The vaginal microbiome and preterm birth

The incidence of preterm birth exceeds 10% worldwide. There are significant disparities in the frequency of preterm birth among populations within countries, and women of African ancestry disproportionately bear the burden of risk in the United States. In the present study, we report a community resource that includes ‘omics’ data from approximately 12,000 samples as part of the integrative Human Microbiome Project. Longitudinal analyses of 16S ribosomal RNA, metagenomic, metatranscriptomic and cytokine profiles from 45 preterm and 90 term birth controls identified harbingers of preterm birth in this cohort of women predominantly of African ancestry. Women who delivered preterm exhibited significantly lower vaginal levels of Lactobacillus crispatus and higher levels of BVAB1, Sneathia amnii, TM7-H1, a group of Prevotella species and nine additional taxa. The first representative genomes of BVAB1 and TM7-H1 are described. Preterm-birth-associated taxa were correlated with proinflammatory cytokines in vaginal fluid. These findings highlight new opportunities for assessment of the risk of preterm birth.As part of the second phase of Human Microbiome Project, the Multi-Omic Microbiome Study: Pregnancy Initiative presents a community resource to help better understand how microbiome and host profiles change throughout pregnancy as well as to identify new opportunities for assessment of the risk of preterm birth.

Jonas Korlach | Stephen S Fong | Ekaterina Smirnova | Hardik I. Parikh | Steven P. Bradley | Yu-Chih Tsai | Jerome F Strauss | Jennifer M. Fettweis | Gregory A Buck | David J Edwards | Bernice Huang | David J. Edwards | J. Korlach | G. Buck | N. Sheth | S. Fong | Y. Tsai | J. Strauss | J. P. Brooks | C. Rubens | A. Glascock | Ekaterina Smirnova | M. Wright | M. Gravett | S. Huzurbazar | M. Serrano | Bernice L Huang | Philippe H. Girerd | K. Jefferson | N. Wijesooriya | V. Koparde | Michael G Gravett | Craig E Rubens | Tom J Arodz | Laahirie Edupuganti | Jie Xu | Nicole R. Jimenez | Stephany C Vivadelli | S. Jean | Vladimir Lee | Yahya Bokhari | A. M. Lara | Shreni D. Mistry | Robert A Duckworth | X. V. Orenda | Sarah H. Milton | S. K. Rozycki | A. Matveyev | E. Jackson | Molly R Dickinson | Jamie L Brooks | Jennifer I. Drake | D. Chaffin | Amber L. Sexton | K. Hendricks-Muñoz | Vishal N Koparde | Hardik I Parikh | Jie Xu | Myrna G Serrano | Jennifer M Fettweis | Kimberly K Jefferson | J Paul Brooks | Snehalata V Huzurbazar | Nihar U Sheth | Abigail L Glascock | Philippe H Girerd | Laahirie Edupuganti | Nicole R Jimenez | Sophonie Jean | Vladimir Lee | Yahya A Bokhari | Ana M Lara | Shreni D Mistry | Steven P Bradley | X Valentine Orenda | Sarah H Milton | Sarah K Rozycki | Andrey V Matveyev | Michelle L Wright | Eugenie M Jackson | Jennifer I Drake | Donald O Chaffin | Amber L Sexton | N Romesh Wijesooriya | Karen D Hendricks-Muñoz | Myrna G Serrano | J. Brooks | Sophonie Jean | A. Lara | V. Kopardé | G. Buck | J. Fettweis | Bernice Huang | Jamie L. Brooks | Tom J. Arodz | Molly R. Dickinson | Robert A. Duckworth | Stephany C. Vivadelli | A. Sexton | J. I. Drake | S. Rozycki | E. Smirnova

[1]  Jamie Perin,et al.  Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the Sustainable Development Goals , 2016, The Lancet.

[2]  Ann-Beth Moller,et al.  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 , 2012, The Lancet.

[3]  P. Gajer,et al.  The vaginal microbiota of pregnant women who subsequently have spontaneous preterm labor and delivery and those with a normal delivery at term , 2014, Microbiome.

[4]  P. Nyirjesy,et al.  Experts explore the state of bacterial vaginosis and the unmet needs facing women and providers , 2017, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[5]  A. Ng Feature selection, L1 vs. L2 regularization, and rotational invariance , 2004, Twenty-first international conference on Machine learning - ICML '04.

