What Role Does the Uterine Microbiome Play in Fertility?

Until the second half of the 20th century, it was believed that the uterine cavity was sterile. Since then, technological advances have provided insight into the nature of the microbiome throughout the female reproductive tract. The role of these microorganisms on the fertility of women of reproductive age has been the subject of research. Is there an “optimal microbiome” for fertility? Can changing the microbiome of the uterine cavity affect fertility? There is still no definitive scientific response to these questions.

Several studies describe the healthy state of the uterine microbiota in women of reproductive age, with most of these studies reporting dominance of Lactobacillus species. However, by contrast, some studies did not observe Lactobacillus predominance inside the uterine cavity in cases of healthy uterine microbiomes. The presence of other microorganisms, such as Gardnerella vaginalis, was associated with reduced success in patients attempting in vitro fertilization (IVF) treatment, such as, for example, embryo implantation failure and miscarriage.

It is also possible that a physiologic endometrial microbiome could be considered healthy despite a minor presence of pathogenic bacteria. Importantly, responses from the host also modulate many aspects of human conception. These shifts correlate with parameters such as age, hormonal changes, ethnicity, sexual activity, and intrauterine devices.

Carlos Simón, MD, PhD, is a gynecologist and obstetrician and professor at the University of Valencia in Valencia, Spain; Harvard University, Cambridge, Massachusetts; and Baylor College of Medicine, Houston. He was in São Paulo at the time of the XXVI Brazilian Congress of Assisted Reproduction and agreed to be interviewed by Medscape Portuguese Edition. Simón, who is Spanish and is an international reference in uterine microbiome studies, created an endometrial receptivity analysis (ERA).

“What we know is that the human uterus has its own microbiome. Thanks to next-generation sequencing (NGS), we can detect microbial DNA. We’re talking about a microbiome that, if changed, affects [embryo] implantation. We have identified that Lactobacilli are the good [microorganisms], but if there are Streptococci, Gardnerella, or other bacteria, the implantation [of the embryo] is affected.”

In 2018, Simón’s team published a pilot study assessing the microbiome of 30 patients during fertilization treatment. It was observed that, when there is a change in the microbiome, the implantation rate drops to half and the miscarriage rate doubles.

Following this study, also in 2018, the team published a multicenter, prospective, observational study. A 16S ribosomal RNA (16S rRNA) gene sequencing technique was used to analyze endometrial fluid and biopsy samples before embryo transfer in a cohort of 342 infertile patients asymptomatic for infection. Participants underwent fertilization procedures in 13 centers on three continents.

A dysbiotic endometrial microbiota profile composed of Atopobium, Bifidobacterium, Chryseobacterium, Gardnerella, Haemophilus, Klebsiella, Neisseria, Staphylococcus, and Streptococcus was associated with unsuccessful outcomes. In contrast, Lactobacillus was consistently enriched in patients with live birth outcomes. The authors concluded that endometrial microbiota composition before embryo transfer is a useful biomarker to predict reproductive outcome.

“You see a microbial signature in patients who become pregnant, another in those who do not become pregnant, and yet another in those who miscarry,” Simón summarized. “By knowing this signature, the microbiome can be analyzed and treated so that it is stabilized before the embryo is transferred.”

What Should Be Done?

Endometrial microbiome profiles do not use microbial cultures. They are obtained by NGS of the endometrial sample. This is because the 16S rRNA gene, which can be found in bacteria, presents hypervariable regions that serve as markers to identify the bacteria present.

If a microbiome is found to be somewhat unhealthy, it is theoretically possible to change its composition, increasing the chances of successful assisted reproduction. The administration of antibiotics and vaginal probiotics are two treatment approaches.

According to Simón, treatment is specific to the bacterium (metronidazole, and, if that fails, rifampicin for Gardnerella, amoxicillin and clavulanic acid for Streptococci). Once the pathogenic bacterium has been treated, the probiotics can be administered. “If all is well, we can then go ahead with the procedure,” he explained.

