If you are struggling with infertility, you may have heard of endometrial testing options, such as the ERA (endometrial receptivity analysis), CD138 for chronic subclinical endometritis, or Receptiva Dx which claims to diagnose patients with endometriosis. All these tests boast strong claims of significantly improving patients’ chances of carrying a successful pregnancy. Please know that your Spring providers will always recommend any test or intervention that they think will help you be successful. While we are our patients’ strongest advocates, we are also data-driven scientists.
Below we break down how these tests work, the validity of their claims, and specific cases in which we may recommend:
What is the stated purpose of these tests?
While all three tests are taken from an endometrial biopsy, they differ in their purpose.
The ERA (Endometrial Receptivity Analysis) is a test that evaluates the pattern of gene expression commonly observed in the endometrium during the window of implantation.
Why do we care about this “window”?
The “window of implantation” is the timing in which the uterine environment is at an appropriate developmental stage to allow for an embryo to implant. In a transfer cycle, this window is predicted based on timing of progesterone exposure (post ovulation or per timing of supplementation). However, in some cases this prediction based on natural physiology may not be accurate for all women. Hence, the ERA suggests an alternative receptive window and the timing of transfer will be adjusted accordingly. Thus, this test must be done at a specific time during the luteal phase.
The CD138 tests for a protein called syndecan-1 or CD138. If present in high levels, It is associated with subclinical chronic endometritis. In this scenario, subclinical implies a very mild level of infections without any symptoms such as pain or fever. Of note, there is a natural increase in CD138 cells in the uterus after ovulation thus this test must be done prior to ovulation.
Why do we care about endometritis?
Subclinical chronic endometritis is a condition that may dysregulate the uterine environment and shift the window of implantation, which is important for embryo implantation. Studies have shown that chronic endometritis may change the immune environment within the endometrial cavity, leading to implantation failure. If the test is positive, treatment with antibiotics (typically 2 weeks) follow by a test of cure would be recommended before proceeding with future transfers.
The Receptiva Dx tests for the presence of a protein called BCL6 which has been found in some patients with undetected and/or recurring endometriosis. This specific protein is transiently produced within the uterus and thus the test must be conducted at a specific time.
Why do we care about endometriosis?
Endometriosis is when endometrium is found outside the uterus and influences fertility in several ways, including distorted anatomy and/or inflammation of pelvic structures, adhesions, scarred fallopian tubes, altered immune system functioning, changes in hormonal environment of eggs, impaired implantation, and altered egg quality. While lacking conclusive evidence and currently controversial, if the test is positive, treatment would typically involve 60–90-day hormone therapy or laparoscopy before proceeding with future transfers.
What does the data say about the efficacy of these tests?
Data on the ERA (Endometrial Receptivity Analysis) have not found it to improve live birth rates (https://www.fertstert.org/article/S0015-0282(20)32374-8/fulltext). Although a randomized-controlled trial found that its use may increase initial pregnancy rates, it ultimately increases the rate of miscarriages and therefor it does not improve live birth rates (https://www.rbmojournal.com/article/S1472-6483(20)30319-9/fulltext). Furthermore, variations in ERA profiles have not been found to be meaningfully different between patients with recurrent implantation failure versus controls (https://www.rbmojournal.com/article/S1472-6483(20)30448-X/fulltext). It is also important to note that all studies on ERA were on patients who utilized a controlled FET protocol. Therefore, any results for ERA would require doing a controlled FET. We can do a modified-natural FET with ERA; however, testing is not validated in this setting.
Data on chronic endometritis, CD138 positive, have demonstrated that patients with recurrent implantation failure tend to have an increased rate of chronic endometritis as determined by a positive CD138 result. Several studies have found that treating chronic endometritis with antibiotics does improve cure rates and/or decrease the amount of inflammation in the endometrium (https://www.fertstert.org/article/S0015-0282(21)00039-X/fulltext). However, there is still debate as to whether treating chronic endometritis ultimately improves pregnancy outcomes, with one study suggesting possible benefit in treatment (https://www.fertstert.org/article/S0015-0282(21)00241-7/fulltext), but a randomized-controlled trial demonstrating no improvement after treatment (https://www.fertstert.org/article/S0015-0282(20)32761-8/fulltext).
Data on Receptiva Dx test are limited by the fact that an elevated BCL6 level can result from several etiologies besides endometriosis, such as hydrosalpinges, ovarian cysts, and pelvic adhesions. Any treatments that might be used to address endometriosis would not have an impact on these other diagnoses. Moreover, while some studies have identified elevated BCL6 as a marker of poorer pregnancy rates, other studies have not been able to reproduce this (https://www.fertstert.org/article/S0015-0282(20)31564-8/fulltext). Furthermore, the default of treatment such as long-term Lupron and/or surgical intervention has not been conclusively shown to increase pregnancy rate based on this test.
What are the costs associated with these tests?
Spring’s price for the endometrial biopsy procedure itself is $315. Other associated costs are test dependent (see below). The biopsy procedure is relatively non-invasive and is an outpatient procedure in which anesthesia is not required. However, it is common to experience moderate discomfort during and following the procedure, including abdominal cramping, and vaginal bleeding.
The ERA (Endometrial Receptivity Analysis) test, through Igenomix, costs anywhere from $800 to $1,000*, directly paid to the company. To complete this testing, you will need to go through a mock transfer cycle in which you have monitoring appointments and take medications up until the biopsy. The biopsy will occur after ovulation (if natural) or progesterone start (if controlled). Therefore, it is important to also consider the added costs of these appointments and medications, similar to an FET cycle. In addition to a significant financial investment, this test also requires delaying your transfer by at least a month.
* Check out Igenomix’s site for the most up to date pricing
The CD138 test, through LabCorp, is determined by the lab doing the testing and the time the analysis requires, ranging from $500 to $1,500*.
*Check out LabCorp’s site for the most up to date pricing
The ReceptivaDx test, through CiceroDx Inc., costs $690* paid directly to the company. They also offer CD138 testing for an additional $125. However, the timing of the BCL6 test is often after ovulation, and it is recommend that the CD138 test be performed prior to ovulation. Like the ERA, this test requires going through a mock transfer cycle in which the biopsied sample is taken after ovulation (if natural) or progesterone start (if controlled). Therefore, to complete this testing it would require additional costs of monitoring appointments and medications, similar to an FET cycle. In addition to a significant financial investment, this test also requires delaying your transfer by at least a month.
*Check out ReceptivaDx’s site for the most up to date pricing
Who would benefit from testing?
These tests should only be considered for patients who have failed a minimum of two embryo transfers. With each transfer of a euploid (genetically tested “normal”) embryo ,there is a 55-65% chance of a successful pregnancy. Therefore, while a failed embryo transfer may be devastating, it is not an unexpected or concerning outcome. However, after failing multiple transfers of a euploid embryo, it becomes more statistically significant, and your provider may discuss considering additional endometrial diagnostic testing.
When deciding which test is right for you, it is important to consider your fertility history, the current data available, and the incremental investment of time and money required to complete these tests.