Infertility, defined as the inability to conceive after 1 year of unprotected sex, is a growing problem affecting 1 million married premenopausal women, according to the Centers for Disease Control and Prevention (CDC).1 An estimated 7.5 million women aged 15-44 years have impaired fertility and fecundity.1 It is well established that the maternal microbiome influences the risk of chronic diseases and mood disorders in the neonate and throughout life, starting in utero.2 But to what extent does the microbiota of the vaginal tract influence a woman’s ability to conceive and carry an infant to term?
The vaginal microbiome plays a central role in protecting and influencing the harmonious balance of bacteria in the vaginal tract. Research has shown that bacterial infections – including sexually transmitted diseases (STDs), bacterial vaginosis (BV), urinary tract infections (UTIs), and Group B Streptococcus (GBS) – affect fertility and the risk of both preterm labor and post-partum complications.3
How does an imbalanced vaginal microbiome affect fertility? What constitutes a “healthy” vaginal microbiome? What probiotics promote an optimal microbial environment for fertility and the health and survival of the next generation? This article will address these questions.
The mechanism by which the vaginal tract is policed and protected is regulated by the vaginal microbiome. Antimicrobial peptides (AMP) – amphipathic, multifunctional molecules – are released from the epithelial cells of the female reproductive tract in response to chemical signals from the local microbial community to protect the host against inflammation and pathogen invasion. Ie, AMPs are an immunological barrier to infections in the female reproductive tract, which are alerted by dybiosis of the vaginal microbiome.4 This microbiome is influenced by hormonal changes and vice versa. Estrogen stimulates the vaginal epithelia to produce glycogen, which is metabolized by lactobacilli. These microbes produce lactic acid and organic acids that lower the vaginal pH to 3.7-4.5, making the vagina more acidic and thereby less hospitable to pathogenic bacteria.5 As a result, estrogen levels play a role in a woman’s susceptibility to vaginal infections and – as we shall see – fertility as well.
In addressing the cause of disease, a sophisticated understanding of health takes into account individual differences and the relationships that microbes have with their host, not just the pathogens that are present. The primary ways that microorganisms relate to their host include: 1) symbiotically beneficial relationships, eg, bifidobacteria that promote infant digestion and immune function; 2) commensals, eg, some strains of Candida albicans that confer neither harm nor benefit; and 3) pathogenic bacteria, eg, certain strains of Gardnerella vaginalis that contribute to BV. In the vaginal microbiome, as in other parts of the body, some bacteria are opportunistic, ie, only creating harm in the host when an imbalance between pathogenic and nonpathogenic bacteria occurs; an example of this is yeast overgrowth due to Candida spp. In order to determine the potential pathogenic vs therapeutic effect of microbes, it is necessary to determine what is normal. In the case of the vaginal microbiome, it may be more appropriate to determine what is normal for each individual.
The Vaginal Microbiome: What is Normal?
The Vaginal Microbiome Project (VMP) is an NIH-funded research study that began in 2011. The VMP seeks to characterize and understand the vaginal microbiota and how it relates to health and disease, using the latest technology in gene sequencing. According to Jennifer M. Fettweis et al (2011) at Virginia Commonwealth University, “the cervix serves a pivotal role as a gatekeeper to protect the upper genital tract from microbial invasion and subsequent reproductive pathology. Microorganisms that cross this barrier can cause preterm labor, pelvic inflammatory disease, and other gynecologic and reproductive disorders. Homeostasis of the microbiome in the vagina and ectocervix plays a paramount role in reproductive health.” Clearly, understanding and promoting the health of the vaginal microbiome can help protect and promote a more fertile environment.
