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BMC Medicine
Published in: BMC Medicine 1/2018

Open Access 01-12-2018 | Research article

Vaginal dysbiosis increases risk of preterm fetal membrane rupture, neonatal sepsis and is exacerbated by erythromycin

Authors: Richard G. Brown, Julian R. Marchesi, Yun S. Lee, Ann Smith, Benjamin Lehne, Lindsay M. Kindinger, Vasso Terzidou, Elaine Holmes, Jeremy K. Nicholson, Phillip R. Bennett, David A. MacIntyre

Published in: BMC Medicine | Issue 1/2018

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Abstract

Background

Preterm prelabour rupture of the fetal membranes (PPROM) precedes 30% of preterm births and is a risk factor for early onset neonatal sepsis. As PPROM is strongly associated with ascending vaginal infection, prophylactic antibiotics are widely used. The evolution of vaginal microbiota compositions associated with PPROM and the impact of antibiotics on bacterial compositions are unknown.

Methods

We prospectively assessed vaginal microbiota prior to and following PPROM using MiSeq-based sequencing of 16S rRNA gene amplicons and examined the impact of erythromycin prophylaxis on bacterial load and community structures.

Results

In contrast to pregnancies delivering at term, vaginal dysbiosis characterised by Lactobacillus spp. depletion was present prior to the rupture of fetal membranes in approximately a third of cases (0% vs. 27%, P = 0.026) and persisted following membrane rupture (31%, P = 0.005). Vaginal dysbiosis was exacerbated by erythromycin treatment (47%, P = 0.00009) particularly in women initially colonised by Lactobacillus spp. Lactobacillus depletion and increased relative abundance of Sneathia spp. were associated with subsequent funisitis and early onset neonatal sepsis.

