimed at culling the poorer quality embryos. Thus embryos that survive to the blastocysts stage are the ones that are most likely to be ‘competent”. This provides a much greater likelihood of embryo “competency” as compared to microscopic grading.
- Preimplantation Genetic Screening (PGS) permits identification and the transfer of embryos that have a full quota of 23 pairs of chromosomes have the greatest likelihood of being “competent”.
MICROSCOPIC GRADING OF DAY-3 EMBRYOS: Several such grading systems are presently in use. By and large, they all try to assess embryo “competency” by quantifying the number of cells (blastomeres) present, their symmetry and the number of embryo fragments (“fragmentation”) observed. Embryos that divide too slowly as well as those that divide too rapidly, as well as those that have irregular sized blastomeres and/or prominent evidence of fragmentation are the ones that are most likely to be “incompetent”. So it is that day-3 embryos that have 5-9 blastomeres which are symmetrical in form and exhibit minimal fragmentation…tend to be the ones more likely to be “competent”. Notwithstanding the above, it is always important to recognize that even the best looking, cleaved embryos are often “incompetent” and that regardless of microscopic embryo grade, the woman’s age profoundly impacts embryo “competency”. For example, at age <35at age <35y, roughly 50-60% of morphologically sound embryos are competent whereas by the time the woman reaches 43 years of age, <10% of her embryos are likely to be “competent”.
BLASTOCYST ASSESSMENT: Embryos that reach the expanded blastocyst stage by day 5-6 post-fertilization are the ones that are most likely to be “competent”. But once again, as with day-3 cleaved embryos, advancing age also profoundly impacts the embryo “competency”. In the past, IVF specialists tended to argue in favor of transferring early cleaved embryos to the uterus the natural “natural uterine environment” than to incubate them for 2-3 more days so as to allow them to reach the blastocyst stage. However, recent research has shown this to be an erroneous belief. In fact, with very few exceptions, embryos that fail to progress to the blastocyst stage in culture are chromosomally/genetically abnormal and even if they had been transferred earlier, would not have been capable of propagating a healthy pregnancy anyway. Since, regardless of the woman’s age, most cleaved embryos will fail to develop into blastocysts because they are “incompetent”, it follows that extending embryo culture to day 5 or 6 and allowing many “incompetent” to be culled in the process, helps select of the best-quality embryos, allowing for fewer to be transferred without compromising outcome in any way. And the transfer of fewer embryos also reduces the incidence of multiple pregnancies.
PREIMPLANTATION GENETIC SCREENING (PGS). This involves the performance of a biopsy of the outer cellular layer (trophectoderm) of day 5-6 blastocysts followed by full karyotyping (counting of all chromosomes). Embryos with a full quota of 46 (23 pairs) chromosomes (i.e. euploid) are the ones most likely (but not inevitably so) to be “competent, while those with an irregular chromosome quota (aneuploid) are the ones that are most likely to be “incompetent”. However, some aneuploid blastocysts will also contain euploid blastomeres. Such embryos are termed “mosaic” and they have the ability post-implantation, to “autocorrect” in the uterus and subsequently propagate viable, healthy babies. It is presently not possible to reliably differentiate between incompetent, aneuploid and mosaic embryos in the laboratory. This is why embryos with single chromosomal aneuploidies should not be discarded and should be considered eligible for transfer. Moreover, PGS testing is also not 100% accurate. Errors occur in 5-8% of tests. For these reasons it is my opinion that PGS while a valuable tool, should be used selectively in IVF. In my practice, I largely reserve recommending PGS to older patients and those with diminished ovarian reserve who because of age have reduced embryo “competency” or because they are running out of time only produce few eggs at a time. I also advise using PGS in cases of recurrent pregnancy loss, unexplained repeated IVF failure and when there are strongly suspected underlying chromosomal/genetic abnormalities.
About Staggered -IVF (St-IVF: St-IVF is the process of separating an IVF cycle into two (or more) segments so as to allow for the PGS-identification of “competent” embryos (i.e. those capable of propagating healthy babies) and thereupon selecting such embryos for transfer in a future cycle. Phase 1 Involves the egg retrieval, fertilization and growing embryos to the blastocyst stage whereupon they are biopsied for PGS analysis. All blastocysts are then cryobanked by ultra-rapid freezing (vitrification) while awaiting availability of the karyotype report from the genetic laboratory…about 1-2 weeks later. Thereupon, plans are made for hormonal preparation and the Staggered (St)-FET with ≤ 2 warmed (thawed), euploid, “competent’ embryos/blastocysts (i.e. Phase 2).
- Embryo Banking: Older women and women with diminished ovarian reserve, who are often running out of time on the biological clock can bank or stockpile their PGS-normal blastocysts (over several cycles, if need be) for subsequent dispensation. This allows them to “make hay while the sun still shines”, thereby affording them a palatable alternative to using donated eggs.
Staggered –IVF (St-IVF) has the potential to vastly improve IVF outcome per embryo transferred (baby-rate per embryo) eliminate aneuploidy-related miscarriages/ birth defects and has heralded a new era, where it only requires the transfer one (1) “competent” blastocyst to propagate a single healthy baby.