There are over 200 bacterial species in the vaginal microbiome.7 In 2011, Ravel et al found that most asymptomatic non-pregnant women carry 5 different microbiomes in their vaginal tract that are likely to be associated with vaginal health.8 Four of the 5 community state types (CSTs) are dominated by Lactobacillus species, including L crispatus (CST I), L gasseri (CST II), L iners (CST III), and L jensenii (CST V). CST IV is associated with low levels of Lactobacillus spp and increased anaerobic diversity, including Prevotella, Dialister, Atopobium vaginae, Gardnerella vaginalis, Megasphaera, Peptoniphilus, Sneathia, Finegoldia, and Mobiluncus. The bacteria in CST IV are associated with BV, which is linked to an increased risk of preterm birth and histological chorioamnionitis. American Black and Hispanic women usually have a diverse microbiome consistent with CST IV, whereas Asian and White women have a vaginal microbiome dominated by Lactobacillus spp (CST I, II, III and V). These findings suggest genetic and/or cultural differences in the vaginal microbiome of healthy women.8
Several species of lactobacilli support an immunological defense system in the genital tract, along with antibacterial substances, cytokines, and defensins that help protect against dysbiosis and infections that affect pregnancy and risk of preterm birth.7 Lactobacillus species are the most abundant strains in the vaginal tract, with variability in the Lactobacillus strains, according to health and disease.7 Variables that influence a woman’s vaginal microbiome throughout her lifetime include a woman age, ethnicity, menstrual cycle, hormonal changes, menopause, pregnancy, and environmental and behavioral factors.7,9-11 According to research by Gajer et al (2012), a woman’s microbiome can change in as little as 24 hours,12 further complicating the establishment of a definition of a healthy vaginal microbiome.
The specific composition of the vaginal microbiome influences a woman’s predisposition to dysbiosis and susceptibility to infection, which in turn affects fertility. An understanding of the vaginal microbial environment during states of health is essential for the identification of risk factors for disease and the development of appropriate treatment.13 The complexity of what constitutes a “healthy” vaginal microbiome makes it challenging to offer general solutions to women for preventing infections and maximizing a fertile microbiome.14 We know that at different points in a woman’s life, the diversity of her microbiome changes. For example, there is less microbial diversity during pregnancy.15 Overall diversity is reduced during pregnancy, and there is a predominance of Lactobacillus species (L iners crispatus, jensenii, and johnsonii), Clostridiales, Bacteroidales, and Actinomycetales.16
Vaginal dysbiosis is characterized by an imbalance whereby there is overabundance in the vaginal microbiome of pathogenic strains of bacteria compared to symbiotic and commensal organisms such as Lactobacillus spp. In a Ukrainian study, lactobacilli were present in 92.7% of the samples. The presence of lactobacilli and a dominance of obligate anaerobes was defined as “normobiosis.” Dysbiosis, in contrast, was defined by the presence of various concentrations of Mycoplasma, Ureaplasma, and Candida.17
BV influences fertility, miscarriage, UTIs, uterine infections, resistance to diseases that affect fertility, and the health and survival of the offspring.18 During pregnancy, vaginal dysbiosis is a risk factor for pregnancy complications, including preterm birth, endometritis, chorioamnionitis, and intrauterine death.7 Dysbiotic conditions that can impact fertility and the ability of a woman to carry offspring to term include STDs, BV, GBS, and UTIs. Again, an accurate, generalizable definition of dysbiosis is challenging because there is variation in what constitutes a healthy vaginal microbiome for each individual. For example, NHANES data from 2001 to 2004 suggests that up to 84% of “dysbiotic” women with BV are asymptomatic.18
When the balance among bacterial species within the vaginal microbiome is disrupted, antibacterial defense mechanisms are weakened, causing pathogenic bacteria to flourish. The antimicrobial properties of vaginal lactobacilli include the expression of lysostaphin, which cleaves the cell wall of Staphylococcus aureus, thus inhibiting its growth, and the production of hydrogen peroxide (H2O2), which destroys pathogenic bacteria.7 Intravaginal colonization by bacterial strains such as GBS is one of the most important risk factors for disease in newborns; GBS colonization occurs in 50-70% of neonates born from infected mothers. In a murine model, L reuteri CRL1324 administration reduced leukocyte influx induced by Streptococcus agalactiae NH17 and had a preventive effect on its vaginal colonization prior to the GBS challenge.7 According to Di Cerbo et al (2016), “The introduction of new antimicrobial agents, such as L. reuteri CRL1324, could be considered a valuable and safer alternative to antibiotics to reduce infections caused by GBS.”7
Using probiotics to treat dysbiotic conditions of the vaginal tract in fertility and pregnancy addresses the cause of the dysfunction, thus could be considered an effective alternative to the conventional approach of using antibiotics in these situations.
