Differences in the vaginal microbiota between fertile and infertile women: a systematic review and meta-analysis
DOI:
https://doi.org/10.5902/2236583493790Keywords:
Vaginal microbiota, Female infertility, Microbial community, Reproductive health, WomenAbstract
Introduction: Infertility, a public health issue with social and emotional impacts, often remains without an apparent cause. Considering the growing interest in the role of the vaginal microbiota in reproductive outcomes, this systematic review with meta-analysis evaluated differences in microbial composition between fertile and infertile women. Methodology: Case-control studies published in English over the past fifteen years were included. The protocol was registered in PROSPERO (No. CRD420251059918). Searches were conducted in the PubMed and Embase databases, using descriptors structured according to the PICO strategy. Data extraction was performed independently by two reviewers. Heterogeneity was assessed using Cochran’s Q test and the I² statistic. Quantitative synthesis was conducted in RevMan 5.3 software. Results: Ten studies were included, totaling 992 participants, of which five were used in the meta-analysis. The pooled analysis revealed greater bacterial abundance in the fertile group (MD = 4.64; 95% CI: 0.55–8.74; p = 0.03; I² = 98%). Stratification by genera showed higher levels of Lactobacillus spp. (p = 0.27), Gardnerella spp. (p = 0.02), and Prevotella spp. (p = 0.03) in the fertile group, with statistical significance for the latter two. Despite the lack of significance for Lactobacillus spp., an individual statistical analysis indicated significantly lower levels of three Lactobacillus species in infertile women (p < 0.00001). Risk of bias (ROBINS-I) was rated as serious in most studies, mainly due to lack of control for confounding factors. The certainty of the evidence, assessed using the GRADE system, ranged from very low to moderate. Conclusion: Despite confirmation of the association between Lactobacillus and fertility, the findings of Gardnerella spp. and Prevotella spp. in fertile women suggest methodological limitations, reinforcing the need for more homogeneous and robust studies.
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References
World Health Organization. Infertility. Geneva: WHO; 2024. Available from: https://www.who.int/news-room/fact-sheets/detail/infertility. Accessed May 27, 2025.
Borumandnia N, Majd HA, Khadembashi N, Alaii. Worldwide trend analysis of primary and secondary infertility rates over past decades: a cross-sectional study. Int J Reprod Biomed. 2022;20(1):37-46. doi:10.18502/ijrm.v20i1.10407.
Weiss RV, Clappauch R. Female infertility of endocrine origin. Arq Bras Endocrinol Metabol. 2014;58(2):144-52. doi:10.1590/0004-2730000003021.
Rebar RW. Problemas de infertilidade relacionados às trompas de Falópio e a anomalias pélvicas. MSD Manual. 2024. Disponível em: https://www.msdmanuals.com/pt/casa/problemas-de-saúde-feminina/infertilidade-e-aborto-espontâneo-recorrente/problemas-de-infertilidade-relacionados-às-trompas-de-falópio-e-a-anomalias-pélvicas. Acesso em May 17, 2025.
Broi MG, Ferriani RA, Nevarro PA. Ethiopathogenic mechanisms of endometriosis-related infertility. JBRA Assist Reprod. 2019;23(3):273-80. doi:10.5935/1518-0557.20190029.
Boucher E, Brichant G, Gridelet V, Nisolle M, Ravet S, Timmermans M, et al. Implantation failure in endometriosis patients: etiopathogenesis. J Clin Med. 2022;11(18):5366. doi:10.3390/jcm11185366.
Li C, Huang Y, Xie L, Huang X. The diagnostic value of hysterosalpingo contrast sonography in female infertility of the fallopian tube. Pak J Med Sci. 2023;39(4):932-5. doi:10.12669/pjms.39.4.7462.
El-Kharoubi AF. Tubal pathologies and fertility outcomes: A review. Cureus. 2023;15(5):e38881. doi:10.7759/cureus.38881.