Conclusions

Our data show that vaginal microbiota composition is a risk factor for subsequent PPROM and is associated with adverse short-term maternal and neonatal outcomes. This highlights vaginal microbiota as a potentially modifiable antenatal risk factor for PPROM and suggests that routine use of erythromycin for PPROM be re-examined.
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Literature
1.
Liu L, Oza S, Hogan D, Perin J, Rudan I, Lawn JE, et al. Global, regional, and national causes of child mortality in 2000–13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet. 2015;385(9966):430–40.CrossRefPubMed
2.
Iacovidou N, Varsami M, Syggellou A. Neonatal outcome of preterm delivery. Ann NY Acad Sci. 2010;1205:130–4.CrossRefPubMed
3.
Parry S, Strauss 3rd JF. Premature rupture of the fetal membranes. N Engl J Med. 1998;338(10):663–70.CrossRefPubMed
4.
Lamont RF, Duncan SLB, Mandal D, Bassett P. Intravaginal clindamycin to reduce preterm birth in women with abnormal genital tract flora. Obstet Gynecol. 2003;101(3):516–22.PubMed
5.
Pappas A, Kendrick DE, Shankaran S, et al. Chorioamnionitis and early childhood outcomes among extremely low-gestational-age neonates. JAMA Pediatr. 2014;168(2):137–47.CrossRefPubMedPubMedCentral
6.
Chandiramani M, Bennett PR, Brown R, Lee Y, MacIntyre DA. Vaginal microbiome-pregnant host interactions determine a significant proportion of preterm labour. Fetal Matern Med Rev. 2014;25(01):73–8.CrossRef
7.
Kanayama N, Terao T, Horiuchi K. The role of human neutrophil elastase in the premature rupture of membranes. Asia Oceania J Obstet Gynaecol. 1988;14(3):389–97.CrossRefPubMed
8.
Fortunato SJ, Menon R, Lombardi SJ. Role of tumor necrosis factor-α in the premature rupture of membranes and preterm labor pathways. Am J Obstet Gynecol. 2002;187(5):1159–62.CrossRefPubMed
9.
Shobokshi A, Shaarawy M. Maternal serum and amniotic fluid cytokines in patients with preterm premature rupture of membranes with and without intrauterine infection. Int J Gynaecol Obstet. 2002;79(3):209–15.CrossRefPubMed
10.
Helmig BR, Romero R, Espinoza J, Chaiworapongsa T, Bujold E, Gomez R, et al. Neutrophil elastase and secretory leukocyte protease inhibitor in prelabor rupture of membranes, parturition and intra-amniotic infection. J Matern Fetal Neonatal Med. 2002;12(4):237–46.CrossRefPubMed
11.
Fortner KB, Grotegut CA, Ransom CE, Bentley RC, Feng L, Lan L, et al. Bacteria localization and chorion thinning among preterm premature rupture of membranes. PloS One. 2014;9(1):e83338.CrossRefPubMedPubMedCentral
12.
Peaceman AM, Lai Y, Rouse DJ, Spong CY, Mercer BM, Varner MW, et al. Length of latency with preterm premature rupture of membranes before 32 weeks' gestation. Am J Perinatol. 2015;32(1):57–62.PubMed
13.
Rocha G, Proenca E, Quintas C, Rodrigues T, Guimaraes H. Chorioamnionitis and brain damage in the preterm newborn. J Matern Fetal Neonatal Med. 2007;20(10):745–9.CrossRefPubMed
14.
Lu H, Wang Q, Lu J, Zhang Q, Kumar P. Risk factors for intraventricular hemorrhage in preterm infants born at 34 weeks of gestation or less following preterm premature rupture of membranes. J Stroke Cerebrovasc Dis. 2016;25(4):807–12.CrossRefPubMed
15.
Vigneswaran R. Infection and preterm birth: evidence of a common causal relationship with bronchopulmonary dysplasia and cerebral palsy. J Paediatr Child Health. 2000;36(4):293–6.CrossRefPubMed
16.
Yoon BH, Romero R, Park JS, Kim CJ, Kim SH, Choi JH, et al. Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol. 2000;182(3):675–81.CrossRefPubMed
17.
Drassinower D, Friedman AM, Obican SG, Levin H, Gyamfi-Bannerman C. Prolonged latency of preterm premature rupture of membranes and risk of cerebral palsy. J Matern Fetal Neonatal Med. 2016;29(17):2748–52.
18.
van Dillen J, Zwart J, Schutte J, van Roosmalen J. Maternal sepsis: epidemiology, etiology and outcome. Curr Opin Infect Dis. 2010;23(3):249–54.CrossRefPubMed
19.
Puri K, Taft DH, Ambalavanan N, Schibler KR, Morrow AL, Kallapur SG. Association of chorioamnionitis with aberrant neonatal gut colonization and adverse clinical outcomes. PloS One. 2016;11(9):e0162734.CrossRefPubMedPubMedCentral
20.