[6]  S. Jolles,et al.  Current understanding and future directions , 2009, Clinical and experimental immunology.

[7]  Jennifer M. Fettweis,et al.  Differences in vaginal microbiome in African American women versus women of European ancestry. , 2014, Microbiology.

[8]  A. Butte,et al.  The Integrative Human Microbiome Project: Dynamic Analysis of Microbiome-Host Omics Profiles during Periods of Human Health and Disease , 2014, Cell host & microbe.

[9]  B. Lehne,et al.  Vaginal dysbiosis increases risk of preterm fetal membrane rupture, neonatal sepsis and is exacerbated by erythromycin , 2018, BMC Medicine.

[10]  Ronald W. Davis,et al.  Diversity of the Vaginal Microbiome Correlates With Preterm Birth , 2014, Reproductive Sciences.

[11]  M. Paley,et al.  Spontaneous Preterm Birth Is Associated with Differential Expression of Vaginal Metabolites by Lactobacilli-Dominated Microflora , 2017, Front. Physiol..

[12]  W. Fraser,et al.  Inflammatory Cytokines and Spontaneous Preterm Birth in Asymptomatic Women: A Systematic Review , 2010, Obstetrics and gynecology.

[13]  M. Leal,et al.  Burden of early-term birth on adverse infant outcomes: a population-based cohort study in Brazil , 2017, BMJ Open.

[14]  Shujing Jane Lim,et al.  Long term cognitive outcomes of early term (37-38 weeks) and late preterm (34-36 weeks) births: A systematic review , 2017, Wellcome open research.

[15]  J. Nicholson,et al.  The interaction between vaginal microbiota, cervical length, and vaginal progesterone treatment for preterm birth risk , 2017, Microbiome.

[16]  S. Akira,et al.  Pathogen Recognition and Innate Immunity , 2006, Cell.

[17]  M. Touchon,et al.  Identification of protein secretion systems in bacterial genomes , 2015, bioRxiv.

[18]  Dieter Wolke,et al.  Very preterm/very low birthweight infants’ attachment: infant and maternal characteristics , 2013, Archives of Disease in Childhood: Fetal and Neonatal Edition.

[19]  Roberto Romero,et al.  Epidemiology and causes of preterm birth , 2008, The Lancet.

[20]  X. Lin,et al.  Inference in generalized additive mixed modelsby using smoothing splines , 1999 .

[21]  Yu-Chieh Liao,et al.  Accurate binning of metagenomic contigs via automated clustering sequences using information of genomic signatures and marker genes , 2016, Scientific Reports.

[22]  R. Cone,et al.  Antimicrobial and immune modulatory effects of lactic acid and short chain fatty acids produced by vaginal microbiota associated with eubiosis and bacterial vaginosis , 2015, Front. Physiol..

[23]  E. Mohammadi,et al.  Barriers and facilitators related to the implementation of a physiological track and trigger system: A systematic review of the qualitative evidence , 2017, International journal for quality in health care : journal of the International Society for Quality in Health Care.

[24]  Stephen S. Fong,et al.  Computational approaches to metabolic engineering utilizing systems biology and synthetic biology , 2014, Computational and structural biotechnology journal.

[25]  Daryl M. Gohl,et al.  Persistent microbial dysbiosis in preterm premature rupture of membranes from onset until delivery , 2015, PeerJ.

[26]  J. H. van de Wijgert,et al.  The association between ethnicity and vaginal microbiota composition in Amsterdam, the Netherlands , 2017, PloS one.

[27]  Mohammed M. Haque,et al.  First-trimester vaginal microbiome diversity: A potential indicator of preterm delivery risk , 2017, Scientific Reports.

[28]  C. Huttenhower,et al.  Metagenomic microbial community profiling using unique clade-specific marker genes , 2012, Nature Methods.

[29]  Roberto Romero,et al.  The composition and stability of the vaginal microbiota of normal pregnant women is different from that of non-pregnant women , 2014, Microbiome.

[30]  Jacques Ravel,et al.  Vaginal microbiome: rethinking health and disease. , 2012, Annual review of microbiology.

[31]  G. Gloor,et al.  Increased richness and diversity of the vaginal microbiota and spontaneous preterm birth , 2018, Microbiome.

[32]  R. Lamont Infection in the prediction and antibiotics in the prevention of spontaneous preterm labour and preterm birth , 2003, Minerva ginecologica.