Steiner AZ, Jukic AMZ. Impact of female age and nulligravidity on fecundity in an older reproductive age cohort. Fertil Steril. 2016;105(6):1584-8.e1. doi:10.1016/j.fertnstert.2016.02.028.
Wang T, Li P, Bai X, Tian SL, Yang M, Long D, et al. Vaginal microbiota are associated with in vitro fertilization during female infertility. iMeta. 2024;3:e185. doi:10.1002/imt2.185.
Silvestre IP, Capel LM. Microbiota vaginal e (in)fertilidade. XIII Encontro Internacional de Produção Científica, Universidade Cesumar. Available from: http://rdu.unicesumar.edu.br/handle/123456789/10786.
Smitch SB, Ravel J. The vaginal microbiota, host defence and reproductive physiology. J Physiol. 2016;595(2):451-63. doi:10.1113/JP271694.
Hong X, Ma J, Yin J, Fang S, Geng J, Zhao H, et al. The association between vaginal microbiota and female infertility: a systematic review and meta-analysis. Arch Gynecol Obstet. 2020;302:1-10. doi:10.1007/s00404-020-05675-3.
Saraf VS, Sheikh SA, Ahmas A, Gillevet PM, Bokhari H, Javed S. Vaginal microbiome: normalcy vs dysbiosis. Arch Microbiol. 2021;203(7):3793-802. doi:10.1007/s00203-021-02414-3.
Plummer EL, Vodstrcil LA, Bradshaw CS. Unravelling the vaginal microbiome, impact on health and disease. Curr Opin Obstet Gynecol. 2024;36(5):338-44. doi:10.1097/GCO.0000000000000976.
Ichiyama T, Kuroda K, Nagai Y, Urushiyama D, Ohno M, Yamaguchi T, et al. Analysis of vaginal and endometrial microbiota communities in infertile women with a history of repeated implantation failure. Reprod Med Biol. 2021;20(3):e12389. doi:10.1002/rmb2.12389.
Balla B, Illés A, Tobiás B, Pikó H, Beke A, Sipos M, et al. The role of the vaginal and endometrial microbiomes in infertility and their impact on pregnancy outcomes in light of recent literature. Int J Mol Sci. 2024;25(23):13227. doi:10.3390/ijms252313227.
Su W, Gong C, Zhong H, Yang HQ, Chen YY, Wu X, et al. Vaginal and endometrial microbiome dysbiosis associated with adverse embryo transfer outcomes. Reprod Biol Endocrinol. 2024;22:111. doi:10.1186/s12958-024-01274-y.
Dutra TGA, Takahashi HE, Cavalcante RD, Santos JPBR. A influência da microbiota vaginal na saúde reprodutiva feminina. Braz J Implantol Health Sci. 2024;6(8):3015-32. doi:10.36557/2674-8169.2024v6n8p3015-3032.
He Y, Na R, Niu X, Xiao B, Yang H. Lactobacillus rhamnosus and Lactobacillus casei affect various stages of Gardnerella species biofilm formation. Front Cell Infect Microbiol. 2021;11:568178. doi:10.3389/fcimb.2021.568178.
Pouresmaeili F, Alidoost S, Azimirad M, Looha MA, Meibodi AE, Abedin-Do A, et al. Characterization of vaginal Lactobacillus species as fertility predictors among Iranian women with unexplained recurrent miscarriage and fertile controls using machine learning modeling. Mol Biol Rep. 2023;50:8785-97. doi:10.1007/s11033-023-08745-2.
Linhares IM, Summers PR, Larsen B, Giraldo PC, Witkin SS. Contemporary perspectives on vaginal pH and Lactobacillus. Am J Obstet Gynecol. 2011;204(2):120.e1-5. doi:10.1016/j.ajog.2010.07.010.
Silva JCN. Citologia Clínica do Trato Genital Feminino. 2nd ed. Rio de Janeiro: Revinter; 2020.