Dr Attila Toth, Director of Macleod Laboratory and Clinical Associate Professor at New York Presbyterian/Weil Cornell Medical Center, outlines the importance of addressing pathogens in fertility.19 Pathogens in the uterine lining affect menstrual flow, implantation, miscarriage, antibody activity, risk of tubal infection and closure, ectopic pregnancy, and tubal fertility. Ovarian infections affect hormonal balance and its pathological consequences, including polycystic ovarian syndrome. Bacterial pathogens can promote endometriosis, pelvic adhesions, and digestive disorders that contribute to inflammatory disorders. Pathogens of particular concern for both male and female fertility include Chlamydia, Mycoplasma, select aerobic and anaerobic bacteria, some yeasts, and Trichomonas. Pathogenic strains in the genital tract of men and women can be shared during intercourse and affect male erectile function, ejaculation, sperm count, viability, and fertilizing capacity. Dr Toth recommends administration of antibiotics via intrauterine lavage in women, or prostate injections in men, to improve infertility that is suspected to be caused by infections.19 Studies have found that infertile couples infected with Mycoplasma, Chlamydia trachomatis, or with a history of miscarriages, who were then treated with antibiotics experienced improved fertility after antibiotic therapy. A 2007 study of couples with primary or multiple previously failed IVF cycles showed a success rate of 68% following antibiotic treatment.19
While antibacterial and antifungal medications may be appropriate in some cases, chronic antibiotic therapy further disrupts the vaginal microbiome.7 If antibiotic therapy is effective in addressing infections and their impact on fertility, appropriate probiotic therapy is a potentially more effective treatment that addresses the cause and has a positive impact on the health of the offspring.
BV, as mentioned, is a dysbiotic condition of the vaginal tract with a well-established impact on fertility, pregnancy, and risk of preterm labor; BV is most common cause of vaginal symptoms in women worldwide.20 BV-associated bacteria in one study included Atopobium vaginae and Clostridiales, and 1 or 2 of 4 strains of Gardnerella vaginalis.7 These strains in various combinations can produce polymicrobial biofilms on the vaginal epithelial cells, which are not dissolved by antibiotic therapies. These biofilms can thus contribute to recurrences of infection, and can disrupt non-pathogenic strains that support vaginal health.7 Aerobic vaginitis is characterized by an overgrowth of the pathogenic aerobic bacteria Streptococcus agalactiae and Escherichia coli.7
In the past, Gardnerella vaginalis was implicated as the main pathogenic agent in BV; however, subsequent studies determined that Gardnerella vaginalis is a commensal organism within the vaginal tract of most women. Harwich et al (2010) revealed through gene sequencing that there are 2 contrasting strains of Gardnerella vaginalis – one strain that is commensal and found in healthy women, and another strain that is pathogenic and found in women infected with BV.3 The BV-associated strain encodes a variant of a biofilm-associated protein gene, resulting in greater aggregation, adherence, and biofilm formation that contributes to its cytotoxicity.3
Probiotics in the Treatment of BV
Standard treatment of BV, consisting of oral or intravaginal antibiotics, is associated with a high rate of recurrence and promotes vaginal dysbiosis by reducing protective microbes. In a placebo-controlled, pilot trial of 34 premenopausal women (ages 18-50) diagnosed with BV, selected strains of Lactobacillus were tested for their ability to inhibit Gardnerella vaginalis.21 Lactobacillus fermentum LF15 (DSM 26955) and L plantarum LP01 (LMG P-21021) were delivered vaginally via slow-release tablets containing 400 million live cells and 50 mg of tara gum [which creates a mechanical barrier against G vaginalis] once daily for 7 consecutive nights, followed by 1 tablet every 3 nights for another 3 weeks (acute phase) and, finally, 1 tablet per week for long-term prevention against reinfection. L fermentum LF15 and L plantarum LP01 significantly reduced BV (as reflected by a gram-stain-based Nugent score of <7) after 28 days in 22 of the 24 patients in the active group (91.7%, p<0.001). Eight women (33.3%) recorded a Nugent score between 4 and 6, suggestive of further improvement, while the remaining 14 (58.3%) showed a score of <4, suggestive of restoration of healthy vaginal microbiota. At the end of the second month, only 4 women showed a Nugent score of >7 after 28 days, definable as BV (16.7%, p=0.065). No significant differences were observed in throughout the study. In vitro, Lactobacillus plantarum LP01 produced the strongest inhibition of G vaginalis American Type Culture Collection 10231. 21
Various in-vitro studies have shown certain specific strains of lactobacilli to inhibit the adherence of G vaginalis to the vaginal epithelium and/or to produce H2O2, bacteriocins, and/or lactic acid that inhibit the growth of dysbiosis-inducing bacteria.22 Clinical trials have shown that intravaginal administration of L acidophilus for 6-12 days, or oral administration of L acidophilus or L rhamnosus GR-1 and L fermentum RC-14 for 2 months, eradicated BV (defined as a 0-1 positive score, according to Amsel’s criteria), and/or reduced recurrences of it, and/or produced an increase in vaginal lactobacilli and restoration of a normal vaginal microbiota, compared to a placebo, acetic acid, or no treatment.22 Other trials have found no significant differences, in terms of cure rate of BV, between vaginal lactobacilli treatment, placebo, and estrogen; however, most existing studies have been positive.22 A careful analysis of research studies examining BV and probiotics must take into account the method of detection and diagnosis of BV, considering there is significant variability in “normal” flora among women and that we now know that not all strains of Gardnerella vaginalis are pathogenic. In addition, the establishment of what constitutes a therapeutic dose of Lactobacillus species is a consideration, as is the quality of the probiotic product.
