NEW YORK (GenomeWeb) – Igenomix, a Spanish reproductive genetics firm, has developed the first commercial assay for diagnosing chronic endometritis, a symptomless infection in the uterine lining that can impact a woman's fertility. The firm is commercializing the test, along with other genetic analyses of endometrial status, in the EU and plans to bring it to its US labs upon CLIA approval.
Called Analysis of Infectious Chronic Endometritis, or ALICE, the Igenomix test uses next-generation sequencing to detect nine different pathogens causing chronic infection - Chlamydia trachomatis, Enterococcus, Escherichia coli, Gardnerella vaginalis, Klebsiella pneumoniae, Mycoplasma hominis, Neisseria gonorrhoeae, Staphylococcus, and Streptococcus.
The presence of pathogens and infection can make the endometrium less conducive to conception and pregnancy, causing infertility that is characterized by repeated implantation failure of fertilized eggs during in vitro fertilization and recurrent miscarriages. And yet, chronic endometritis typically causes no other symptoms.
"There are many women that have chronic endometritis and they don't even know," said Inmaculada Moreno, a researcher at Igenomix who co-developed the assay.
Because there are no symptoms, "this is not a disease that is very relevant for the whole population," Moreno explained. If a woman happens to have a silent uterine infection but she is not trying to get pregnant, she probably won't notice any problems. Yet, "in the case of infertile women, it is important," Moreno added.
Approximately 10 percent of women in the general population may have chronic endometritis, but among infertile women undergoing IVF, the rate is 15 percent, with rates estimated as high as 60 percent among women experiencing recurring implantation failure or miscarriage. Importantly, if those two conditions are caused by chronic endometritis, they can be ameliorated by antibiotic treatments.
Unfortunately, it is only after a period of infertility or multiple miscarriages that physicians think to look for a chronic infection, Moreno said. "We see a lot of situations where there is a very long [IVF] treatment, you finally only have one embryo that is considered to be normal, and when you are ready, nobody checks whether there is an infection in your uterus," Moreno said. "The endometrium matters."
The very existence of a uterine microbiome has gone against long-established dogma, and what constitutes a healthy microbiota is still being elucidated. But there is evidence that certain species are pathogens and that a non-Lactobacillus-dominated microbiota is detrimental to pregnancy.
In a recent study published in the American Journal of Obstetrics and Gynecology, Moreno and her colleagues compared the ALICE test to three gold standard methods — hysteroscopy, histology, and microbiological culture — and found that the test had nearly 80 percent concordance.
Moreover, the molecular ALICE test may be less costly, less painful, and more specific and sensitive than the gold standard methods, Moreno said.
Hysteroscopy — which involves inserting a thin camera into the uterus — is painful and considered to be expensive. It looks for visible signs of infection, like redness or edema, which are not always obvious, and the results are non-specific with respect to the pathogen causing infection. Similarly, histological examination of a biopsy can also be painful and expensive, and can show inflammation but can't identify a pathogen. In both cases, patients are often given broad-spectrum antibiotics and find out whether or not the treatment worked when they have another implantation failure or miscarry a pregnancy.
Microbiological culture, meanwhile, can identify the pathogen in some cases and lead to tailored antibiotic treatment. But cultures are laborious and time consuming, and some pathogens that are quite typical causes of endometritis don't grow under standard culture conditions, so infections can be missed using this method.
Igenomix offers its genetics services primarily in the assistive reproductive technology setting. Founded in 2009 in Valencia, Spain, the company has 14 labs worldwide, in North and South America, Europe, the Middle East, and Asia.
The firm's work is "science driven" and it has published more than 350 papers, according to Gonzalo Echevarría, marketing manager at Igenomix. CSO Carlos Simon also has research affiliations at Stanford University and has led many of the uterine microbiota and endometrial receptivity studies.
The ALICE test will be commercialized along with two other genetic assays the firm has already been marketing, which assess receptivity of the endometrium and health of the uterine microbiome, respectively. The Igenomix endometrial microbiome metagenomic analysis, or EMMA, uses 16S RNA sequencing to determine the proportion of Lactobacillus, or healthy bacteria, in the uterus. The firm's researchers recently demonstrated that Lactobacillus-dominated microbiota led to improved implantation rates and pregnancy outcomes in a small preliminary study.
The Igenomix endometrial receptivity test, or ERA, measures the expression of 248 genes involved in receptivity to embryo implantation, and is designed to tell physicians a woman's personalized optimal window for an embryo transfer. Echevarría said the test has now been used by more than 32,000 patients worldwide.
Overall, the cost of the EMMA and ALICE tests care "reasonable," Echevarría said, especially considering the backdrop of IVF treatment costs. The three tests can be performed at the same time with the same sample, he said.
"Distribution in the EU of EMMA and ALICE just started and we have received very good feedback from clinics and patients. For the US, we are now waiting for CLIA approval and we hope this will happen soon," Echevarría said.
Approximately 12 percent of women in the US have difficulty becoming pregnant or carrying a pregnancy to term, according to the Centers for Disease Control and Prevention. And while one in five women in the US have their first child after age 35, one third of couples in which the woman is 35 or older have fertility problems. These women frequently turn to artificial reproductive technology, but it is extremely expensive, rarely covered by insurance, and unsuccessful most of the time.
Specifically, in 2015, the most recent year for which the CDC has complete data, ART resulted in pregnancy for only 40 percent of women under 35, and success rates dropped to 23 percent for women in the 38 to 40 bracket, and 13 percent for women 41 to 42. The typical cost of in vitro fertilization treatment, meanwhile, is estimated to be around $15,000. It is only after multiple failed attempts — usually paid out of pocket — that a clinician would test for a chronic bacterial infection.
Echevarría said Igenomix plans to continue its international expansion, opening in at least one other country in 2019.
Igenomix also markets preconception genetic testing, such as a carrier genetic compatibility test for couples and a sperm aneuploidy test, preimplantation tests like prenatal genetic screening and a mitochondrial DNA test, as well as a noninvasive prenatal genetic tests.
The firm is also "building a digital ecosystem to educate and mentor the market" Echevarría said, through a learning platform and other digital tools. "There is a lot of work to be done to show how reproductive genetics can help women and doctors achieve their dreamed-of goals."