Infertility affects about 48 million couples worldwide and, in a significant number of cases, the specific cause is not identified. In this context, the study of the relationship between reproductive health and the microorganisms that inhabit our bodies (the microbiome) and reproduction has recently emerged, although with a significant bias. The focus had been especially on the female body, but a study just published in The Lancet Obstetrics, Gynaecology & Women’s Health has taken a different path. The work also shifts the focus to the semen microbiome, its role in spontaneous abortions, and the success of fertility treatments.
According to the research team, the set of bacteria, viruses, and fungi that inhabit seminal fluid could influence the chances of achieving a pregnancy. Specifically, the authors found that the imbalance of these microorganisms is related to spontaneous abortions and fewer births after a reproduction treatment.
For Ida Behrendt-Møller, a physician and the first author of the article, the most important element of the research is that it tries to overcome the bias with which the microbiome and its relationship with infertility had been studied. “Much research has been done on the vaginal microbiome, but not on the seminal one. In the latter, studies have been few and very small,” says the Danish researcher.
The work, carried out with couples treated at two university hospitals in Denmark, simultaneously analyzes three microbial ecosystems: the vaginal, the female intestinal, and the male seminal. The results suggest that certain alterations of the microbiome, both of the semen and the female intestine, are associated with cases of spontaneous abortions and a lower probability of achieving a birth after treatments.
Paradoxically, the vaginal microbiome — the most studied so far — did not show a consistent association with birth. However, the author argues that this does not mean the vaginal microbiome has no role. “So far, we have only found associations. We have not demonstrated causality,” emphasizes Behrendt-Møller.
Previously, some studies have linked certain bacterial alterations in the vagina with a higher risk of problems during embryo implantation. “The theory is that an altered microbiome could affect both implantation and the maintenance of pregnancy through a higher risk of infections or by activating an immune response in the woman,” the physician highlights.
Pernille Neve Myers, a bioinformatician and author of the study, explains that the work arose to try to demonstrate that relationship. If couples constantly exchange microorganisms, she argues, perhaps they also share microbiomes capable of influencing reproduction. “We know that couples can transmit HIV and other sexually transmitted infections during sexual intercourse. So, why couldn’t they also share beneficial or potentially pathogenic bacteria?” the researcher points out.
A study of almost nine years
The study followed couples undergoing in vitro fertilization or intracytoplasmic sperm injection treatments, and couples with recurrent pregnancy losses. They did so for nine years.
The authors explain that the long process was due both to the time needed to recruit participating couples — many in emotionally difficult situations — and to the high cost and complexity of genetic sequencing analyses. “These people are going through something extremely complicated, but still want to participate to improve treatments for future patients,” comments Behrendt-Møller.
More than 350 women and nearly 200 men belonging to two independent cohorts with infertility or recurrent pregnancy losses participated. The patients were between 18 and 41 years old, and their male partners were 18 years or older.
After the analyses, they found that cases where the semen presented a bacterial profile similar to bacterial vaginosis took longer to achieve birth and had a higher risk of losses.
In couples undergoing in vitro fertilization, 57% of those in which the man presented this profile finally achieved a live birth, compared to 85% when that pattern was not present. Additionally, in both cohorts, the risk of pregnancy loss increased.
The experts identified a pattern called seminal dysbiosis. “We know which bacteria we consider harmful when they appear in the vagina. So we looked to see if those same bacteria were present in the semen and if they could potentially negatively influence the female genital microbiome,” explains Behrendt-Møller.
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However, the exact mechanism remains unknown. “It could affect implantation or the maintenance of pregnancy through the woman’s exposure to the seminal microbiome during sexual intercourse,” the physician maintains.
Research on the intestine
The next step was to study the female intestine. “Our intestine plays a very important role in health and disease in general. It can modulate the immune response, metabolism, and hormones, factors that can also be related to fertility,” explains the lead author.
Women with a “more altered” intestinal microbiome showed less likelihood of achieving pregnancy. “We know that fertility decreases rapidly after age 35, but we found that women with a less altered intestinal microbiome had better chances of conceiving,” Myers points out.
They suggest this could be related to inflammation, metabolism, or immune regulation. But it is not yet clear. “It still needs to be verified whether modifying the microbiome can increase the chances of pregnancy,” warns Behrendt-Møller.
The author calls for caution. “I would not recommend using antibiotics because we still do not know if they would really change the man’s or the woman’s microbiome, nor if they would improve reproductive outcomes,” she warns. “Nor can we say that a specific diet will improve the chances of pregnancy based on this study,” she states.
Belén Acevedo Martín, a physician in the Assisted Reproduction Unit of the Jiménez Díaz Foundation in Madrid, agrees with that caution. “This cannot be seen as the panacea for the cause of infertility,” warns the gynecology and obstetrics expert who did not participate in the study.
In her opinion, the findings will need to be reproduced in larger and more diverse populations, as the work was carried out exclusively with Danish patients. “The composition of the microbiome can vary depending on diet, geographic origin, or genetics. All participants come from the same country, and we know there are significant differences between populations,” she recalls.
Furthermore, she considers it necessary to compare these profiles with those of fertile people who have had uncomplicated pregnancies. “We can detect an alteration in patients who have suffered miscarriages, but we need to know if that same alteration is also present in women who have had children without problems,” she maintains.
Despite these limitations, she considers the study a significant advance. “Until now, almost all research had focused on the vaginal microbiome,” she points out. “This work understands the couple as a unit that shares microorganisms,” adds the expert.
Reproductive medicine has devoted efforts to understanding female physiology — a historical debt after centuries in which women were excluded from biomedical research — but that necessary shift remains biased. The male body had been left aside.
“Although a very high proportion of patients in fertility clinics receive treatment for a male factor, many times we still mainly treat the woman,” notes Behrendt-Møller.
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