BV indirectly affects fertility when anaerobic bacteria produce polyamines and other toxic compounds that trigger the release of the proinflammatory cytokines interleukin (IL)-1β and IL-8.23 BV can directly affect fertility by increasing the risk of infections in the fallopian tubes.22 High-quality probiotic strains can not only eliminate BV but also exert antiviral effects, which, by reducing viral load, helps prevent fetal and neonatal infection.23 By assisting recovery from infection, and restoring and maintaining a healthy vaginal ecosystem, probiotic administration supports a woman’s reproductive health.23
The use of bacteriocins (toxic bacterial proteins that inhibit other microbes) have also shown promise in vitro, either synergistically or as an alternative to current antibiotics in the treatment of organisms associated with BV.24
The Vaginal Microbiome in Pregnancy
The vaginal microbiome, which is mostly dominated by Lactobacillus spp, becomes less diverse and more stable during a healthy pregnancy; this varies somewhat depending on ethnicity.15 During pregnancy and post-delivery, the risk of postpartum endometritis and sepsis is influenced by the presence of anaerobic vaginal microbiota.15 Similarly, early postpartum endometritis is associated with the presence of microbes typically associated with BV, including Gardnerella vaginalis, Bacteroides spp, Peptococcus spp, Staphylococcus epidermidis, Streptococcus agalactiae, and Ureaplasma urealyticum.15
Irrespective of ethnicity, in the post-partum period, the vaginal microbiome dramatically changes to become less Lactobacillus-dominant. There is also greater alpha-diversity irrespective of an individual’s original microbial composition.15 The Lactobacillus dominance seen in American women is most often observed in White and Asian women, while a more diverse microbiome is more frequently seen in Blacks and Hispanics.15
Bacterial infections are associated with approximately 40-50% of preterm births.25 In women without a predominance of vaginal lactobacilli, antibacterial defense mechanisms are reduced. As a result, pathogenic bacteria are able to proliferate, which promote degradation of the cervical barrier that normally prevents the passage of bacteria into the endometrium and amniotic cavity; as a result, preterm myometrial contractions are more easily triggered.25 Detecting the absence of lactobacilli dominance in pregnant women via self-measurement of vaginal pH, along with measures to encourage lactobacilli growth can help prevent the occurrence of preterm birth.
