The impact of the vaginal and endometrial microbiome on reproductive health and IVF outcomes

This post reviews what research currently shows about the vaginal and endometrial microbiome and how it may relate to fertility and IVF outcomes. While Lactobacillus species are often considered beneficial and are commonly found in the reproductive tract, studies examining whether microbiome differences actually affect IVF success have produced mixed results.

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How bacteria are classified

When we’re talking about bacteria, or any kind of organism in general, they’re classified by their genus and species name.

In biology, organisms can be classified based on similarities and put into different categories, such as domain, kingdom, phylum, class, class, order, family, genus and species.

Let’s look at the example of humans:

• Domain: Eukarya
• Kingdom: Animalia
• Phylum: Chordata
• Class: Mammalia
• Order: Primates
• Family: Homininae
• Genus: Homo
• Species: Homo sapiens

The most specific rank is called species, and right before species is genus.

Organisms are often described by binomial classification, based on their genus and species name. Humans are Homo sapiens: Homo is the genus rank, and sapiens is the species rank. Notice that these words are italicized, and the first letter of the genus name is capitalized, which is done as a scientific convention.

A well known genus is Canis, which include Canis lupus (wolf), Canis latrans (coyote) and Canis familiaris (a dog!).

The plural of genus is genera.

The members of the vaginal and endometrial microbiome

As reviewed by Cocomazzi et al. (2023), common members of the vaginal microbiome include Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus iners, and Lactobacillus jensenii.

Besides Lactobacillus, there are also members of the Gardnerella, Atopobium, Mobiluncus, Prevotella and other genera present in the vagina. Fungi can also be found in the vagina, including species of the Candida and Cryptococcus.

As reviewed by Toson et al. (2022), studies examining the endometrial microbiota vary, with some reporting a predominance of Lactobacillus species while others found a diverse range of bacteria, including Gardnerella, Prevotella, Bifidobacterium, and Streptococcus. Some studies observed non-Lactobacillus dominant compositions with bacteria like Acinetobacter, Pseudomonas, Sphingobium, and Vagococcus.

The uterine microbiota composition varies across populations and patient groups, indicating the influence of genetic and environmental factors.

The role of Lactobacillus in the vagina and endometrium

Lactobacillus plays a protective role in the vaginal ecosystem. They produce lactic acid, hydrogen peroxide, and antibiotics called bacteriocins that inhibit the growth of other potentially harmful microorganisms in the vagina. (Cocomazzi et al. (2023))

The uterus was once believed to be sterile but is now known to contain diverse microbial communities. The origins of these microbes are still debated, but they may come from the gut, oral cavity, bloodstream, vaginal ascension, or other sources. The uterine microbiome is less populated and more diverse than the vagina, but its composition and significance are not fully understood. (Toson et al. (2022))

The composition of the vaginal and endometrial microbiota changes throughout a woman’s life, and is influenced by factors such as hormonal changes, age, menstrual cycle, sexual practices, and pregnancy. (Cocomazzi et al. (2023) and Toson et al. (2022))

Studies have shown that women from different ethnic groups can have a functional vaginal microbiome without Lactobacilli dominance, which is influenced by genetic, geographic, and social factors. (Cocomazzi et al. (2023))

The role of the microbiome in infertility

Studies have shown a correlation between infertility and the microbiome.

Bacterial pathogens like E. coli, Atopobium vaginae, Sneathia sanguinegens, Chlamydia trachomatis, and others, when present in the female genital tract, can lead to pelvic inflammatory disease. PID can damage the fallopian tubes, ovaries, uterus, and pelvic peritoneum, potentially compromising fertility and increasing the risk of ectopic pregnancy. (Sharma et al. (2014))

Additionally, women with endometriosis have been found to have higher concentrations of certain bacteria in menstrual blood and peritoneal fluid. However, how these microbes give rise to endometriosis isn’t clear, but may have to do with increased inflammation. (Khan et al. (2010))

Bacterial vaginosis is a common genital tract disorder in women, characterized by an imbalance of bacteria. It has been linked to increased risk of infertility, particularly tubal infertility, and second-trimester miscarriage and preterm deliveries. This may be due to an excessive immune response and interactions with the maternal-fetal barrier. (Gaudoin et al. (1999), Isik et al. (2016))

Chronic endometritis is associated with specific bacterial communities, including lower abundance of Lactobacillus and higher numbers of other bacteria, including Anaerococcus, Bifidobacterium, Dialister, Gardnerella, Prevotella, Ralstonia, Gardnerella, Phyllobacterium and Sphingomonas being reported in some studies. Inflammatory signaling disruptions may contribute to endometrial dysfunction. (Toson et al. (2022))

Shifts in endometrial microbiota are associated with recurrent implantation failure, characterized by lower microbial diversity and higher rates of Burkholderia, Atopobium, Delftia, Gardnerella, Prevotella, L. helveticus and Sneathia amnii being reported by some studies (Toson et al. (2022)).

The role of the vaginal and endometrial microbiome on IVF outcomes

Different studies have reported on how alterations of the vaginal microbiome correlate with a reduction in IVF pregnancy rates:

• Selman et al. (2007) found that the presence of Entrobacteriaceae and Staphylococcus in the vagina, cervix or introduced by contamination was associated with decreased pregnancy rates. There was no difference in patients with or without Lactobacillus.
• Hyman et al. (2012) found that the diversity of vaginal bacterial species was associated with live birth outcomes.
• Haahr et al. (2016) found that women with abnormal vaginal microbiota (Gardnerella vaginalis and/or Atopobium vaginae) had a decreased clinical pregnancy rate.
• Koedooder et al. (2019) found that women with low levels of Lactobacillus in vaginal samples were less likely to become pregnant after embryo transfer.