Gajer P, Brotman RM, Bai G, Sakamoto J, Schutte UM, Zhong X, et al. Temporal dynamics of the human vaginal microbiota. Sci Transl Med. 2012;4(132):132ra152.CrossRef
21.
Aagaard K, Riehle K, Ma J, Segata N, Mistretta TA, Coarfa C, et al. A metagenomic approach to characterization of the vaginal microbiome signature in pregnancy. PloS One. 2012;7(6):e36466.CrossRefPubMedPubMedCentral
22.
MacIntyre DA, Chandiramani M, Lee YS, Kindinger L, Smith A, Angelopoulos N, et al. The vaginal microbiome during pregnancy and the postpartum period in a European population. Sci Rep. 2015;5:8988.CrossRefPubMedPubMedCentral
23.
Romero R, Hassan SS, Gajer P, Tarca AL, Fadrosh DW, Nikita L, et al. The composition and stability of the vaginal microbiota of normal pregnant women is different from that of non-pregnant women. Microbiome. 2014;2:10.CrossRefPubMedPubMedCentral
24.
Reid G, Younes JA, Van der Mei HC, Gloor GB, Knight R, Busscher HJ. Microbiota restoration: natural and supplemented recovery of human microbial communities. Nat Rev Microbiol. 2011;9(1):27–38.CrossRefPubMed
25.
Kindinger LM, Bennett PR, Lee YS, Marchesi JR, Smith A, Cacciatore S, et al. The interaction between vaginal microbiota, cervical length, and vaginal progesterone treatment for preterm birth risk. Microbiome. 2017;5(1):6.CrossRefPubMedPubMedCentral
26.
Petricevic L, Domig KJ, Nierscher FJ, Sandhofer MJ, Fidesser M, Krondorfer I, et al. Characterisation of the vaginal Lactobacillus microbiota associated with preterm delivery. Sci Rep. 2014;4:5136.CrossRefPubMedPubMedCentral
27.
McGregor JA, French JI, Seo K. Premature rupture of membranes and bacterial vaginosis. Am J Obstet Gynecol. 1993;169(2 Pt 2):463–6.CrossRefPubMed
28.
Flynn CA, Helwig AL, Meurer LN. Bacterial vaginosis in pregnancy and the risk of prematurity: a meta-analysis. J Fam Pract. 1999;48(11):885–92.PubMed
29.
Hillier SL, Nugent RP, Eschenbach DA, Krohn MA, Gibbs RS, Martin DH, et al. Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant. N Engl J Med. 1995;333(26):1737–42.CrossRefPubMed
30.
DiGiulio DB, Callahan BJ, McMurdie PJ, Costello EK, Lyell DJ, Robaczewska A, et al. Temporal and spatial variation of the human microbiota during pregnancy. Proc Natl Acad Sci USA. 2015;112(35):11060–5.CrossRefPubMedPubMedCentral
31.
Kindinger LM, MacIntyre DA, Lee YS, Marchesi JR, Smith A, McDonald JA, et al. Relationship between vaginal microbial dysbiosis, inflammation, and pregnancy outcomes in cervical cerclage. Sci Transl Med. 2016;8(350):350ra102.CrossRefPubMed
32.
33.
Martius J, Eschenbach DA. The role of bacterial vaginosis as a cause of amniotic fluid infection, chorioamnionitis and prematurity – a review. Arch Gynecol Obstet. 1990;247(1):1–13.CrossRefPubMed
34.
Takei H, Ruiz B. Shift in vaginal flora (bacterial vaginosis) and the frequency of chorioamnionitis in a high-risk population. Acta Cytol. 2006;50(4):410–14.CrossRefPubMed
35.
Baldwin EA, Walther-Antonio M, MacLean AM, Gohl DM, Beckman KB, Chen J, et al. Persistent microbial dysbiosis in preterm premature rupture of membranes from onset until delivery. PeerJ. 2015;3:e1398.CrossRefPubMedPubMedCentral
36.
Kacerovsky M, Vrbacky F, Kutova R, Pliskova L, Andrys C, Musilova I, et al. Cervical microbiota in women with preterm prelabor rupture of membranes. PloS One. 2015;10(5):e0126884.CrossRefPubMedPubMedCentral
37.
Paramel Jayaprakash T, Wagner EC, van Schalkwyk J, Albert AY, Hill JE, Money DM. High diversity and variability in the vaginal microbiome in women following preterm premature rupture of membranes (PPROM): a prospective cohort study. PloS One. 2016;11(11):e0166794.CrossRefPubMedPubMedCentral
38.
Ramsey PS, Nuthalapaty FS, Lu G, Ramin S, Nuthalapaty ES, Ramin KD. Contemporary management of preterm premature rupture of membranes (PPROM): a survey of maternal-fetal medicine providers. Am J Obstet Gynecol. 2004;191(4):1497–502.CrossRefPubMed
39.
Kenyon S, Pike K, Jones D, Brocklehurst P, Marlow N, Salt A, et al. Has publication of the results of the ORACLE Children Study changed practice in the UK? BJOG. 2010;117(11):1344–9.CrossRefPubMed
40.
41.
Kenyon S, Taylor DJ, Tarnow-Mordi WO. ORACLE – antibiotics for preterm prelabour rupture of the membranes: short-term and long-term outcomes. Acta Paediatr Suppl. 2002;91(437):12–5.CrossRefPubMed