Preterm Birth & the Vaginal Microbiome
Reproductive tract infection is a significant initiator of preterm birth (PTB), defined as delivery at less than 37 weeks of gestation.26 The 2012 World Health Organization global action reported that premature births are the world’s leading cause of neonatal death and a major cause of neurodevelopmental/behavior disorders and other chronic morbidities.27 Uncultured vaginal bacteria play an important role in PTB, with a higher risk of PTB in African Americans (17.8%) compared to Caucasians (11.5%) and Asian/Pacific Islanders (10.5%);25 both race/ethnicity and sampling location significantly influence the composition of the vaginal microbiome.26 A review of the Cochrane Pregnancy and Childbirth Group trials register and the Cochrane Controlled Trials (2002) found that “the effect of treating BV during pregnancy showed a trend toward fewer births before 37 weeks’ gestation (OR, 0.78; 95 percent CI, 0.60 to 1.02). The prevention of preterm birth at less than 37 weeks’ gestation was most marked in the subgroup of women with a previous preterm birth (OR, 0.37; 95 percent CI, 0.23 to 0.60).”28
Approximately 25% of pregnant women with a history of unexplained spontaneous PTB will experience another unexplained PTB.26 The specific species of Lactobacillus colonizing the vaginal tract appears to play a role in risk of PTB. A small prospective cohort study of 88 participants found no correlation between the vaginal microbiome, Lactobacillus concentration, and PTB; however, the vaginal microbiomes of both PTB participants [both Caucasians] were dominated by Lactobacillus crispatus.26 For the Caucasian participants who carried to term, 3 vaginal microbiomes were dominated by L crispatus, while 3 were dominated by Lactobacillus gasseri (except Atopobium, which dominated 1 third-trimester swab). The vaginal microbiomes of the 2 Hispanic women and 1 “Other” were dominated by Lactobacillus iners.26 The Lactobacillus content was higher among participants with lower risk of PTB (91.4% vs 80.7%, for low vs high risk, respectively) but did not distinguish PTB from term birth (86.2% vs 84.9%).26
In this same study of pregnant women, several species of Lactobacillus (eg, L crispatus, L iners, and L jensenii) were common in women of most or all races/ethnicities, although the vaginal microbiomes of pregnant African American and Hispanic participants showed higher concentrations of L iners.26 Caucasians showed relatively higher counts of L crispatus and L gasseri, compared to other ethnicities. Although there was no correlation between the vaginal microbiome, Lactobacillus content, and PTB, there was a statistically significant difference in the average microbial diversity (as measured by Shannon Diversity Index) between Caucasians who experienced a PTB and those who carried to term.26 None of the pregnant women with PTB harbored Atopobium. Other pathogenic bacteria were found in the vagina of women with PTB, although the researchers proposed that larger studies focused on Bifidobacterium and Ureaplasma may be warranted for possible relevance to PTB risk.26
There is little evidence to support the use of antibiotic therapy in the treatment of BV in pregnancy. A systematic review in Denmark by Haahr et al (2016) found that treating BV in pregnancy with metronidazole had minimal impact on reducing risk of preterm delivery: RR was 1.11 (95% CI 0.93–1.34) in low-risk pregnancies and 0.96 (95% CI 0.78–1.18) in high-risk pregnancies.29 Clindamycin treatment for BV was only slightly more effective: RR was 0.87 (95% CI 0.73-10.5). The review concluded with recommendations against the use of either metronidazole or clindamycin for reducing reduce the risk of PTD in both high-risk and low-risk pregnancies.29
A Cochrane Review (2013), which included 21 trials involving 7847 women diagnosed with BV or intermediate vaginal flora antibiotic therapy, determined that antibiotics eradicated BV during pregnancy and reduced the risk of late miscarriage treatment, but did not reduce the risk of PTB prior to 37 weeks or the risk of preterm pre-labor rupture of membranes.30 Antibiotic therapy also increased the risk of side effects to the point of some participants stopping or changing treatment. Similar to the previous review, this one provides little evidence that screening and treating all pregnant women with BV with antibiotics will effectively prevent PTB and its consequences.30 When screening criteria were expanded to include women with vaginal dysbiosis, a 47% reduction in preterm birth was observed; however, this effect was seen in only in 2 studies.30
A prospective cohort study enrolled women at 5 urban obstetric practices at Temple University Hospital in Philadelphia, PA.31 Women with pregnancies at less than 16 weeks gestation self-collected vaginal swabs at 2 points during their pregnancy – prior to 16 weeks gestation and between 20 and 24 weeks gestation, in order to measure the presence and level of 8 specific BV-associated bacteria. Among women with a history of preterm delivery, those with higher levels of Leptotrichia/Sneathia spp, BVAB1, and Mobiluncus spp, prior to 16 weeks gestation were significantly more likely to experience a preterm delivery.31 Pregnant women with a prior preterm delivery and increasing levels of Leptotrichia/Sneathia spp or Megasphaera phylotype 1, through 24 weeks gestation, were significantly more likely to experience preterm birth. Overall, the levels of BV-associated bacteria were not related to preterm delivery.31
In another cohort study of 924 Swedish women, BV prevalence was 15.6%. BV in early pregnancy was significantly associated with postpartum endometritis (RR=3.26), and was insignificantly associated with preterm birth (RR=2.10).32
Again, probiotics may represent a superior approach to treating BV during pregnancy, especially since antibiotic therapy has been determined to be neither useful nor warranted.