Simón pointed out that, with respect to treatment, knowledge is still limited and primarily based on case reports. “You look for issues in the microbiome when the patient experiences reproductive failure and there are no other causes,” he emphasized. “Microbiology plays a role in reproduction, affecting the human uterus. It’s good to know about it to improve reproductive outcomes. When there are repeated [embryo] implantation failures, we suggest an endometrial biopsy to identify the implantation window and determine whether the uterine microbiome is healthy or not. And if there are any abnormalities in the microbiome, they can be treated.”

There are still many open questions, such as how long the “good microbiome” lasts after antibiotic therapy. “We suggest checking the microbiome after [antibiotic] treatment and before implanting the embryo,” said Simón.

Although there is no consensus on how the endometrial microbiota relate to reproductive outcomes, the analysis and change in microbiome are already being offered in clinical practice as a way to increase the chances of conception. Márcia Riboldi, PhD, a genetics specialist serving as Country Manager for Igenomix Brasil and Argentina, the company that offers the analyses, provides an idea of the market for such analyses in Brazil. “We perform approximately 500 analyses per month,” she said, adding that most patients have a history of [embryo] implantation failure or miscarriage.

Matheus Roque, MD, PhD, an IVF specialist, shared two IVF case reports from the Mater Prime Human Reproduction Clinic in the southern region of the city of São Paulo, Brazil. He emphasized that the decision to perform a microbiome analysis was made only after repeated implantation failure.

“With the outcomes the doctors started to see, the paradigm started to shift,” said Riboldi. “Why wait for the patient to have [an embryo] transfer failure? Let’s study the endometrium, check the ideal moment for the transfer, see whether it’s receptive or not, if there’s any disease and if there are Lactobacilli,” she proposed. “We need medical training and awareness, and we need to use them appropriately. We have the tests. Doctors need to learn about them and know when and how to use them.” The microbiome analysis costs approximately BRL 2000, plus expenses with the medical procedure.

Is It Too Early?

Caio Parente Barbosa, MD, PhD, is an obstetrician/gynecologist specializing in human reproduction, as well as the Director‑General and founder of the Fertile Idea Institute for Reproductive Health. He shared a few of his experiences in an interview with Medscape. “I would say it is still too early to confirm that [the microbiome analysis] produces effective outcomes.”

Barbosa, who is also provost of graduate studies, research, and innovation of the ABC School of Medicine, Santo André, São Paulo, Brazil, emphasized there is still little global experience with these analyses. “There are doubts worldwide regarding whether these analyses produce effective outcomes. Scientific studies are entirely controversial.”

He stated that some professionals recommend the microbiome analysis for “patients who don’t know what else to do,” but also recognized that there is already a demand for patients who don’t fit this category, who research the analyses on social networks and YouTube. “But it is the smallest of demands. Patients are not as worried about this yet.”

Barbosa recognized that the idea of an increasingly tailored treatment plan is inevitable. He believes that the study and treatment of the microbiome will become more critical in the future, but he thinks it still “does not offer any value.”

Barbosa emphasized that the financial side of things must also be considered. “If we add all these tests when investigating a patient’s issues, the treatment becomes ridiculously expensive.” He pointed out that healthcare professionals need to be careful to perform minimal testing. “We have already added some tests, such as the karyotype test, to the minimal testing for all patients.”

Simón responded to this criticism, stating: “The cost of repeating cycles is always greater than that of being thorough and knowing what’s going on. Nothing is certain, but if my daughter or wife needed it, I would like to have as much information as possible to make this decision.”

Barbosa and Simón reported no relevant financial relationships. Riboldi is Country Manager for Igenomix Brasil and Argentina, the company that offers the analyses.

Roxana Tabakman is a biologist, freelance reporter, and writer who resides in São Paulo, Brazil. She is the author of the books A Saúde na Mídia, Medicina para Jornalistas, Jornalismo para Médicos (in Portuguese), and Biovigilados (in Spanish). Follow her on Twitter: @roxanatabakman.

This article was translated from the Medscape Portuguese edition.

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