In the beginning…
Since its introduction in 1978, IVF has become a mainstay in the treatment of infertility. Original success rates were very low with a 5% pregnancy rate per transfer being considered excellent. Today that number if closer to 40 – 50 % in younger patients. The majority of research and improvement in success in IVF was initially due to attention to the embryo and the culture conditions which promoted normal embryo growth.
Over the years, we have learned that the most significant advancement for evaluating the embryo is the ability to determine if an embryo has a normal number of chromosomes. Information that was obtained from pre-implantation embryo biopsy revealed that most human embryos do not have the correct number of chromosomes. The embryos generated from cycles using donor oocytes, which have the highest reproductive potential, have as much as 30% of the embryos with the wrong number of chromosomes. The ability to transfer only embryos with the correct number of chromosomes has increased the pregnancy rate per transfer and reduced the miscarriage rate. The actual clinical pregnancy rate per normal embryo transferred is stated as between 50 and 70% per embryo. Quite an improvement!
Practice makes Perfect?
But why is it not 100%? Suddenly, attention has turned to the uterus, specifically the lining of the uterus (endometrium) which is where the embryo implants and starts to develop, baby’s ‘home’ for the duration of the pregnancy. Although it may seem that this change in focus is new, many investigators have been trying to assess the endometrium for years. In the early 1950s, physicians did an endometrial biopsy and then estimated if the lining was at the proper developmental stage or if it was out of phase. This spawned the term “luteal phase defect” and initiated the use of progesterone in the second half of the cycle. This concept has largely been proven not to be true and the luteal phase defect is now defunct. The technological development of the vaginal ultrasound lead to a large body of evidence trying to correlate the thickness and pattern of the endometrium to a successful pregnancy. Considerable attention is focused by both patients and healthcare providers on the lining of the uterus as women progress through IVF or frozen embryo transfer cycles. Attention to the endometrium is the standard of care today but the accuracy of the thickness or pattern of the endometrium to predict a successful live birth does not support this theory. Does that mean people should stop measuring the lining and documenting the pattern? Probably not- at least until a more predictive method to evaluate the endometrium becomes available.
So, is there a more predictive way to evaluate the endometrium to increase the ability to predict if the cycle will result in a live birth? Enter the world of ‘omics.” Omics refers to the technological advances in molecular biology and data analysis which allows the evaluation of thousands of pieces of data to form patterns that can be associated with success or failure. A successful pregnancy may have a few hundred genes turned on and a few hundred turned off forming a pattern for success. An unsuccessful pregnancy may have a completely different set of genes turned on or turned off. Taking a small piece of the lining of the uterus by performing an endometrial biopsy could help the patient determine if she had a favorable or an unfavorable pattern.
Bringing ERA to the table
One testing being used to evaluate the lining of the uterus is the endometrial receptivity array (ERA). The physiology underlying this test involves the concept of the window of implantation (WOI). Constructing a favorable lining is much like building a house. You start with a foundation, add walls and then the roof. There is a logical and necessary sequence to this, since building the roof first would create a rather unique, upside-down house. Likewise, there is an established sequence of events required to create a favorable endometrium. The construction of the lining ultimately requires proteins. These start from the activation of genes which then tell the cells how to make the proteins. Different proteins are needed at various stages in the development of the endometrium, so different sets of genes are activated at differing times and in a necessary sequence. As the endometrium develops, there appears a time during which an embryo can implant. If the embryo enters the uterus too soon or too late, the window is closed, and the embryo will not implant or die.
The ERA is a test done on a sample of the lining of the uterus obtained by an endometrial biopsy that evaluates over 230 genes to determine if the correct genes have been activated or silenced. There have been a number of studies that have evaluated the accuracy of the ERA. Since this is a new area of research and since the number of studies is small with a limited number of patients in each study, the results are conflicting. This lack of robust research creates a gray zone for deciding if the ERA if worth the cost and effort. Among reproductive endocrinologists, there exists significant disagreement about the use of the ERA. Until a large, well- designed study is published, this controversy will continue.
However, for certain patients under certain circumstances, the ERA may allow an adjustment in when progesterone is started or on what day an embryo is transferred in a fresh IVF cycle so that the chance of success is increased. One approach to the use of the ERA involves the use of both PGT-A (testing for the chromosome number before the embryo is transferred) and the ERA. When the embryo has the correct number of chromosomes (euploid embryo) and is transferred without success, the possibility exists that the WOI was not in phase. A mock cycle can be done were the lining of the uterus is prepared as if an embryo would be transferred but instead no embryo is transferred and the lining of the uterus is sampled using an endometrial biopsy on the day the embryo would have been transferred. An ERA can be done on this sample to determine if the lining is in phase or the transfer needs to be adjusted to meet the optimal time for transfer. This process was used by this author for 12 patients in 2019 with a clinical pregnancy rate of 60-70%. These numbers are small and the approach is new, but the early experience of this author is encouraging.
The ERA is an early player in the evolving field of “omics” as applied to the endometrium. Other studies evaluating a number of systems will be evaluated in the near future. Caution needs to be exercised before these newer diagnostic tests can be relied upon. In the balance is always the benefit- risk- cost balance when deciding if any of these test s are worth performing. As physicians, we are continuously evaluating new technologies which help patients achieve the highest success rate possible.