Dynamic changes of cervical microbiome during pregnancy for preterm birth risk prediction: A prospective cohort study

Honglian Ma, Kaiyue Hu, Youxin Wang

Abstract

This prospective cohort study investigated the dynamic changes in the cervical microbiome during pregnancy and developed a predictive model for preterm birth risk. Ninety-three singleton pregnant women were enrolled, including 41 with preterm birth and 52 with term delivery. Cervical secretions were collected at four gestational stages and analyzed using 16S rRNA sequencing, alongside ELISA testing for inflammatory markers. The preterm group exhibited significantly lower microbial diversity and a progressively increasing ratio of Lactobacillus iners to Lactobacillus crispatus throughout pregnancy. Early pregnancy IL-6 levels were also significantly elevated in this group. Logistic regression identified the L. iners/L. crispatus ratio, IL-6, history of preterm birth, and short cervical length as independent risk factors. The integrated prediction model demonstrated high accuracy (AUC 0.847), with even stronger performance in predicting births before 34 weeks (AUC 0.892). These findings suggest that microbiome patterns and inflammatory markers can effectively predict preterm birth risk, supporting early clinical intervention.

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Costa A, Moller AB, Blencowe H, Johansson EW, Hussain-Alkhateeb L, Ohuma EO, Okwaraji YB, Cresswell J, Requejo JH, Bahl R, Oladapo OT, Lawn JE and Moran AC. Study protocol for WHO and UNICEF estimates of global, regional, and national preterm birth rates for 2010 to 2019. PLoS One. 2021 Oct20;16(10):e0258751.doi:10.1371/journal.pone.0258751.

Ohuma EO, Moller AB, Bradley E, Chakwera S, Hussain-Alkhateeb L, Lewin A, Okwaraji YB, Mahanani WR, Johansson EW, Lavin T, Fernandez DE, Domínguez GG, de Costa A, Cresswell JA, Krasevec J, Lawn JE, Blencowe H, Requejo J, Moran AC. National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. Lancet. 2023 Oct 7;402(10409):1261-1271. doi: 10.1016/S0140-6736(23)00878-4.

Chawanpaiboon S, Vogel JP, Moller AB, Lumbiganon P, Petzold M, Hogan D, Landoulsi S, Jampathong N, Kongwattanakul K, Laopaiboon M, Lewis C, Rattanakanokchai S, Teng DN, Thinkhamrop J, Watananirun K, Zhang J, Zhou W, Gülmezoglu AM. Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis. Lancet Glob Health. 2019 Jan;7(1):e37-e46. doi: 10.1016/S2214-109X(18)30451-0.

Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, Adler A, Vera Garcia C, Rohde S, Say L, Lawn JE. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012 Jun 9;379(9832):2162-72. doi: 10.1016/S0140-6736(12)60820-4.

Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008 Jan 5;371(9606):75-84. doi: 10.1016/S0140-6736(08)60074-4.

Romero R, Dey SK and Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014 Aug 15;345(6198):760-5. doi: 10.1126/science.1251816.

Menon R. Spontaneous preterm birth, a clinical dilemma: etiologic, pathophysiologic and genetic heterogeneities and racial disparity. Acta Obstet Gynecol Scand. 2008;87(6):590-600. doi: 10.1080/00016340802005126.

Abbott DS, Hezelgrave NL, Seed PT, Norman JE, David AL, Bennett PR, Girling JC, Chandirimani M, Stock SJ, Carter J, Cate R, Kurtzman J, Tribe RM and Shennan AH. Quantitative fetal fibronectin to predict preterm birth in asymptomatic women at high risk. Obstet Gynecol. 2015 May;125(5):1168-1176. doi: 10.1097/AOG.0000000000000754.

Honest H, Bachmann LM, Gupta JK, Kleijnen J, Khan KS. Accuracy of cervicovaginal fetal fibronectin test in predicting risk of spontaneous preterm birth: systematic review. BMJ. 2002 Aug 10;325(7359):301. doi: 10.1136/bmj.325.7359.301.

Son M, Grobman WA, Ayala NK and Miller ES. A universal mid-trimester transvaginal cervical length screening program and its associated reduced preterm birth rate. Am J Obstet Gynecol. 2016 Mar;214(3):365.e1-5. doi: 10.1016/j.ajog.2015.12.020.

Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SS, McCulle SL, Karlebach S, Gorle R, Russell J, Tacket CO, Brotman RM, Davis CC, Ault K, Peralta L, Forney LJ. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1(Suppl 1):4680-7. doi: 10.1073/pnas.1002611107.

DiGiulio DB, Callahan BJ, McMurdie PJ, Costello EK, Lyell DJ, Robaczewska A, Sun CL, Goltsman DS, Wong RJ, Shaw G, Stevenson DK, Holmes SP, Relman DA. Temporal and spatial variation of the human microbiota during pregnancy. Proc Natl Acad Sci U S A. 2015 Sep 1;112(35):11060-5. doi: 10.1073/pnas.1502875112.

Kindinger LM, Bennett PR, Lee YS, Marchesi JR, Smith A, Cacciatore S, Holmes E, Nicholson JK, Teoh TG, MacIntyre DA. The interaction between vaginal microbiota, cervical length, and vaginal progesterone treatment for preterm birth risk. Microbiome. 2017 Jan 19;5(1):6. doi: 10.1186/s40168-016-0223-9.

Gudnadottir U, Debelius JW, Du J, Hugerth LW, Danielsson H, Schuppe-Koistinen I, Fransson E, Brusselaers N. The vaginal microbiome and the risk of preterm birth: a systematic review and network meta-analysis. Sci Rep. 2022 May 13;12(1):7926. doi: 10.1038/s41598-022-12007-9.

Huang C, Gin C, Fettweis J, Foxman B, Gelaye B, MacIntyre DA, Subramaniam A, Fraser W, Tabatabaei N, Callahan B. Meta-analysis reveals the vaginal microbiome is a better predictor of earlier than later preterm birth. BMC Biol. 2023 Sep 25;21(1):199. doi: 10.1186/s12915-023-01702-2.

Fettweis JM, Serrano MG, Brooks JP, Edwards DJ, Girerd PH, Parikh HI, Huang B, Arodz TJ, Edupuganti L, Glascock AL, Xu J, Jimenez NR, Vivadelli SC, Fong SS, Sheth NU, Jean S, Lee V, Bokhari YA, Lara AM, Mistry SD, Duckworth RA 3rd, Bradley SP, Koparde VN, Orenda XV, Milton SH, Rozycki SK, Matveyev AV, Wright ML, Huzurbazar SV, Jackson EM, Smirnova E, Korlach J, Tsai YC, Dickinson MR, Brooks JL, Drake JI, Chaffin DO, Sexton AL, Gravett MG, Rubens CE, Wijesooriya NR, Hendricks-Muñoz KD, Jefferson KK, Strauss JF 3rd, Buck GA. The vaginal microbiome and preterm birth. Nat Med. 2019 Jun;25(6):1012-1021. doi: 10.1038/s41591-019-0450-2.

Blostein F, Gelaye B, Sanchez SE, Williams MA, Foxman B. Vaginal microbiome diversity and preterm birth: results of a nested case-control study in Peru. Ann Epidemiol. 2020 Jan;41:28-34. doi: 10.1016/j.annepidem.2019.11.004.

Anton L, Sierra LJ, DeVine A, Barila G, Heiser L, Brown AG, Elovitz MA. Common Cervicovaginal Microbial Supernatants Alter Cervical Epithelial Function: Mechanisms by Which Lactobacillus crispatus Contributes to Cervical Health. Front Microbiol. 2018 Oct 8;9:2181. doi: 10.3389/fmicb.2018.02181.

Petrova MI, Reid G, Vaneechoutte M, Lebeer S. Lactobacillus iners: Friend or Foe? Trends Microbiol. 2017 Mar;25(3):182-191. doi: 10.1016/j.tim.2016.11.007.

France MT, Mendes-Soares H, Forney LJ. Genomic Comparisons of Lactobacillus crispatus and Lactobacillus iners Reveal Potential Ecological Drivers of Community Composition in the Vagina. Appl Environ Microbiol. 2016 Nov 21;82(24):7063-7073. doi: 10.1128/AEM.02385-16.

