Why Does A Genetically Normal Embryo Fail To Implant?
In recent years we have developed technology that enables us to determine if an embryo is genetically normal before it is transferred to the uterus. Various technologies are available toanalyze cells taken from the embryo at the blastocyst stage of development and these technologies continue to become more sensitive and comprehensive. With the ability to confidently transfer genetically normal (euploid) embryos, our expectations for successful implantation are high. However, in spite of the application of this technology, a substantial number of these embryos fail to result in a live birth and we are left with the task of understanding these failures and explaining them to our patients.
A recent article by Dr. David Meldrum published in Fertility and Sterility (March, 2016) addresses this question and provides potential explanations for these failures. Dr. Meldrum suggests the following interesting and provocative thoughts on this subject:
1) The egg is a very large cell and it is possible that the cytoplasm is more important than the
nucleus. The cytoplasm of the embryo may not be sufficient to support a fully capable
embryo.
2) Environmental influences such as smoking and obesity may negatively influence the quality of the egg, and later the embryo. The available data suggest that a 3-6 month recovery period may be necessary to overcome the effects of these environmental influences on egg cytoplasm.
3) Male hormones (androgens) play an important role in achieving competence of the egg and
it is well understood that androgen levels wane with advancing age. The use of androgen
supplements such as DHEA (dehydroepiandrosterone) to overcome this adverse influence
on the egg seem to require 2 to 3 months to be effective. Mild stimulation of the ovary with
low dose testosterone requires about 3 weeks to achieve a benefit.
4) Mitochondria within the egg are critical for chromosome division and cell division especially
in the early days of embryo development. CoQ 10 has been proven to improve
mitochondrial activity in animal models and has been advocated as one method of
improving mitochondrial energy in the egg after at least 2 months of supplementation.
5) Emotional stress leading to the "fight or flight" response may improve blood flow to the vital
organs such as the heart and lungs, while diverting blood from the nonessential organs such
as the ovary. Mind-body programs aimed at reducing stress may be beneficial.
6) Some investigators have associated poor outcomes in older patients with the use of high
doses of pituitary hormones. While it is tempting to use more and more medication to
stimulate greater numbers of eggs to maturity, this may not be the best strategy for obtaining
the best quality eggs especially for our older patients.
7) Growth hormone levels are known to fall as women age and low growth hormone levels
within the ovarian follicles are associated with poor IVF pregnancy rates. It may be that
growth hormone plays an important part in preparing egg cytoplasm for early embryo
development.
8) In has been observed that there should be a natural surge in FSH at the time of the LH
surge. However, since the earliest days of IVF, HCG has replaced the LH surge.
The HCG trigger shot seems to eliminate the FSH surge. It has been suggested that
restoration of the FSH surge might improve the quality of the egg and early embryo.
9) Optimization in the IVF laboratory including culturing in low oxygen environment,
optimization of culture media, possibly co-culture, and the use of bench top incubators that
recover more quickly after opening and closing.
10) Embryo biopsy techniques need to be optimized in order to minimize the impact on the
developing embryo.
11) Each individual patient may have their own unique window of endometrial receptivity and
technologies are being developed to identify the precise window of receptivity on an
individual basis. This approach may be an important method to improve IVF live birth rates
and decrease failure rates especially when transferring genetically normal embryos.
Since the first IVF success in 1978, we have witnessed slow and steady improvements in treatment outcomes. With each step forward, new challenges invariably arise as we strive to create and identify the ideal embryo and place it in the optimal uterine environment. This blog post reviews the thoughts of Dr. David Meldrum, one of the most recognized and respected leaders in our profession.
