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GEN Exclusives: February 15, 2018

The Potential Role of Vaginal Microbiota in Fertility

Could Probiotics Impact Fertility Efforts?

  • As researchers continue to sort out the complex and crucial balance of a woman’s vaginal microbiome in protecting against infection, some have recently turned their attention toward a new target—its potential role with infertility.

    To that end, researchers in Denmark have launched a randomized study, looking at whether a probiotic vaginal product could be used to restore a more optimal vaginal microbiome, and thus boost the chance that a woman struggling with infertility might get pregnant. The study’s design rests in large part on prior research, published in 2016 in the journal Human Reproduction, which found that just 9% of Danish women undergoing in vitro fertilization (IVF), who also had abnormal vaginal microbiota, got pregnant versus 44% among those with a more optimal balance.

    “We were surprised to see this,” said Thor Haahr, a researcher on the Human Reproduction study. As a M.D./Ph.D. student, he’s serving as a project coordinator on the new study, which will randomize 333 women at five clinics undergoing infertility treatment.

    In the Human Reproduction analysis, 28% of the 130 IVF patients were found to have abnormal vaginal microbiota, per qPCR assays. (Although the women might not have symptoms related to these abnormalities, so the problem could go unrecognized.) But Haahr said that it appears that the figure is likely closer to one in five women, based on a larger meta-analysis that he’s involved with that’s been accepted for publication.

    The 333 women, once they’re determined to have abnormal vaginal microbiota, will be randomized into three groups: one won’t get any treatment, the second will receive antibiotics only, and the third will get antibiotics plus a vaginal probiotic that contains the bacterium Lactobacillus crispatus. The probiotic product, called Lactin-V, is made by California-based Osel, Inc. and also is being tested in other clinical trials against bacterial vaginosis and recurrent urinary tract infections (UTIs).

    The active ingredient in Lactin-V is Lactobacillus crispatus CTV-5, a naturally occurring strain that was isolated from the vagina of a healthy woman, according to Tom Parks, director of product development at Osel, Inc. Parks explains: "Briefly, the strain is grown by fermentation, dried by lyophilization (also called freeze drying), and milled to a powder. The powder containing the live bacteria is filled into specially designed applicators for vaginal administration."

    The primary outcome of the Danish study will be to track pregnancy rates—defined as those whose pregnancy reaches seven to nine weeks gestation, said Haahr, who works at The Fertility Clinic, Regional Hospital Skive in Denmark. But, he said, “Ultimately the goal is to increase the baby take-home rate.”

  • Optimal Microbiota?

    The protective role of a woman’s vaginal microbiota has become increasingly apparent, as researchers have linked imbalances with a number of medical conditions, from bacterial vaginosis to urinary tract infections to sexually transmitted diseases such as HIV. The lactic-acid producing bacteria, and particularly several species of Lactobacillus, are credited with that protective assist, likely through several mechanisms, including ecological competition with potentially harmful bacteria and lowering vaginal pH through lactic acid production.

    “I view this vaginal microbiome as almost like a second immune system for women—it really protects women from all kinds of things,” said Peter P. Lee, M.D., founder and chair of Osel, who also chairs the department of immuno-oncology at City of Hope in Duarte, California.

    Researchers now are trying to sort out what the optimal balance is and how to restore it. A phylogenetic analysis was performed of the vaginal microbiota of 396 North American women who were of reproductive age and represented several ethnic/racial groups (white, black, Hispanic, and Asian). Four bacterial species dominated: Lactobacillus inersL. crispatusL. gasseri, and L. jensenii. But their relative proportion varied across the ethnic/racial groups studied, according to the findings, published in 2011 in the Proceedings of the National Academy of Sciences.

    While differing racial and ethnic groups might have variations in what vaginal microbiota might be considered optimal in terms of health, it’s becoming increasingly apparent that carrying Lactobacillus is more optimal than not and that Lactobacillus crispatus is “particularly good,” said Scott McClelland, M.D., a vaginal microbiome researcher and professor of medicine, epidemiology, and global health at the University of Washington in Seattle. “L. crispatus is probably the best in terms of what I would call optimal vaginal flora, based on the data we have available now, for being associated with the lowest risk of most disease outcomes,” he said.

  • Restoring Balance

    Even if a more optimal vaginal microbiota environment can be restored, such as by introducing L. crispatus through Lactin-V, that doesn’t mean long-term colonization can be achieved, Dr. McClelland pointed out. A number of activities, including menstruation or sexual activity, can potentially disrupt a woman’s microbiome.

    “I think that what really needs to be shown still is that you can restore that long-term balance,” Dr. McClelland said. “That’s the Achilles heel of BV [bacterial vaginosis] treatment—it keeps coming back.”

    Another ongoing National Institutes of Health study that also uses Lactin-V is looking at whether the probiotic is more effective against bacterial vaginosis than treating with an antibiotic (metronidazole) by itself. (Dr. McClelland is serving in an unpaid role as chair of the data safety and monitoring board for the BV study.)

    Craig Cohen, M.D., who is leading the bacterial vaginosis study, said that the 228 randomized women involved will receive treatment for 12 weeks and be followed for an additional 12 weeks. The goal: to continue to assess the safety of Lactin-V and also track rates of BV recurrence.

    “Hopefully a large majority of women will remain colonized with the [L. crispatus] bacteria and decrease the risk of recurrence,” said Dr. Cohen, a professor of obstetrics, gynecology and reproductive sciences at UCSF School of Medicine.

    The participants also will be asked to keep a calendar tracking menstruation and sexual activity. “We don’t expect every woman to remain colonized with crispatus,” so it will be helpful to try to identify what factors might be associated with a decrease, Dr. Cohen said.

    Cohen anticipates that the Phase II study, which had enrolled roughly three-fourths of the women by early 2018, will have results by late 2019. The new study that Haahr is involved with, which has started enrolling women, will have results by 2020 at the earliest, he said. The study is jointly funded by Osel, Aarhus University. and Statens Serum Institute, according to Haahr.

    Dr. McClelland, whose research has primarily focused on the vaginal microbiome’s influence on contracting HIV and other sexually transmitted diseases, said that the field’s work is progressing along two tracks. One involves observational studies that are using various tools, such as quantitative PCR or deep sequencing, to identify vulnerable populations of women, as well as look at which underlying bacterial species might contribute to disease vulnerability. The second line of research is looking at whether, by restoring a more optimal microbiota environment, the woman’s health might benefit in some way, he said.

    “The real question is not can we can make the gram stain normal, but can we decrease the adverse outcome or increase the likelihood of a good outcome, like fertility,” Dr. McClelland said.

    In the case of the Danish study, there will be a clear-cut outcome—pregnancy—and two groups of women who will be aggressively aided in achieving that happy result by the fertility clinics involved, Dr. McClelland said.

    If the Lactin-V application makes a statistically significant difference, Dr. McClelland said, “it moves us beyond simply microbiome association—that having BV as a condition is associated with a lower fertility rate. To actually proving that—[being able to say] ‘Yes, we can do something about this’—both proves the mechanism and gives you an intervention at the same time.”