Lactobacillus species have been associated with improved fertility outcomes and are associated with vaginal health and – as mentioned – possible protection against preterm birth. A study of 92 fertile and 22 postmenopausal healthy Chinese women found that only 3% of the fertile women were colonized by 1 species of Lactobacillus, whereas 97% were colonized by 2 or more species.33 In contrast, among the postmenopausal women, 91% were colonized by 1 species of Lactobacillus, while 9% were colonized by 2 species. The total Lactobacillus DNA concentrations were higher in the fertile women than in the postmenopausal women.33
Testing the vaginal microbiome has been found helpful for diagnosing abnormal vaginal microbiota and predicting pregnancy outcomes in in-vitro fertilization (IVF) treatment.34 BV prevalence among infertile women is approximately 19%.34 As mentioned, BV is often subclinical and is associated with changes in the vaginal microbiota from being Lactobacillus spp-dominated to a more heterogeneous environment dominated by anaerobic bacteria.34
In a cohort study of 130 infertile women, 84 of whom completed IVF treatment, only 9% of the women with BV (as indicated by high concentrations of Gardnerella vaginalis and/or Atopobium vaginae) achieved clinical pregnancy (as compared to an overall clinical pregnancy rate of 35%).34
Using Lactobacillus treatment in place of direct antimicrobial therapies to restore a healthy vaginal microbiome may promote fertility. A mouse study demonstrated the ability L plantarum 2621 strain to prevent the vaginal colonization of E coli that can cause sperm to agglutinate.35 The mice were divided into 5 groups: control group, E coli group, Lactobacillus group, prophylactic and therapeutic groups. The control group was infused vaginally with phosphate buffer saline (PBS) the E coli group was infused with E coli, and the probiotic group was infused with Lactobacillus for 10 consecutive days. The prophylactic group was infused vaginally with 10 consecutive doses of Lactobacillus, and after 24 hours was administered 10 days of intravaginal E coli for 10 days. The therapeutic group was treated in the opposite fashion: 10 consecutive days of intravaginal E coli, followed by 10 days of Lactobacillus after 24 hours. After mating and completion of the gestation period, only the control-, probiotic, and therapeutic groups had litters; in the prophylactic group, inoculations of E coli eradicated Lactobacillus on day 21, rendering the mice infertile.35
Probiotics represent an effective treatment for dysbiotic conditions affecting fertility. Lactobacillus species, in particular, are helpful in the treatment of infertility, since they are the predominant microorganisms of a healthy human vaginal microbiome and have been shown to prevent pathogenic infections associated with fertility and PTB. Probiotic therapy addresses the cause of dysbiosis by restoring the ecological equilibrium of the urogenital tract.36
Addressing the microbiome including the use of probiotics may also be helpful in male infertility. A study of infertile women and sperm donors revealed a significant negative association between sperm quality and the presence of Anaerococcus in the seminal fluid of the male subjects.37 Many of the bacteria identified in semen were also found to occur in the vaginal microbiomes of some of the women, especially those with BV, suggesting that heterosexual sex partners may share microbiota. Findings also raised the question of whether the presence of Anaerococcus in semen might constitute a biomarker for low sperm quality.37
In men, a combination of probiotics that have been found to be effective in eradicating BV in women intravaginally, specifically Lactobacillus brevis [CD2], Lactobacillus plantarum [FV9], and Lactobacillus salvarius [FV2], prevented sperm lipid peroxidation, thus preserving sperm motility and viability.38 Findings suggest potential therapeutic benefit of probiotic administration to men in order to improve fertility in their female partners.