42.
Kenyon S, Pike K, Jones DR, Brocklehurst P, Marlow N, Salt A, et al. Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial. Lancet. 2008;372(9646):1310–18.CrossRefPubMed
43.
Marlow N, Bower H, Jones D, Brocklehurst P, Kenyon S, Pike K, et al. The ORACLE Children Study: educational outcomes at 11 years of age following antenatal prescription of erythromycin or co-amoxiclav. Arch Dis Child Fetal Neonatal Ed. 2016;102(2):F131-F135.
44.
Kuriyama T, Williams DW, Yanagisawa M, Iwahara K, Shimizu C, Nakagawa K, et al. Antimicrobial susceptibility of 800 anaerobic isolates from patients with dentoalveolar infection to 13 oral antibiotics. Oral Microbiol Immunol. 2007;22(4):285–8.CrossRefPubMed
45.
Lee MY, Kim MH, Lee WI, Kang SY, Jeon YL. Prevalence and antibiotic susceptibility of Mycoplasma hominis and Ureaplasma urealyticum in pregnant women. Yonsei Med J. 2016;57(5):1271–5.CrossRefPubMedPubMedCentral
46.
Desjardins M, Delgaty KL, Ramotar K, Seetaram C, Toye B. Prevalence and mechanisms of erythromycin resistance in group A and group B Streptococcus: implications for reporting susceptibility results. J Clin Microbiol. 2004;42(12):5620–3.CrossRefPubMedPubMedCentral
47.
Meeraus WH, Petersen I, Gilbert R. Association between antibiotic prescribing in pregnancy and cerebral palsy or epilepsy in children born at term: a cohort study using the health improvement network. PloS One. 2015;10(3):e0122034.CrossRefPubMedPubMedCentral
48.
Korpela K, Salonen A, Virta LJ, Kekkonen RA, Forslund K, Bork P, et al. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Nat Commun. 2016;7:10410.CrossRefPubMedPubMedCentral
49.
Sundquist A, Bigdeli S, Jalili R, Druzin ML, Waller S, Pullen KM, et al. Bacterial flora-typing with targeted, chip-based pyrosequencing. BMC Microbiol. 2007;7:108.CrossRefPubMedPubMedCentral
50.
Kozich JJ, Westcott SL, Baxter NT, Highlander SK, Schloss PD. Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform. Appl Environ Microbiol. 2013;79(17):5112–20.CrossRefPubMedPubMedCentral
51.
Wang Q, Garrity GM, Tiedje JM, Cole JR. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl Environ Microbiol. 2007;73(16):5261–7.CrossRefPubMedPubMedCentral
52.
Edgar RC. Search and clustering orders of magnitude faster than BLAST. Bioinformatics. 2010;26(19):2460–1.CrossRefPubMed
53.
Liu CM, Aziz M, Kachur S, Hsueh P-R, Huang Y-T, Keim P, et al. BactQuant: an enhanced broad-coverage bacterial quantitative real-time PCR assay. BMC Microbiol. 2012;12(1):1–13.CrossRef
54.
Parks DH, Beiko RG. Identifying biologically relevant differences between metagenomic communities. Bioinformatics. 2010;26(6):715–21.CrossRefPubMed
55.
56.
Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SS, McCulle SL, et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci USA. 2011;108:4680–7.CrossRefPubMed
57.
Borgdorff H, Tsivtsivadze E, Verhelst R, Marzorati M, Jurriaans S, Ndayisaba GF, et al. Lactobacillus-dominated cervicovaginal microbiota associated with reduced HIV/STI prevalence and genital HIV viral load in African women. ISME J. 2014;8(9):1781–93.CrossRefPubMedPubMedCentral
58.
Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture of membranes. Cochrane Database Syst Rev. 2013;12:CD001058.
59.
Cousens S, Blencowe H, Gravett M, Lawn JE. Antibiotics for pre-term pre-labour rupture of membranes: prevention of neonatal deaths due to complications of pre-term birth and infection. Int J Epidemiol. 2010;39 Suppl 1:i134–143.CrossRefPubMedPubMedCentral
60.
61.
Yudin MH, van Schalkwyk J, Van Eyk N, Boucher M, Castillo E, Cormier B, et al. Antibiotic therapy in preterm premature rupture of the membranes. J Obstet Gynaecol Can. 2009;31(9):863–7.CrossRefPubMed
62.
Seelbach-Goebel B. Antibiotic therapy for premature rupture of membranes and preterm labor and effect on fetal outcome. Geburtshilfe Frauenheilkd. 2013;73(12):1218–27.CrossRefPubMedPubMedCentral
63.
64.
Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75–84.CrossRefPubMed
65.
66.
Romero R, Espinoza J, Goncalves LF, Kusanovic JP, Friel L, Hassan S. The role of inflammation and infection in preterm birth. Semin Reprod Med. 2007;25(1):21–39.CrossRefPubMed
