Every last baby out of every last egg: The appropriate goal for fertility treatment in women over 40 years of age [Study]
Last week, a patient around the age of 40 came to our office for a second opinion. Her history was typical and could easily be summarized in general terms. She was 42 years old and had already undergone three IVF cycles without success.
More specifically, she was subjected to three IVF treatments, but none resulted in an embryo transfer. This was because she was told that all embryos were found to be chromosomally abnormal. She was also told that she seems to be producing only abnormal embryos and that she should consider egg donation.
However, before moving on with egg donation, she wanted to know if her eggs were given every available chance to produce a pregnancy. It should be noted that although ovarian reserve had not diminished in relation to her age, she was producing six to ten eggs per cycle, of which four or five were fertilized and progressed to Day-3 embryos. Two to three of these embryos would reach blastocyst stage, and would then be submitted to pre-implantation genetic screening (PGS) by comparative genomic hybridization, revealing aneuploidy. As there were no normal embryos, no embryo transfer was performed.
The first time I saw this, I was surprised that the clinic had stopped at the PGS result; but the story is now common and seems to be the rule rather than the exception. I wondered, when did this become a standard treatment for women at the age of 40? How could we rely on this practice that much, that even after the first or second cycle had failed, the same treatment would be recommended again for the third cycle, despite the small number of embryos and poor prognosis?
When a woman is at the age of 42, each embryo reaching the 8-cell stage has approximately a 6% chance of implanting. The associated risk of multiple gestation is so low, that the guidelines issued by the Society of Reproductive Medicine allow up to five embryos to be transferred each time. When embryos reach this age group selection by PGS, it is not based on which embryo to transfer, but on whether the patient is fit for an embryo transfer or not. We cannot save time, as the patient must still go through the luteal phase.
The patient may suffer less emotional stress from a negative result after a PGS procedure, than from having to wait for 2 weeks to find out whether the embryos that were transferred have actually been successfully implanted. PGS is considered more accurate. It is also an alternative to embryo transfer and having to wait for the pregnancy test.
Nevertheless, it is assumed that embryos are not harmed during the trophectoderm biopsy, and that PGS analysis is 100% accurate in predicting the embryo’s viability, however that is something we do not actually know. And that is where the problem lies. To this day, there is only one study showing that embryo biopsy at the blastocyst stage produces negligible (or immeasurable) reduction in embryo implantation potential.
This study evaluated 70 blastocysts on which a biopsy was performed and compared their implantation potential with that of 70 blastocysts that had not been biopsied. All patients in that study were under 35 years of age with normal egg reserve, and all embryos that were transferred during the fresh cycle were not in cryopreservation. We cannot be sure whether we can extrapolate these results to women over the age of 40 with low ovarian reserve. Given that these embryos were produced from younger eggs, they may be able to tolerate laboratory manipulation without measurable results.
In older embryos with limited implantation potential, the trauma caused by the trophectoderm biopsy may be the reason or the cause of a successful or unsuccessful implantation, respectively. The question of a potential false-positive misdiagnosis in the PGS laboratory causes even more concerns. Most PGS laboratories use comparative genomic hybridization technology, which is linked to more than 16% of false-positive findings.
Proving that false-positive findings are indeed a reality, a recent case series has confirmed the birth of healthy babies following transfer of mosaic aneuploid embryos. Even if there were no such reports, it seems reasonable that the false-positive rates of complex tests like the PGS cannot be 0%. This means that we should accept the reality that PGS tests will lead us to discard embryos that would otherwise have progressed to live-born babies.
Patients who read about the PGS procedure also learn that it increases implantation rates. However, they are wrong to conclude that this should also increase the reproductive potential of their embryos, and therefore increase their chance of a successful pregnancy. It is difficult to explain that PGS does not improve the embryo, but simply provides a method of selecting the best embryos for the transfer. In women over the age of 40, this means having one embryo transfer or no embryo transfer at all. Doctors suggest PGS in women over the age of 40, thus making sure that the patient will not go through additional stress.
Every last baby out of every last egg: The appropriate goal for fertility treatment in women over 40 years of age. Richard J. Paulson, 2016. Fertility and Sterility, Vol.105, No.6, pp: 1443-1444