Probiotics can be an effective treatment for dysbiotic conditions affecting fertility. Lactobacillus species, in particular, are helpful in the treatment of infertility, since they are the predominant microorganisms in a healthy human vaginal tract and have been shown to protect the vaginal microbiome against pathogenic infections associated with fertility and PTB. Probiotic therapy also addresses the cause of dysbiosis by restoring the ecological equilibrium of the urogenital tract.36
Probiotics work on multiple levels to establish a healthy microbiome, which in turn is associated with a fertile microbiome. It is essential to prevent and/or treat infections that can ascend from the vagina to the rest of the urogenital tract when addressing fertility and ensuring a healthy pregnancy. Treatment with antibiotic therapy alone can disrupt the vaginal microbiota for several weeks, further increasing the risk of BV and pregnancy complications. Probiotic treatment with lactobacilli constitutes an effective means of preventing infections associated with infertility, preterm labor, and pregnancy risk factors.
- Centers for Disease Control and Prevention. Infertility. Last updated July 15, 2016. CDC Web site. http://www.cdc.gov/nchs/fastats/infertility.htm. Accessed September 21, 2016.
- Collado MC, Rautava S, Aakko J, et al. Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci Rep. 2016,6:23129.
- Harwich MD Jr, Alves JM, Buck GA, et al. Drawing the line between commensal and pathogenic Garderella vaginalis through genome analysis and virulence studies. BMC Genomics. 2010;11:375.
- Yarbrough VL, Winkle S, Herbst-Kralovetz MM. Antimicrobial peptides in the female reproductive tract: a critical component of the mucosal immune barrier with physiological and clinical implications. Hum Reprod Update. 2015;21(3):353-377.
- Boskey ER, Telsch KM, Whaley KJ, et al. Acid production by vaginal flora in vitro is consistent with the rate and extent of vaginal acidification. Infect Immun. 1999;67(10):5170-5175.
- Fettweis JM, Alves JP, Borzelleca JF, et al. The Vaginal Microbiome: Disease, Genetics and the Environment. Last updated March 9, 2011. Nature Precedings: Prepublication Research and Preliminary Findings. Available at: http://precedings.nature.com/documents/5150/version/1. Accessed September 21, 2016.
- Mendling W. Vaginal Microbiota. Adv Exp Med Biol. 2016;902:83-93.
- Ravel J, Gajer P, Abdo Z, et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci U S A. 2011;108 Suppl 1:4680-4687.
- Di Cerbo A, Palmieri B, Aponte M, et al. Mechanisms and therapeutic effectiveness of lactobacilli. J Clin Pathol. 2016;69(3):187-203.
- Fettweis JM, Serrano MG, Sheth NU, et al. Species-level classification of the vaginal microbiome. BMC Genomics. 2012;13 Suppl 8):S17.
- Aagaard K, Riehle K, Ma J, et al. A metagenomic approach to characterization of the vaginal microbiome signature in pregnancy. PLoS One. 2012;7(6):e36466.
- Gajer P, Brotman RM, Bai G, et al. Temporal dynamics of the human vaginal microbiota. Sci Transl Med. 2012 May 2;4(132):132ra52.
- Green KA, Zarek SM, Catherino WH. Gynecologic health and disease in relation to the microbiome of the female reproductive tract. Fertil Steril. 2015;104(6):1351-1357.
- Huang B, Fettweis JM, Brooks JP, et al. The changing landscape of the vaginal microbiome. Clin Lab Med. 2014;34(4):747-761.
- MacIntyre DA, Chandiramani M, Lee YS, et al. The vaginal microbiome during pregnancy and the postpartum period in a European population. Sci Rep. 2015;5:8988.
- Pathak D. Vaginal microbiome naturally less diverse, rich during pregnancy. June 13, 2012. Baylor College of Medicine. Available at: https://www.bcm.edu/news/obstetrics-and-gynecology/vaginal-microbiome-less-rich-pregnancy. Accessed September 21, 2016.
- Skylar TV, Krysensko OV, Voronkova OS, et al. Definition of Women Reproductive Tract Microflora Composition Using Test-System “Femoflor-17”. Mikrobiol Z. 2015;77(5):87-94. [Article in Ukrainian]
- Koumans EH, Sternberg M, Bruce C, et al. The prevalence of bacterial vaginosis in the United States, 2001-2004; associations with symptoms, sexual behaviors, and reproductive health. Sex Transm Dis. 2007;34(11):864-869.
- Toth A. Infections and Infertility. [Slide presentation] September 16, 2010. Available at: http://www.medigogy.com/sites/default/files/attachments/TothMedigogyPowerpoint.pdf. Accessed September 21, 2016.
