SEARCHCOHORTobstetrics, neonatology

cohort·obstetrics, neonatology, infectious_disease, microbiology, perinatology·PMC10009945

Vaginal and neonatal microbiota in pregnant women with preterm premature rupture of membranes and consecutive early onset neonatal sepsis

BMC Medicine · 14 authors, 4 centres

AI SUMMARY

FIDELITY 100%

POPULATION78 pregnant women with PPROM (22+0 to 34+0 weeks gestation) and their 89 neonates

INTERVENTIONStandard antibiotic therapy (aminopenicillin ± macrolide) after PPROM diagnosis; 16S rRNA gene sequencing of maternal vaginal and neonatal microbiota

COMPARISONWomen/neonates who developed EONS vs. those who did not; vaginal microbiota before vs. during vs. after antibiotic treatment

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TL;DR

This study analyzed vaginal and neonatal microbiota in 78 women with preterm premature rupture of membranes (PPROM) and their 89 neonates. Standard antibiotic therapy depleted protective Lactobacillus species and increased bacterial diversity, while specific taxa like Escherichia/Shigella and Facklamia were identified as risk factors for early-onset neonatal sepsis (EONS). Vaginal and meconium microbiota analysis shows promise for individualized EONS risk assessment after PPROM.

Full summary

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**Background:** Preterm premature rupture of membranes (PPROM) accounts for up to one-third of preterm births and is associated with vaginal dysbiosis. Ascending bacterial colonization can lead to chorioamnionitis and early-onset neonatal sepsis (EONS), which occurs in 14–22% of PPROM cases. Standard antibiotic therapy aims to prolong pregnancy but may disrupt protective Lactobacillus-dominated vaginal communities. This study assessed vaginal microbial composition in PPROM patients under antibiotic therapy and evaluated its utility for predicting EONS, while also characterizing neonatal microbiota as a potential mirror of in utero conditions.

**Methods:** This prospective multicenter cohort study (PEONS, NCT03819192) recruited 78 women with PPROM (22+0 to 34+0 weeks) and their 89 neonates (11 twin pregnancies) from three German trial sites. Maternal vaginal swabs were collected at admission (V0, prior to antibiotics), after 2–6 days of antibiotic treatment (V1), and within 24 hours before delivery (V2). Neonatal samples included pharyngeal swabs, rectal swabs, umbilical cord blood, and meconium (collected within 48 hours of life). All 78 mothers received guideline-compliant antibiotic therapy (aminopenicillin in all cases, supplemented with a macrolide in most). DNA was extracted using the FastDNA SpinKit for Soil, and the V1V2 region of the 16S rRNA gene was sequenced via Illumina MiSeq (2×300 bp paired-end). Data were processed with DADA2; sequence variants were annotated using RDP set18. Contaminants (Burkholderia, Ralstonia) were identified and removed. Alpha diversity (Shannon, Chao1, Pielou indices) was compared using Mann–Whitney tests. Beta diversity was assessed via Bray–Curtis similarity and PERMANOVA. Potential EONS biomarkers were analyzed using MetaboAnalyst 5.0 with logistic regression, support vector machine, and random forest classifiers.

**Key Results:** At admission (V0), 65.4% of women had Lactobacillus-dominated vaginal microbiota (L. crispatus in 32/78, L. iners in 17/78). Antibiotic treatment for >48 hours significantly increased bacterial diversity (Shannon index, p=0.0054), evenness (Pielou index, p=0.03), and richness (Chao1 index, p=0.0084). Lactobacillus spp. were depleted, and Ureaplasma parvum became dominant in 14 of 44 V1 samples (vs. 0 at baseline). Of 34 women treated >48 hours, 10 (29%) delivered neonates who developed EONS, compared to 4 of 29 (14%) treated <48 hours (not statistically significant). Only 1 of 14 communities recovered to L. crispatus dominance after antibiotic cessation. Neonatal microbiota was heterogeneous: meconium samples showed distinct taxa (Bacteroides ovatus, Bifidobacterium longum, Agathobacter rectale) and were not significantly affected by delivery mode or maternal antibiotic duration. Umbilical cord blood from vaginal deliveries showed high similarity to maternal vaginal communities, suggesting surface contamination. For EONS prediction, vaginal microbiota at birth (V2) showed significant differences between EONS and non-EONS cases (PERMANOVA p=0.044), with Escherichia/Shigella, Enterococcus faecalis, Facklamia, and Staphylococcus aureus as risk taxa, and Anaerococcus obesiensis and Campylobacter ureolyticus as protective taxa. A 4-taxon model (Escherichia/Shigella, Facklamia, Anaerococcus obesiensis, Campylobacter ureolyticus) yielded AUCs of 0.674 (training) and 0.788 (validation). Meconium models using Bifidobacterium longum, Agathobacter rectale, and S. epidermidis achieved AUCs of 0.592 (training) and 0.753 (validation). Pharyngeal swab models correctly classified 86% of EONS cases but only 58% of non-EONS cases.

