Whenever IVF fails to resolve reproductive failure, the explanation is almost invariably either:  a) embryo “incompetence” (usually …although not always due to the embryo being karyotypically abnormal or aneuploid) or b) implantation dysfunction (anatomical/ immunologic). So…should the transfer of  up to two (2) karyotypically  normal (euploid) embryos fail to propagate a viable pregnancy, while the uterine cavity is free of surface lesions (polyps, fibroids or scar tissue) and the estrogenic uterine lining is thick enough (>8mm) …then (through a simple process of elimination), IID tops the list as the probable cause. It follows that the performance of IVF with concomitant NGS (or CGH) embryo karyotyping could represent a game-changer in the diagnosis and treatment of “unexplained” infertility, IVF failure, and/or RPL.

All women who undergo embryo transfer (ET) are focused on having a healthy baby. The truth is that fewer than 40% will succeed after a single attempt. And when they fail, the questions that follow will be ….why did I not succeed… should I try again,  and …what can we do differently next time round to prevent repeat failure?  In most cases the treating physician will not be able to satisfactorily and with confidence, answer such questions. This is because of a relative inability to differentiate between an implantation dysfunction (anatomical or IID) and an embryo defect as being causal and whether (in the case of the latter) a sperm or an egg issue was involved.  There is no doubt an urgent need for the treating physician to be able to address such concerns upfront, before initiating any IVF cycle of treatment, whether an initial or a repeat attempt.

There is little doubt that the numerical chromosomal integrity (karyotype) of the embryo is one of the most important factors that determines IVF outcome and that it is largely chromosomal integrity of the egg rather than the sperm that determines the integrity of the embryo karyotype. In fact, abnormal embryo karyotype (aneuploidy) is believed to be responsible for >70% both of IVF failures and miscarriages and also for many birth defects such as Down’s syndrome, Turner’s syndrome etc.

While light microscopic embryo morphologic  assessment  can in some cases identify those embryos that are   structurally defective, they would be highly unlikely to propagate healthy offspring (i.e. “incompetent”), it is also indisputable that morphologically normal looking embryos are often (in most cases) aneuploid and thus, “incompetent”.  While slightly less than 50% of embryos derived through fertilization of the eggs of a woman in her early 30’s are likely to be chromosomally normal (euploid) this declines ever more rapidly as she reaches her late 30’s and by the time she gets to being in her mid-40’s, less than 1 in 10 of her eggs/embryos are likely to be euploid. The truth is that without genetic assessment to confirm the presence of all 23 chromosome pairs, it is impossible to reliably affirm embryo “competence”.

Preimplantation Genetic Sampling (PGS)/Karyotyping:

  • Comparative Genomic Hybridization (CGH): The last decade witnessed the introduction of tests such as CGH which fully karyotype embryos. This resulted in a new-found ability to choose only the most “competent” embryos for selective transfer and in the process vastly improve the efficiency of IVF as well as outcome.  But CGH (whether array or metaphase) as well as most other chromosomal embryo karyotyping methods currently in use for embryo karyotyping, are far from being  devoid of problems. They all tend to be associated with “false positive” results, some of which are due to the unavoidable occurrence of “embryo mosaicism” (which is often/usually is auto-correctable), and others that are due to “noise” in the analytic recordings that all too often falsely points to an erroneous increase or decrease in chromosomal material, thereby confounding accurate interpretation of results. 
  • Next Generation Gene Sequencing (NGS): Gene sequencing determines the precise order of nucleotides within a DNA molecule. It includes any method or technology that is used to determine the order of the four bases—adenine, guanine, cytosine, and thymine—in a strand of DNA. A new generation of sequencing technologies (also called next generation gene sequencing) has provided unprecedented opportunities for high-throughput functional genomic research. To date, these technologies have been applied in a variety of contexts, including full karyotyping of embryos), targeted re-sequencing, discovery of transcription factor binding sites, and noncoding RNA expression profiling.  NGS, as performed to identify human embryo aneuploidy, is in my opinion is more reliable than CGH When performed on more than one blastocyst (trophectoderm) cell NGS can help differentiate between meiotic and mitotic aneuploidy. This has potential advantages because unlike meiotic aneuploidy which is permanent and often lethal to the embryo, mitotic aneuploidy is often self-correcting with further embryo development. NGS testing will also identify the gender of each karyotyped embryo. NGS can also be performed at lower cost than most other PGS  methods Given all these and other emerging benefits, NGS embryo karyotyping is in my opinion a method of choice and holds great promise for the future.