- Centers for Disease Control and Prevention. Bacterial Vaginosis (BV) Statistics. Last updated September 14, 2010. CDC Web site. http://www.cdc.gov/std/bv/stats.htm. Accessed September 21, 2016.
- Vicariotto F, Mogna L, Del Piano M. Effectiveness of the two microorganisms Lactobacillus fermentum LF15 and Lactobacillus plantarum LP01, formulated in slow-release vaginal tablets, in women affected by bacterial vaginosis: a pilot study. J Clin Gastroenterol. 2014;48 Suppl 1:S106-S112.
- Falagas M, Betsi GI, Athanasiou S. Probiotics for the treatment of women with bacterial vaginosis. Clin Microbiol Infect. 2007;13(7):657-664.
- Mastromarino P, Hemalatha R, Barbonetti A, et al. Biological control of vaginosis to improve reproductive health. Indian J Med Res. 2014;140 Suppl:S91-S97.
- Cavera VL, Volski A, Chikindas ML. The Natural Antimicrobial Subtilosin A Synergizes with Lauramide Arginine Ethyl Ester (LAE), ε-Poly-L-lysine (Polylysine), Clindamycin Phosphate and Metronidazole, Against the Vaginal Pathogen Gardnerella vaginalis. Probiotics Antimicrob Proteins. 2015;7(2):164-171.
- Witkin SS. The vaginal microbiome, vaginal anti-microbial defence mechanisms and the clinical challenge of reducing infection-related preterm birth. BJOG. 2015;122(2):213-218.
- Hyman RW, Fukushima M, Jiang H, et al. Diversity of the vaginal microbiome correlates with preterm birth. Reprod Sci. 2014;21(1):32-40.
- The Partnership for Maternal, Newborn & Child Health. Born Too Soon: The Global Action Report on Preterm Birth. May 2, 2012. Available at: http://www.who.int/pmnch/media/news/2012/preterm_birth_report/en/. Accessed September 25, 2016.
- Chandran Cochrane for clinicians: putting evidence into practice. Screening for and treating asymptomatic bacterial vaginosis in pregnancy. Am Fam Physician. 2002;66(5):780-783.
- Haahr T, Ersbøll AS, Karlsen MA, et al. Treatment of bacterial vaginosis in pregnancy in order to reduce the risk of spontaneous preterm delivery – a clinical recommendation. Acta Obstet Gynecol Scand. 2016;95(8):850-860.
- Brocklehurst P, Gordon A, Heatley E, Milan SJ. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev. 2013;(1):CD000262.
- Nelson DB, Hanlon A, Nachamkin I, et al. Early pregnancy changes in bacterial vaginosis-associated bacteria and preterm delivery. Paediatr Perinat Epidemiol. 2014;28(2):88-
- Jacobsson B, Pernevi P, Chidekel L, et al. Bacterial vaginosis in early pregnancy may predispose for preterm birth and postpartum endometritis. Acta Obstet Gynecol Scand. 2002;81(11):1006-1010.
- Zhang R, Daroczy K, Xiao B, et al. Qualitative and semiquantitative analysis of Lactobacillus species in the vaginas of healthy fertile and postmenopausal Chinese women. J Med Microbiol. 2012;61(Pt 5):729-739.
- Haahr T, Jensen JS, Thomsen L, et al. Abnormal vaginal microbiota may be associated with poor reproductive outcomes: a prospective study in IVF patients. Hum Reprod. 2016;31(4):795-803.
- Bhandari P, Prabha V. Evaluation of profertility effect of probiotic Lactobacillus plantarum 2621 in a murine model. Indian J Med Res. 2015;142(1):79-84.
- Nader-Macías ME, Juárez Tomás MS. Profiles and technological requirements of urogenital probiotics. Adv Drug Deliv Rev. 2015;92:84-104.
- Hou D, Zhou X, Zhong X, et al. Microbiota of the seminal fluid from healthy and infertile men. Fertil Steril. 2013;100(5):1261-1269.
- Barbonetti A, Cinque B, Vassallo MR, et al. Effect of vaginal probiotic lactobacilli on in vitro-induced sperm lipid peroxidation and its impact on sperm motility and viability. Fertil Steril. 2011;95(8):2485-2488.