Rosca AS, Castro J, Sousa LGV, Cerca N. Gardnerella and vaginal health: the truth is out there. FEMS Microbiol Rev. 2020;44:73-105. doi:10.1093/femsre/fuz027.
Reznichenko H, Henyk N, Maliuk V, Khyzhnyak T, Tynna Y, Filipiuk I, et al. Oral intake of lactobacilli can be helpful in symptomatic bacterial vaginosis: a randomized clinical study. J Low Genit Tract Dis. 2020;24(3):284-9. doi:10.1097/LGT.0000000000000518.
Souza SV, Monteiro PB, Moura GA, Santos NO, Fontanezi CTB, Gomes IA, et al. Vaginal microbioma and the presence of Lactobacillus spp. as interferences in female fertility: a review system. JBRA Assist Reprod. 2023;27(3):496-506. doi:10.5935/1518-0557.20230006.
Jiménez PP, Labarta E. The impact of the female genital tract microbiome in woman health and reproduction: a review. J Assist Reprod Genet. 2021;38:2519-41. doi:10.1007/s10815-021-02247-5.
Holm J, Carter AM, Ravel J, Brotman RM. Lactobacillus iners and genital health: molecular clues to an enigmatic vaginal species. Curr Infect Dis Rep. 2023;25(4):67-75. doi:10.1007/s11908-023-00798-5.
Petrova MI, Gregor R, Vaneechoutte M, Lebber S. Lactobacillus iners: friend or foe? Trends Microbiol. 2017;25(3):182-91. doi:10.1016/j.tim.2016.11.007.
Vick EJ, Park SH, Hiff AK, Brooks KM, Farone AL, Farone MB. Gardnerella vaginalis triggers NLRP3 inflammasome recruitment in THP-1 monocytes. J Reprod Immunol. 2014;106:67-75. doi:10.1016/j. jri.2014.08.005.
Morrill S, Gilbart NM, Lewis AL. Gardnerella vaginalis as a cause of bacterial vaginosis: appraisal of the evidence from in vivo models. Front Cell Infect Microbiol. 2020;10:168. doi:10.3389/fcimb.2020.00168.
Han Y, Liu Z, Chen T. Role of vaginal microbiota dysbiosis in gynecological diseases and the potential interventions. Front Microbiol. 2021;12:643422. doi:10.3389/fmicb.2021.643422.
Liu L, Feng T, Liu Q, Liao M, Liu B, Li M. Characterization of the vaginal microbiota in infertile women with repeated implantation failure. Acta Microbiol Immunol Hung. 2024;71(3):263-71. doi:10.1556/030.2024.02323.
George SD, van Gerwen OT, Dong C, Sousa LGV, Cerca N, Elnaggar JH, et al. The role of Prevotella species in female genital tract infection. Pathogens. 2024;13(5):364. doi:10.3390/pathogens13050364.
Fazoulakis Z, Papageorgiou D, Papanikolaou A, Chatziioannou M, Sapantzoglou I, Pegkou A, et al. Impact of the female genital microbiota on outcomes of assisted reproductive techniques. Biomedicines. 2025;13(6):1332. doi:10.3390/biomedicines13061332.
Fu M, Zhang X, Liang Y, Lin S, Qian W, Fan S. Alterations in vaginal microbiota and associated metabolome in women with recurrent implantation failure. mBio. 2020;11(3):e03242-19. doi:10.1128/mBio.03242-19.
Kroon SJ, Revel J, Huston WM. Cervicovaginal microbiota, women’s health, and reproductive outcomes. Fertil Steril. 2018;110:327-36. doi:10.1016/j.fertnstert.2018.06.036.
Oliver A, Lamere B, Weihe C, Wandro S, Lindsay KL, Wandwa PD, et al. Cervicovaginal microbiome composition is associated with metabolic profiles in healthy pregnancy. mBio. 2020;11(4):e01851-20. doi:10.1128/mBio.01851-20.