Besides the vaginal microbiome, studies have shown a relationship with the endometrial microbiome and pregnancy outcomes after IVF.

• Hashimoto et al. (2019) found that pregnancy, implantation, and miscarriage rates were comparable between Lactobacillus-dominant and non-dominant groups. Pregnancy in patients with complete absence of Lactobacillus was reported.
• Kyono et al. (2018) found that pregnancy rates were slightly higher in Lactobacillus-dominated group, although the difference was not statistically significant.
• Moreno et al. (2016) found that non-Lactobacillus-dominant endometrial microbiota was associated with poorer clinical outcomes (decreased implantation, pregnancy, ongoing pregnancy rates, and live birth rates).
• Moreno et al. (2021) found the increased abundance of Lactobacillus was consistently associated with higher live birth rates, while higher levels of Atopobium, Bifidobacteirum, Gardnerella, Klesbiella, Streptococcus, and others were associated with poorer clinical outcomes.

Moreno et al. (2021) suggest that the presence of pathogens in the uterus may be what ultimately impacts fertility, instead of the absence of bacteria like Lactobacillus.

The use of probiotics to modify the microbiome

Probiotics are supplements that contain live microorganisms that can be administered to provide health benefits.

In terms of combating bacterial vaginosis, Mastromarino et al. (2009) gave Lactobacillus-containing probiotics to women with BV which led to a healthy microbiome in most patients and reversal of symptoms. Recine et al. (2016) found that Lactobacillus-containing probiotics prevented BV recurrence.

In terms of pregnancy complications, Nordqvist et al. (2018) found that consumption of probiotic Lactobacillus-containing milk was associated with lower risk of preeclampsia and preterm delivery.

Gilboa et al. (2005) found that women who received vaginal probiotics containing Lactobacillus after egg retrieval resulted in no changes in Lactobacillus levels during embryo transfer 2-3 days later and had no effect on pregnancy rate.

Iwami et al. (2023) treated an abnormal microbiome in women with recurrent implantation failure using targeted antibiotics followed by a probiotic, which resulted in improved cumulative pregnancy rates and ongoing pregnancy rates.

In a randomized controlled trial, Jepsen et al. (2022) found that the use of daily Lactobacilli-loaded vaginal capsules, taken for 10 days before fertility treatment, wasn’t effective in improving an unfavorable vaginal microbiome in patients with low Lactobacillus or high levels of disrupting bacteria. A follow-up analysis found that 34% of women showed an improvement a month to 3 months later, regardless of whether they took the probiotic or not.

The challenges of linking the microbiome to reproductive outcomes

There are some concerns in studying the vaginal/endometrial microbiome and the reliability of the data.

Gajer et al. (2012) evaluated the vaginal microbiome twice a week over a 16-week period in 32 women and found that some women show unstable bacterial communities that frequently change in species composition. This study raises concerns about the reliability of studies linking the microbiome to reproductive outcomes, as the bacterial communities can vary over time due to factors like the menstrual cycle and sexual activity.

Variation in the microbiome was also seen in the Jepsen et al. (2022) study as mentioned above.

Toson et al. (2022) consider patient characteristics to be one of the biggest limitations of endometrial microbiome studies, and the type of patients used should be considered carefully when designing a study.

Women of different ethnicities have been shown to have different microbiomes, while other factors like hormonal treatment, antibiotic/probiotic use, the presence of intrauterine devices and diagnosis have also been shown to affect the microbiome.

Furthermore, endometrial samples collected through the vaginal-cervical route risk contamination with vaginal microbiota, which can impact analysis. There are also variations between endometrial fluid and biopsy samples, highlighting the need for standardization in experimental design and control of contaminants.

Another issue is that many studies involving the microbiome and reproductive outcomes are small, making it difficult to compare studies and draw conclusions.

Conclusions

The vaginal and endometrial microbiome plays an important role in reproductive health and protection against pathogens, and is mainly composed of Lactobacilli, but other genera are also present.

Lactobacillus can produce lactic acid, hydrogen peroxide, and antibiotics called bacteriocins that inhibit the growth of other potentially harmful microorganisms in the vagina.

Bacterial imbalances in the reproductive tract have been linked to a variety of disorders that can affect fertility, including pelvic inflammatory disease, endometriosis, chronic endometritis, bacterial vaginosis and recurrent implantation failure.

A number of studies have found that the vaginal and endometrial microbiome can influence pregnancy outcomes, with higher levels of Lactobacillus being linked to favorable outcomes, and higher levels of other bacteria associated with poorer outcomes.

Probiotics with Lactobacillus have been successful in treating bacterial vaginosis and reducing pregnancy complications, but data that shows their ability to improve IVF outcomes is lacking. One study found no benefit, while another found that probiotic use had no impact on improving the microbiome.

There are some concerns in studying the vaginal and endometrial microbiome and the reliability of the data. One study found that the microbiome was unstable and changed over a 16-week period. Differences in the microbiome have also been associated with sexual activity, the menstrual cycle, hormone levels, age and ethnicity, making it challenging to study and draw conclusions.

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About Embryoman

Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.

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