**Clinical Implications:** Standard antibiotic therapy for PPROM depletes protective Lactobacillus species and increases vaginal diversity, potentially promoting pathogens like Ureaplasma parvum. Only 1 of 14 patients recovered Lactobacillus dominance after treatment cessation, highlighting the need for alternative approaches (e.g., probiotics, targeted therapy). Vaginal microbiota analysis identified clinically relevant organisms (Facklamia spp., Winkia neuii) not captured by conventional diagnostics. Meconium microbiota, minimally contaminated by birth mode, may reflect in utero colonization and offers predictive value for EONS. Bifidobacterium longum in meconium was associated with lower EONS risk, though this may reflect greater gut maturity (gestational age 32.4±2.0 vs. 30.9±3.2 weeks, p=0.028). Microbiota-based prediction models show promise for individualized risk assessment, but larger cohorts are needed before clinical implementation.

PICO

PPOPULATION

78 pregnant women with PPROM (22+0 to 34+0 weeks gestation) and their 89 neonates

IINTERVENTION

Standard antibiotic therapy (aminopenicillin ± macrolide) after PPROM diagnosis; 16S rRNA gene sequencing of maternal vaginal and neonatal microbiota

OOUTCOME

Changes in vaginal microbial composition; prediction of EONS using microbial biomarkers (AUC up to 0.788 for vaginal, 0.753 for meconium models)

STUDY TYPE

cohort

SPECIALTY

obstetrics

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10009945

Vaginal and neonatal microbiota in pregnant women with preterm premature rupture of membranes and consecutive early onset neonatal sepsis

BMC Medicine

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ABSTRACT

Background Preterm premature rupture of membranes (PPROM), which is associated with vaginal dysbiosis, is responsible for up to one-third of all preterm births. Consecutive ascending colonization, infection, and inflammation may lead to relevant neonatal morbidity including early-onset neonatal sepsis (EONS). The present study aims to assess the vaginal microbial composition of PPROM patients and its development under standard antibiotic therapy and to evaluate the usefulness of the vaginal microbiota for the prediction of EONS. It moreover aims to decipher neonatal microbiota at birth as possible mirror of the in utero microbiota. Methods As part of the PEONS prospective multicenter cohort study, 78 women with PPROM and their 89 neonates were recruited. Maternal vaginal and neonatal pharyngeal, rectal, umbilical cord blood, and meconium microbiota were analyzed by 16S rRNA gene sequencing. Significant differences between the sample groups were evaluated using permutational multivariate analysis of variance and differently distributed taxa by the Mann–Whitney test. Potential biomarkers for the prediction of EONS were analyzed using the MetaboAnalyst platform. Results Vaginal microbiota at admission after PPROM were dominated by Lactobacillus spp. Standard antibiotic treatment triggers significant changes in microbial community (relative depletion of Lactobacillus spp. and relative enrichment of Ureaplasma parvum ) accompanied by an increase in bacterial diversity, evenness and richness. The neonatal microbiota showed a heterogeneous microbial composition where meconium samples were characterized by specific taxa enriched in this niche. The vaginal microbiota at birth was shown to have the potential to predict EONS with Escherichia/Shigella and Facklamia as risk taxa and Anaerococcus obesiensis and Campylobacter ureolyticus as protective taxa. EONS cases could also be predicted at a reasonable rate from neonatal meconium communities with the protective taxa Bifidobacterium longum , Agathobacter rectale , and S. epidermidis as features. Conclusions Vaginal and neonatal microbiota analysis by 16S rRNA gene sequencing after PPROM may form the basis of individualized risk assessment for consecutive EONS. Further studies on extended cohorts are necessary to evaluate how far this technique may in future close a diagnostic gap to optimize and personalize the clinical management of PPROM patients. Trial registration NCT03819192, ClinicalTrials.gov. Registered on January 28, 2019. Supplementary Information The online version contains supplementary material available at 10.1186/s12916-023-02805-x.

CITATION EXPORT

Luiz Gustavo dos Anjos Borges, Jana Pastuschek, Yvonne Heimann et al.. Vaginal and neonatal microbiota in pregnant women with preterm premature rupture of membranes and consecutive early onset neonatal sepsis. BMC Medicine. (2023). https://doi.org/10.1186/s12916-023-02805-x

AUTHORS

14 · 4 CENTRES

Luiz Gustavo dos Anjos Borges, Jana Pastuschek, Yvonne Heimann, Kristin Dawczynski, Michael Bergner, Roland Haase, Johannes Stubert, Dirk Olbertz, Iris Plumeier, Silke Kahl, Ann Kathrin Heroven, Ekkehard Schleußner, Dietmar H. Pieper, Janine Zöllkau

1grid.7490.a0000 0001 2238 295XMicrobial Interactions and Processes Research Group, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Brunswick, Germany
2grid.275559.90000 0000 8517 6224Department of Obstetrics, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany
3grid.275559.90000 0000 8517 6224Center for Sepsis Control and Case (CSCC), Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany
4grid.275559.90000 0000 8517 6224Department of Pediatrics, Section Neonatology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany