SP 2: Vaginal and Endometrial Microbiome and Early Pregnancy Complication

Research questions, aims 

Microbial colonization and infections are extraordinarily significant and often underappreciated in the context of reproductive health from implantation and placentation to early pregnancy loss (due to, e.g., chronic endometritis, CE) and extreme preterm birth (due to, e.g., preterm premature rupture of membranes, PPROM) with high neonatal mortality and lifelong morbidity. The research objective is to develop and evaluate personalized therapeutic strategies for CE and PPROM based on vaginal and endometrial microbiome analyses.

Scientific Background

Up to 60% of women undergoing infertility treatment may have CE (1), resulting in reduced implantation, pregnancy, and live birth rates. Current antibiotic therapy recommendations for CE do not include prior microbial diagnosis. 40% of all spontaneous preterm births are due to PPROM, in 20% leading to early onset neonatal sepsis (EONS) (2). A specific antibiotic therapy would help to save the protective Lactobacillus colonization.

Own preceding work

Our laboratory has a bank of >20,000 endometrial biopsies, including >2,500 samples from women before and after antibiotic CE therapy. Micro/molecular-biological analyses of the endometrium were applied to define individualized antibiotic therapy. Currently, nanopore-based sequencing, the latest generation of long-read sequencing, is the only option for real-time microbiome analysis and pathogen phenotyping in clinical settings. In our own preliminary work, vaginal samples have been analyzed (3) and optimized protocols have been established. The PEONS pilot study (4) showed a correlation of non-Lactobacillus species in the vaginome prior to antibiotic therapy with PPROM and subsequent EONS (5).

Method spectrum and involvement of the Clinician Scientist 

The existing pool of endometrial samples will be used by the Clinician Scientist for immunohistochemical endometrium diagnostics. Vaginal samples will be collected from PPROM patients and high-risk pregnancies by the Clinician Scientists in our prenatal outpatient clinic and perinatal center. Standard 16S rRNA sequencing and nanopore-based vaginal microbiome analysis are established in the facilities of the Center for Sepsis Control & Care (CSCC) at the JUH.

Relevance for CEPRE and for Reproductive Health

This subprogram will cover the aspects of reproductive tract infection and vagino-endometrial microbiome for reproductive health from recurrent implantation failure and early pregancy loss to infection associated late losses, stillbirth and extreme preterm birth. The Clinician Scientist will integrate in the translational research process with focus on clinical research.

References

1. Kato H, Yamagishi Y, Hagihara M, Hirai J, Asai N, Shibata Y, Iwamoto T, Mikamo H. Systematic review and meta-analysis for impacts of oral antibiotic treatment on pregnancy outcomes in chronic endometritis patients. J Infect Chemother. 2022;28(5):610-5.
2. Shah BA, Padbury JF. Neonatal sepsis: an old problem with new insights. Virulence. 2014;5(1):170-8.
3. Marquet M, Zollkau J, Pastuschek J, Viehweger A, Schleussner E, Makarewicz O, Pletz MW, Ehricht R, Brandt C. Evaluation of microbiome enrichment and host DNA depletion in human vaginal samples using Oxford Nanopore's adaptive sequencing. Sci Rep. 2022;12(1):4000.
4. Borges LG, Pastuschek, J., Heimann, Y., Dawczynski, K., Schleußner, E., Pieper, D.H. Vaginal and neonatal microbiota in pregnant women with preterm premature rupture of membranes and consecutive early onset neonatal sepsis. in peparation.
5. Zöllkau J, Pastuschek, J., Schleußner, E., Makarewicz, O., Brandt, C., Marquet, M. . Vaginal microbiome nanopore sequencing in preterm premature rupture of membranes (PPROM) and early onset neonatal sepsis (EONS). in prepration.