Gholiof M, De Luca EA, Wessels JM. The female reproductive tract microbiotas, inflammation, and gynecological conditions. Front Reprod Health. 2022;4:963752. doi:10.3389/frph.2022.963752.
Gilbert JA, Blaser MJ, Caporaso JG, Jansson JK, Lynch SV, Knight R. Current understanding of the human microbiome. Nat Med. 2018;24(4):392-400. doi:10.1038/nm.4517.
Naeem A, Shah J, Ali S. Hypothalamic-pituitary-ovarian axis disorders impacting female fertility. Biomedicines. 2019;7(1):5. doi:10.3390/biomedicines7010005.
Aghayeva S, Sonmezer M, Sukur YE, Jafarzade A. The role of thyroid hormones, vitamins, and microelements in female infertility. Rev Bras Ginecol Obstet. 2023;45(11):683-8. doi:10.1055/s-0043-1772478.
Jia Y, Wang Z, Feng Y, Wang M, Jiang L, Yu Z, et al. Validity of the association between five steroid hormones quantification and female infertility conditions: a new perspective for clinical diagnosis. Steroids. 2022;186:109086. doi:10.1016/j.steroids.2022.109086.
Ehsani M, Mohammadnia-Afrouzi M, Mirzakhani M, Esmaeilzadeh S, Shahbazi M. Female unexplained infertility: a disease with imbalanced adaptive immunity. J Hum Reprod Sci. 2019;12(4):274-82. doi:10.4103/jhrs.JHRS_3019.
Kamath MS, Bhattacharya S. Demographics of infertility and management of unexplained infertility. Best Pract Res Clin Obstet Gynaecol. 2012;26(6):729-38. doi:10.1016/j.bpobgyn.2012.08.001.
Campisciano G, Florian F, D’Eutacchio A, Stancovic D, Ricci G, Comar M. Subclinical alteration of the cervical-vaginal microbiome in women with idiopathic infertility. J Cell Physiol. 2017;232:1681-96. doi:10.1002/jcp.25806.
Wee BA, Thomas M, Sweeney EL, Frentiu FD, Samios M, Ravel J, et al. A retrospective pilot study to determine whether the reproductive tract microbiota differs between women with a history of infertility and fertile women. Aust N Z J Obstet Gynaecol. 2017;58(3):341-8. doi:10.1111/ajo.12754.
Kyono K, Hashimoto T, Nagai Y, Sakuraba Y. Analysis of endometrial microbiota by 16S ribosomal RNA gene sequencing among infertile patients: a single-center pilot study. Reprod Med Biol. 2018;17(3):297-306. doi:10.1002/rmb2.12105.
Azpiroz MA, Orguilia L, Palacio MI, Malpartida A, Mayol S, Mor G, et al. Potential biomarkers of infertility associated with microbiome imbalances. Am J Reprod Immunol. 2021;85:e13438. doi:10.1111/aji.13438.
Sezer O, Çaliskan CS, Celik S, Kilic SS, Kuruoglu T, Ustun GU, et al. Assessment of vaginal and endometrial microbiota by real-time PCR in women with unexplained infertility. J Obstet Gynaecol Res. 2021;48(1):129-39. doi:10.1111/jog.15060.
Patel N, Patel N, Pal S, Nathani N, Pandit R, Patel M, et al. Distinct gut and vaginal microbiota profile in women with recurrent implantation failure and unexplained infertility. BMC Womens Health. 2022;22:168. doi:10.1186/s12905-022-01681-6.
Chopra C, Kumar V, Kumar M, Bhushan I. Role of vaginal microbiota in idiopathic infertility: a prospective study. Microbes Infect. 2024;26:105308. doi:10.1016/j.micinf.2024.105308.
Sousa LGV, Novak J, França A, Muzny CA, Cerca N. Gardnerella vaginalis, Fannyhessea vaginae, and Prevotella bivia strongly influence each other’s transcriptome in triple-species biofilms. Microb Ecol. 2024;87:117. doi:10.1007/s00248-024-02433-9.
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