[33]  Christopher. Simons,et al.  Machine learning with Python , 2017 .

[34]  S. Yooseph,et al.  Cultivation of a human-associated TM7 phylotype reveals a reduced genome and epibiotic parasitic lifestyle , 2014, Proceedings of the National Academy of Sciences.

[35]  Ignacio González,et al.  Visualising associations between paired ‘omics’ data sets , 2012, BioData Mining.

[36]  Gregory A. Buck,et al.  MeFiT: merging and filtering tool for illumina paired-end reads for 16S rRNA amplicon sequencing , 2015, BMC Bioinformatics.

[37]  Methodius G. Tuuli,et al.  Early pregnancy vaginal microbiome trends and preterm birth , 2017, American journal of obstetrics and gynecology.

[38]  Neonatal and 5-Year Outcomes After Birth at 30–34 Weeks of Gestation , 2007, Obstetrics and gynecology.

[39]  T. Van den Bosch,et al.  Predictive value for preterm birth of abnormal vaginal flora, bacterial vaginosis and aerobic vaginitis during the first trimester of pregnancy , 2009, BJOG : an international journal of obstetrics and gynaecology.

[40]  N. Angelopoulos,et al.  The vaginal microbiome during pregnancy and the postpartum period in a European population , 2015, Scientific Reports.

[41]  The vaginal microbiome of pregnant women is less rich and diverse, with lower prevalence of Mollicutes, compared to non-pregnant women , 2017, Scientific Reports.

[42]  S. Delany-Moretlwe,et al.  A longitudinal analysis of the vaginal microbiota and vaginal immune mediators in women from sub-Saharan Africa , 2017, Scientific Reports.

[43]  Nihar U. Sheth,et al.  MEEPTOOLS: a maximum expected error based FASTQ read filtering and trimming toolkit , 2017, Int. J. Comput. Biol. Drug Des..

[44]  J. Marrazzo,et al.  Targeted PCR for Detection of Vaginal Bacteria Associated with Bacterial Vaginosis , 2007, Journal of Clinical Microbiology.

[45]  A. Hanlon,et al.  Early pregnancy changes in bacterial vaginosis-associated bacteria and preterm delivery. , 2014, Paediatric and perinatal epidemiology.

[46]  V. Preedy,et al.  Prospective Cohort Study , 2010 .

[47]  J. Sobel,et al.  Current Treatment of Bacterial Vaginosis-Limitations and Need for Innovation. , 2016, The Journal of infectious diseases.

[48]  J. Sobel Bacterial vaginosis. , 1990, British journal of clinical practice. Supplement.

[49]  Curtis Huttenhower,et al.  High-Specificity Targeted Functional Profiling in Microbial Communities with ShortBRED , 2015, PLoS Comput. Biol..

[50]  Hardik I. Parikh,et al.  Racioethnic diversity in the dynamics of the vaginal microbiome during pregnancy , 2019, Nature Medicine.

[51]  C. Lockwood Predicting premature delivery--no easy task. , 2002, The New England journal of medicine.

[52]  S. Fisher,et al.  Preterm labor: One syndrome, many causes , 2014, Science.

[53]  D. MacIntyre,et al.  Prospective observational study of vaginal microbiota pre‐ and post‐rescue cervical cerclage , 2019, BJOG : an international journal of obstetrics and gynaecology.

[54]  S. Oh,et al.  Prevalence of vaginal microorganisms among pregnant women according to trimester and association with preterm birth , 2017, Obstetrics & gynecology science.

[55]  Christine L. Sun,et al.  Temporal and spatial variation of the human microbiota during pregnancy , 2015, Proceedings of the National Academy of Sciences.

[56]  J. Hibbert,et al.  CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications , 2011, Cytokine & growth factor reviews.

[57]  L. Malinina,et al.  Nonvesicular trafficking by a ceramide-1-phosphate transfer protein regulates eicosanoids , 2013, Nature.

[58]  E. Wagner,et al.  High Diversity and Variability in the Vaginal Microbiome in Women following Preterm Premature Rupture of Membranes (PPROM): A Prospective Cohort Study , 2016, PloS one.

[59]  E. Lefkowitz,et al.  Vaginal Microbiota in Pregnancy: Evaluation Based on Vaginal Flora, Birth Outcome, and Race , 2015, American Journal of Perinatology.