67.
Kenyon SL, Taylor DJ, Tarnow-Mordi W. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. Lancet. 2001;357(9261):979–88.CrossRefPubMed
68.
Iliopoulou A, Thin RN, Turner P. Fluorimetric and microbiological assays of erythromycin concentrations in plasma and vaginal washings. Br J Vener Dis. 1981;57(4):263–7.PubMedPubMedCentral
69.
Harwich MD, Serrano MG, Fettweis JM, Alves JM, Reimers MA, Buck GA, et al. Genomic sequence analysis and characterization of Sneathia amnii sp. nov. BMC Genomics. 2012;13(8):S4.CrossRefPubMedPubMedCentral
70.
Salminen MK, Rautelin H, Tynkkynen S, Poussa T, Saxelin M, Valtonen V, et al. Lactobacillus bacteremia, species identification, and antimicrobial susceptibility of 85 blood isolates. Clin Infect Dis. 2006;42(5):e35–44.CrossRefPubMed
71.
72.
Desaki M, Okazaki H, Sunazuka T, Omura S, Yamamoto K, Takizawa H. Molecular mechanisms of anti-inflammatory action of erythromycin in human bronchial epithelial cells: possible role in the signaling pathway that regulates nuclear factor-κB activation. Antimicrob Agents Chemother. 2004;48(5):1581–5.CrossRefPubMedPubMedCentral
73.
Celik H, Ayar A, Sapmaz E. Effects of erythromycin on stretch-induced contractile activity of isolated myometrium from pregnant women. Acta Obstet Gynecol Scand. 2001;80(8):697–701.CrossRefPubMed
74.
Bulska M, Szczesniak P, Pieta-Dolinska A, Oszukowski P, Orszulak-Michalak D. The placental transfer of erythromycin in human pregnancies with group B streptococcal infection. Ginekologia polska. 2015;86(1):33–9.CrossRefPubMed
75.
Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci USA. 2010;107(26):11971–5.CrossRefPubMedPubMedCentral
76.
Dominguez-Bello MG, De Jesus-Laboy KM, Shen N, Cox LM, Amir A, Gonzalez A, et al. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med. 2016;22(3):250–3.CrossRefPubMedPubMedCentral
77.
Yassour M, Vatanen T, Siljander H, Hamalainen AM, Harkonen T, Ryhanen SJ, et al. Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci Transl Med. 2016;8(343):343ra381.CrossRef
78.
Bokulich NA, Chung J, Battaglia T, Henderson N, Jay M, Li H, et al. Antibiotics, birth mode, and diet shape microbiome maturation during early life. Sci Transl Med. 2016;8(343):343ra382.CrossRef
79.
Fujimura KE, Sitarik AR, Havstad S, Lin DL, Levan S, Fadrosh D, et al. Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat Med. 2016;22(10):1187–91.CrossRefPubMedPubMedCentral
80.
Jasarevic E, Howerton CL, Howard CD, Bale TL. Alterations in the vaginal microbiome by maternal stress are associated with metabolic reprogramming of the offspring gut and brain. Endocrinology. 2015;156(9):3265–76.CrossRefPubMedPubMedCentral
81.
Koumans EH, Sternberg M, Bruce C, McQuillan G, Kendrick J, Sutton M, 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):864–9.CrossRefPubMed
82.
Boennelycke M, Christensen JJ, Arpi M, Krause S. Leptotrichia amnionii found in septic abortion in Denmark. Scand J Infect Dis. 2007;39(4):382–3.CrossRefPubMed
83.
Hanff PA, Rosol-Donoghue JA, Spiegel CA, Wilson KH, Moore LH. Leptotrichia sanguinegens sp. nov., a new agent of postpartum and neonatal bacteremia. Clin Infect Dis. 1995;20 Suppl 2:S237–9.CrossRefPubMed
84.
Devi U, Bora R, Das JK, Malik V, Mahanta J. Sneathia species in a case of neonatal meningitis from Northeast India. Oxf Med Case Rep. 2014;2014(6):112–14.CrossRef
85.
Han YW, Shen T, Chung P, Buhimschi IA, Buhimschi CS. Uncultivated bacteria as etiologic agents of intra-amniotic inflammation leading to preterm birth. J Clin Microbiol. 2009;47(1):38–47.CrossRefPubMed
86.
Underwood MA, Gilbert WM, Sherman MP. Amniotic fluid: not just fetal urine anymore. J Perinatol. 2005;25(5):341–8.CrossRefPubMed
Metadata
Title
Vaginal dysbiosis increases risk of preterm fetal membrane rupture, neonatal sepsis and is exacerbated by erythromycin
Authors
Richard G. Brown
Julian R. Marchesi
Yun S. Lee
Ann Smith
Benjamin Lehne
Lindsay M. Kindinger
Vasso Terzidou
Elaine Holmes
Jeremy K. Nicholson
Phillip R. Bennett
David A. MacIntyre
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2018
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-017-0999-x

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