2019 Update on fertility
Progress is being made in recognizing infertility as a disease (thus meriting insurance coverage) and in improving embryo selection techniques for IVF treatment, but more work is needed. Plus, the SART's redesigned report includes a new feature for calculating a personalized prognosis that can aid in treatment decision making. Two fertility experts boil down these complex issues.
That concept was initially applied to cleavage-stage embryos through the use of fluorescence in situ hybridization (FISH) technology to interrogate a maximum of 5 to 9 chromosomes in a single cell (single blastomere); however, although initial results from observational studies were encouraging, subsequent randomized controlled studies unexpectedly showed a reduction in pregnancy rates.9 This was attributed to several factors, including biopsy-related damage to the cleavage-stage embryo, inability of FISH technology to assess aneuploidies of more than 5 to 9 chromosomes, mosaicism, and technical limitations associated with single-cell analysis.
Second-generation PGT-A testing has promise, and limitations
The newer PGT-A tests the embryos at the blastocyst stage by using biopsy samples from the trophectoderm (which will form the future placenta); this is expected to spare the inner cell mass ([ICM] which will give rise to the embryo proper) from biopsy-related injury.
On the genetics side, newer technologies, such as array comparative genomic hybridization, single nucleotide polymorphism arrays, quantitative polymerase chain reaction, and next-generation sequencing, offer the opportunity to assess all 24 chromosomes in a single biopsy specimen. Although a detailed discussion of these testing platforms is beyond the scope of this Update, certain points are worth mentioning. All these technologies require some form of genetic material amplification (most commonly whole genome amplification or multiplex polymerase chain reaction) to increase the relatively scant amount of DNA obtained from a sample of 4 to 6 cells. These amplification techniques have limitations that can subsequently impact the validity of the test results.
,Furthermore, there is no consistency in depth of coverage for various parts of the genome, and subchromosomal (segmental) copy number variations below 3 to 5 Mb may not be detected. The threshold used in bioinformatics algorithms employed to interpret the raw data is subject to several biases and is not consistent among laboratories. As a result, the same sample assessed in different laboratories can potentially yield different results.
In addition to these technical limitations, mosaicism can pose another biologic limitation, as the biopsied trophectoderm cells may not accurately represent the chromosomal makeup of the ICM. Also, an embryo may be able to undergo self-correction during subsequent stages of development, and therefore even a documented trophectoderm abnormality at the blastocyst stage may not necessarily preclude that embryo from developing into a healthy baby.
Standardization is needed. Despite widespread promotion of PGT-A, well-designed randomized clinical trials (RCTs) have not yet consistently shown its benefits in improving pregnancy rates or reducing miscarriage rates. Although the initial small RCTs in a selected group of good prognosis patients suggested a beneficial effect in ongoing pregnancy rates per transfer, the largest multicenter RCT to date did not show any improvement in pregnancy rates or reduction in miscarriage rates.10 In that study, a post hoc subgroup analysis suggested a possible beneficial effect in women aged 35 to 40. However, those results must be validated and reproduced with randomization at the start of stimulation, with the primary outcome being the live birth rate per initiated cycle, instead of per transfer, before PGT-A can be adopted universally in clinical practice.
Continue to: With all the above considerations...