[60]  R. Tibshirani,et al.  A penalized matrix decomposition, with applications to sparse principal components and canonical correlation analysis. , 2009, Biostatistics.

[61]  Florian Rohart,et al.  mixOmics: an R package for ‘omics feature selection and multiple data integration , 2017 .

[62]  Lingling An,et al.  Investigating microbial co-occurrence patterns based on metagenomic compositional data , 2015, Bioinform..

[63]  G. Buck,et al.  Automated System for Gene Annotation and Metabolic Pathway Reconstruction Using General Sequence Databases , 2007, Chemistry & biodiversity.

[64]  V. Yotova,et al.  Vaginal microbiome in early pregnancy and subsequent risk of spontaneous preterm birth: a case–control study , 2018, BJOG : an international journal of obstetrics and gynaecology.

[65]  D. Nelson,et al.  Blood Pressure Profiles Across Pregnancy in Women with Chronic Hypertension , 2016, American Journal of Perinatology.

[66]  Jennifer M. Fettweis,et al.  Genomic sequence analysis and characterization of Sneathia amnii sp. nov , 2012, BMC Genomics.

[67]  R. Romero,et al.  Spontaneous preterm birth: advances toward the discovery of genetic predisposition , 2017, American journal of obstetrics and gynecology.

[68]  D. Wolke,et al.  Effects of gestational age at birth on health outcomes at 3 and 5 years of age: population based cohort study , 2012, BMJ : British Medical Journal.

[69]  Rob Knight,et al.  UCHIME improves sensitivity and speed of chimera detection , 2011, Bioinform..

[70]  Hardik I. Parikh,et al.  Relationship between Vitamin D status and the vaginal microbiome during pregnancy , 2019, Journal of Perinatology.

[71]  Joy Lawn,et al.  Born Too Soon: The global epidemiology of 15 million preterm births , 2013, Reproductive Health.

[72]  D. Nelson,et al.  The Gestational Vaginal Microbiome and Spontaneous Preterm Birth among Nulliparous African American Women , 2016, American Journal of Perinatology.

[73]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[74]  Christine L. Sun,et al.  Replication and refinement of a vaginal microbial signature of preterm birth in two racially distinct cohorts of US women , 2017, Proceedings of the National Academy of Sciences.

[75]  Jennifer M. Fettweis,et al.  Species-level classification of the vaginal microbiome , 2012, BMC Genomics.

[76]  Peter Chung,et al.  Uncultivated Bacteria as Etiologic Agents of Intra-Amniotic Inflammation Leading to Preterm Birth , 2008, Journal of Clinical Microbiology.

[77]  J. Marrazzo,et al.  The Vaginal Microbiome: Current Understanding and Future Directions. , 2016, The Journal of infectious diseases.

[78]  Gaël Varoquaux,et al.  Scikit-learn: Machine Learning in Python , 2011, J. Mach. Learn. Res..

[79]  Jesse R. Zaneveld,et al.  Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences , 2013, Nature Biotechnology.

[80]  D. Harville Maximum Likelihood Approaches to Variance Component Estimation and to Related Problems , 1977 .

[81]  Gregory A. Buck,et al.  Changes in vaginal community state types reflect major shifts in the microbiome , 2017, Microbial ecology in health and disease.

[82]  M. Burns,et al.  Case-Control Study , 2020, Definitions.

[83]  Assuring Healthy Outcomes,et al.  Committee on Understanding Premature Birth and Assuring Healthy Outcomes , 2007 .

[84]  D. Eschenbach,et al.  [Bacterial vaginosis]. , 1985, Archives of gynecology.

[85]  Kim-Anh Lê Cao,et al.  mixOmics: An R package for ‘omics feature selection and multiple data integration , 2017, bioRxiv.

[86]  Zaid Abdo,et al.  Differences in the composition of vaginal microbial communities found in healthy Caucasian and black women , 2007, The ISME Journal.

[87]  D. Wolke,et al.  Effects of Gestational Age at Birth on Health Outcomes at 3 and 5 Years of Age: Population-based Cohort Study , 2013 .

[88]  P. Gajer,et al.  Vaginal microbiome of reproductive-age women , 2010, Proceedings of the National Academy of Sciences.

[89]  K. Nelson,et al.  Pregnancy's Stronghold on the Vaginal Microbiome , 2014, PloS one.