Petricevic L, Domig KJ, Nierscher FJ, Sandhofer MJ, Fidesser M, Krondorfer I, Husslein P, Kneifel W, Kiss H. Characterisation of the vaginal Lactobacillus microbiota associated with preterm delivery. Sci Rep. 2014 May 30;4:5136. doi: 10.1038/srep05136.

Nori SRC, Walsh CJ, McAuliffe FM, Moore RL, Van Sinderen D, Feehily C, Cotter PD. Strain-level variation among vaginal Lactobacillus crispatus and Lactobacillus iners as identified by comparative metagenomics. NPJ Biofilms Microbiomes. 2025 Mar 23;11(1):49. doi: 10.1038/s41522-025-00682-1.

Prairie E, Côté F, Tsakpinoglou M, Mina M, Quiniou C, Leimert K, Olson D, Chemtob S. The determinant role of IL-6 in the establishment of inflammation leading to spontaneous preterm birth. Cytokine Growth Factor Rev. 2021 Jun;59:118-130. doi: 10.1016/j.cytogfr.2020.12.004.

Omere C, Richardson L, Saade GR, Bonney EA, Kechichian T, Menon R. Interleukin (IL)-6: A Friend or Foe of Pregnancy and Parturition? Evidence From Functional Studies in Fetal Membrane Cells. Front Physiol. 2020 Jul 24;11:891. doi: 10.3389/fphys.2020.00891.

Brou L, Almli LM, Pearce BD, Bhat G, Drobek CO, Fortunato S, Menon R. Dysregulated biomarkers induce distinct pathways in preterm birth. BJOG. 2012 Mar;119(4):458-73. doi: 10.1111/j.1471-0528.2011.03266.x.

Robertson SA, Hutchinson MR, Rice KC, Chin PY, Moldenhauer LM, Stark MJ, Olson DM, Keelan JA. Targeting Toll-like receptor-4 to tackle preterm birth and fetal inflammatory injury. Clin Transl Immunology. 2020 Apr 14;9(4):e1121. doi: 10.1002/cti2.1121.

Sadowsky DW, Adams KM, Gravett MG, Witkin SS, Novy MJ. Preterm labor is induced by intraamniotic infusions of interleukin-1beta and tumor necrosis factor-alpha but not by interleukin-6 or interleukin-8 in a nonhuman primate model. Am J Obstet Gynecol. 2006 Dec;195(6):1578-89. doi: 10.1016/j.ajog.2006.06.072.

Menon R, Fortunato SJ. Fetal membrane inflammatory cytokines: a switching mechanism between the preterm premature rupture of the membranes and preterm labor pathways. J Perinat Med. 2004;32(5):391-9. doi: 10.1515/JPM.2004.134.

Golob JL, Oskotsky TT, Tang AS, Roldan A, Chung V, Ha CWY, Wong RJ, Flynn KJ, Parraga-Leo A, Wibrand C, Minot SS, Oskotsky B, Andreoletti G, Kosti I, Bletz J, Nelson A, Gao J, Wei Z, Chen G, Tang ZZ, Novielli P, Romano D, Pantaleo E, Amoroso N, Monaco A, Vacca M, De Angelis M, Bellotti R, Tangaro S, Kuntzleman A, Bigcraft I, Techtmann S, Bae D, Kim E, Jeon J, Joe S; Preterm Birth DREAM Community; Theis KR, Ng S, Lee YS, Diaz-Gimeno P, Bennett PR, MacIntyre DA, Stolovitzky G, Lynch SV, Albrecht J, Gomez-Lopez N, Romero R, Stevenson DK, Aghaeepour N, Tarca AL, Costello JC, Sirota M. Microbiome preterm birth DREAM challenge: Crowdsourcing machine learning approaches to advance preterm birth research. Cell Rep Med. 2024 Jan 16;5(1):101350. doi: 10.1016/j.xcrm.2023.101350.

Oliver A, LaMere B, Weihe C, Wandro S, Lindsay KL, Wadhwa PD, Mills DA, Pride DT, Fiehn O, Northen T, de Raad M, Li H, Martiny JBH, Lynch S, Whiteson K. Cervicovaginal Microbiome Composition Is Associated with Metabolic Profiles in Healthy Pregnancy. mBio. 2020 Aug 25;11(4):e01851-20. doi: 10.1128/mBio.01851-20.

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