Fertility and genetic tests have come a long way in the past decade. When pregnancy tests keep coming up negative, or when embryo transfers in an IVF cycle have been unsuccessful, fertility doctors now have extra tools to figure out what might be going on.
You can think of the implantation of an embryo into the uterine lining (A.K.A. the endometrium) as a symphony of processes and interactions. When getting ready for implantation, endometrial cells undergo structural and functional changes at just the right time.
But these dynamic cells aren’t the only ones that affect implantation: they play host to a whole ecosystem of bacteria and microorganisms. Experts used to think that the inner cavity of the uterus was a sterile environment, but that couldn’t be further from the truth. It’s easy to see why—our skin has a massive amount of microflora on it, and it's all connected to the vulva, vagina, cervix and then the endometrial cavity. The uterine microbiome is an exciting new frontier in reproductive medicine, and it may very well play a major role in implantation. The species we host could be a reason for “unexplained infertility.”
When it comes to recurrent implantation failure (in IVF, when healthy embryos don’t implant after multiple transfer attempts), 25 to 30 percent of cases are believed to be due to endometrial factors such as receptivity and the uterine microbiome. Three new tests have become available to give doctors and patients more information in these tough instances, and they can be done together (called EndomeTRIO) from one biopsy sample of the inside of the uterus. Specialists can then use genetic sequencing technology to determine when the endometrium is most receptive for implantation and also identify the profile of microorganism species living in the uterus.
What is an ERA in IVF?
The endometrial receptivity analysis (ERA) was developed to help doctors determine the best time for transferring an embryo to improve the chances of implantation in an IVF cycle. Just like with ovulation and the fertile window, the implantation window doesn’t occur on the exact same day(s) for each person. We can have variations in our windows skewing them a few days earlier or later than the standard set cycle day(s).
In a study of patients undergoing IVF who had at least one cycle where transferring a genetically normal (euploid) embryo hadn’t worked, it was found that 22.5 percent had a displaced implantation window. When these patients repeated their cycle with a personalized embryo transfer day based on their ERA results, both implantation and pregnancy rates were higher, by about 20 percent.
This coincides with another small preliminary study that found about 26 percent of participants with recurrent implantation failure didn’t have a receptive endometrium, and most in that group (68 percent) had a displaced implantation window. In these cases, an ERA could help identify this and tailor the transfer timing to improve the odds of the embryo sticking.
On the flip side, there are also studies that have questioned if the ERA is helpful or not in personalizing the timing of the embryo transfer. An ERA isn't considered to be a required test prior to an embryo transfer, and whether it’s recommended or not should be discussed with your clinical team.
What is the EMMA test in IVF?
The EMMA test, which stands for endometrial microbiome metagenomic analysis, can determine the composition of microbial species in the uterus. From the biopsied endometrial tissue, it can help identify the proportions of microorganism species and can flag dysbiosis (an imbalance between the “good” and “bad” bacteria). A normal healthy endometrial microbiome should consist of more than 90 percent Lactobacillus species. The presence of other species can throw off the ecosystem and interfere with the good stuff’s ability to thrive. One study demonstrated that an abnormal microbiome is associated with significantly lower rates of embryo implantation (23 versus 60 percent), pregnancy (33 versus 70 percent) and live birth (7 versus 59 percent), when compared to microbiomes dominated by Lactobacillus species.
If an EMMA test identifies that more than 10 percent of the uterine microbiome consists of non-lactobacillus species, some doctors may consider a course of antibiotics followed by probiotics. The type of treatment recommended will depend on your specific results, including what species are found and how much of the microbiome they take up. The main goal is to increase the amount of lactobacillus bacteria in the uterus. Sometimes that requires kicking out other bacteria with either antibiotics, herbal antimicrobials or vaginal boric acid suppositories, but the most important step is to introduce more healthy lactobacillus bacteria to the area using both oral and vaginal probiotics.
To date, there aren’t many studies on the use of probiotics for the uterine microbiome, but we do know that probiotic treatments can improve the vaginal microbiome and pH and can kick out unwanted bacterial species. Two of the most well-studied strains for vaginal health are L. rhamnosus GR-1 and L. fermentum RC-14. In one study, treatment with these strains was 90 percent effective for correcting an abnormal vaginal microbiome. Probiotic treatments will take at least two weeks and, in stubborn cases, as long as six months.
You'll want to talk to your doctor about whether the EMMA biopsy is recommended prior to your embryo transfer (and if so, how to manage those results). If you've had unsuccessful embryo transfers with no identified causes, it's at least worth a discussion.
What is the ALICE test in IVF?
The ALICE test (analysis of infectious chronic endometritis) test also looks at bacteria in the biopsied tissue, but it detects the ones that can cause chronic endometritis (inflammation of the uterine lining). Endometritis may affect up to 30 percent of infertility patients and some studies have even suggested that this might be closer to 66 percent in those who have had repeated embryo transfer failures and/or recurrent pregnancy losses.
There are many different species that can cause endometritis, such as E. coli, chlamydia and mycoplasma. The infection itself doesn’t usually cause symptoms so it can be easily missed (it's referred to as a "silent" infection). Once these species are identified, the infection can be treated with antibiotics. From there, your doctor might recommend a repeat endometrial biopsy to confirm that the infection has been cleared from the uterus.
Antibiotics have been shown to resolve 75 to 99 percent of chronic endometritis cases, and has led to increased pregnancy and live birth rates post-treatment. One study found that resolving endometrial infections led to significantly greater pregnancy rates (76 versus 20 percent) and live birth rates (65.8 versus 6.6 percent) when compared against those with persistent infections.
Similar results were seen in another study that followed up with women one year after their diagnosis and treatment. In those whose chronic endometritis resolved after antibiotics, there was a higher pregnancy rate compared to those with persistent infections (78 versus 17 percent, respectively).
Who should do ERA/EMMA/ALICE tests?
The ERA, EMMA and ALICE tests are options that IVF patients can explore if they’ve had euploid embryos not implant, although many patients are now considering it prior to their first embryo transfer (note: studies on this practice don't yet support that it should be part of routine care). The ERA can give insights on the best timing for a transfer, while the EMMA and ALICE can help determine if the uterine environment is optimized for implantation. Talk to your doctor about whether these tests might be helpful for you. Factors to consider include cost, with the trio ringing in at about $1,000 (plus your clinic may charge for the cycle-monitoring and timing of the biopsy), and the invasiveness, since a biopsy requires entering the uterus to take a sample. It’s quick but can be pretty painful for about 10 seconds while your doctor takes the sample, and sometimes leaves lingering cramping for a few hours afterwards (your doc might recommend a painkiller beforehand).