Preterm prelabour rupture of membranes (PPROM) complicated by intra-amniotic inflammation (IAI) represents a substantial proportion of preterm birth cases. Currently, IAI is frequently defined as amniotic fluid IL-6 concentration above 2,600 pg/mL. However, the amniotic fluid IL-6 concentration was never correlated with the global response of other proinflammatory proteins to the ongoing IAI. In this cross-sectional study, protein quantification was performed using mass spectrometry (MS) analysis followed by target quantification of selected proinflammatory proteins. Levels of amniotic fluid proteins determined by MS were put into the correlation with IL-6 concentration determined by electrochemiluminescence immunoassay method (ECLIA). In total, 925 proteins were efficiently quantified and differential expression analysis revealed 378 proteins upregulated towards IL-6 concentration above 10,000 pg/mL. Four proteins (LCN2, MMP8, MPO, and S100A12) were selected to verify the achieved results and IL-6 concentration of 10,000 pg/mL was determined as the cut-off value for global IAI response.

Biomedical Research Centre University Hospital Hradec Kralove Hradec Kralove Czech Republic

Department of Obstetrics and Gynecology Faculty of Medicine in Hradec Kralove University Hospital Hradec Kralove Charles University Hradec Kralove Czech Republic

Department of Obstetrics and Gynecology Hospital Most Krajska zdravotni a s Most Czech Republic

Institute of Clinical Microbiology University Hospital Hradec Kralove Hradec Kralove Czech Republic

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Mercer, B. M. Preterm premature rupture of the membranes. Obstet. Gynecol.101 (1), 178 (2003). PubMed

Mercer, B. M. Preterm premature rupture of the membranes: current approaches to evaluation and management. Obstet. Gynecol. Clin.32 (3), 411–428 (2005). PubMed

Kacerovsky, M. et al. Prelabor rupture of membranes between 34 and 37 weeks: the intraamniotic inflammatory response and neonatal outcomes. Am. J. Obstet. Gynecol.210 (4), 325e1–325e10 (2014). PubMed

Rose, R. & Engle, W. A. Optimizing care and outcomes for late preterm neonates. Curr. Treat. Options Peds. 3 (1), 32–43 (2017).

Boyle, E. M. et al. Neonatal outcomes and delivery of care for infants born late preterm or moderately preterm: a prospective population-based study. Archives Disease Child. - Fetal Neonatal Ed.100 (6), F479–F485 (2015). PubMed PMC

Freeman, S. W., Denoble, A., Kuller, J. A., Ellestad, S. & Dotters-Katz, S. Management of preterm premature rupture of membranes in the late preterm period. Obstet. Gynecol. Surv.77 (5), 283 (2022). PubMed

Quist-Nelson, J. et al. Immediate delivery compared with expectant management in late preterm prelabor rupture of membranes: an individual participant data Meta-analysis. Obstet. Gynecol.131 (2), 269 (2018). PubMed

Shim, S. S. et al. Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes. Am. J. Obstet. Gynecol.191 (4), 1339–1345 (2004). PubMed

Romero, R. et al. The diagnostic and prognostic value of amniotic fluid white blood cell count, glucose, interleukin-6, and gram stain in patients with preterm labor and intact membranes. Am. J. Obstet. Gynecol.169 (4), 805–816 (1993). PubMed

Yoon, B. H. et al. Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes. Am. J. Obstet. Gynecol.185 (5), 1130–1136 (2001). PubMed

Chaemsaithong, P. et al. A point of care test for interleukin-6 in amniotic fluid in preterm prelabor rupture of membranes: a step toward the early treatment of acute intra-amniotic inflammation/infection. J. Maternal-Fetal Neonatal Med.29 (3), 360–367 (2016). PubMed PMC

Musilova, I. et al. Interleukin-6 measured using the automated electrochemiluminescence immunoassay method for the identification of intra-amniotic inflammation in preterm prelabor rupture of membranes. J. Maternal-Fetal Neonatal Med.33 (11), 1919–1926 (2020). PubMed

Musilova, I. et al. Intraamniotic inflammation in women with preterm prelabor rupture of membranes. PLOS ONE. 7 (7), e0133929 (2015). PubMed PMC

Romero, R. et al. Sterile and microbial-associated intra-amniotic inflammation in preterm prelabor rupture of membranes. J. Maternal-Fetal Neonatal Med.28 (12), 1394–1409 (2015). PubMed PMC

Vajrychová, M. et al. Comprehensive proteomic investigation of infectious and inflammatory changes in late preterm prelabour rupture of membranes. Sci. Rep.10 (1), 17696 (2020). PubMed PMC

Kacerovsky, M. et al. Amniotic fluid myeloperoxidase in pregnancies complicated by preterm prelabor rupture of membranes. J. Maternal-Fetal Neonatal Med.26 (5), 463–468 (2013). PubMed

Lenčo, J. et al. Conventional-Flow liquid Chromatography–Mass spectrometry for exploratory Bottom-Up proteomic analyses. Anal. Chem.90 (8), 5381–5389 (2018). PubMed

Salafia, C. M., Weigl, C. & Silberman, L. The prevalence and distribution of acute placental inflammation in uncomplicated term pregnancies. Obstet. Gynecol.73 (3 Pt 1), 383–389 (1989). PubMed

Kacerovsky, M. et al. Presence of Chlamydia trachomatis DNA in the amniotic fluid in women with preterm prelabor rupture of membranes. J. Matern Fetal Neonatal Med.34 (10), 1586–1597 (2021). PubMed PMC

Cox, J. & Mann, M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol.26 (12), 1367–1372 (2008). PubMed

Tyanova, S. et al. The perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods. 13 (9), 731–740 (2016). PubMed

R Core Team. R: A language and environment for statistical computing. https://www.R-project.org/ (R Foundation for Statistical Computing, Vienna, Austria, 2021).

Ritchie, M. E. et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res.43 (7), e47 (2015). PubMed PMC

DeLong, E. R., DeLong, D. M. & Clarke-Pearson, D. L. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics44 (3), 837–845 (1988). PubMed

Musilova, I. et al. Late preterm prelabor rupture of fetal membranes: fetal inflammatory response and neonatal outcome. Pediatr. Res.83 (3), 630–637 (2018). PubMed

Mihara, M., Hashizume, M., Yoshida, H., Suzuki, M. & Shiina, M. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin. Sci. (Lond). 122 (4), 143–159 (2012). PubMed

Musilova, I. et al. Maternal serum C-reactive protein concentration and intra-amniotic inflammation in women with preterm prelabor rupture of membranes. PLOS ONE. 8 (8), e0182731 (2017). PubMed PMC

Musilova, I. et al. Maternal white blood cell count cannot identify the presence of microbial invasion of the amniotic cavity or intra-amniotic inflammation in women with preterm prelabor rupture of membranes. PLoS ONE12 (12), e0189394. (2017). PubMed PMC

Tsiartas, P. et al. The association between histological chorioamnionitis, funisitis and neonatal outcome in women with preterm prelabor rupture of membranes. J. Matern Fetal Neonatal Med.26 (13), 1332–1336 (2013). PubMed

Park, C. W., Park, J. S., Moon, K. C., Jun, J. K. & Yoon, B. H. Preterm labor and preterm premature rupture of membranes have a different pattern in the involved compartments of acute Histologoic chorioamnionitis and/or funisitis: Patho-physiologic implication related to different clinical manifestations. Pathol. Int.66 (6), 325–332 (2016). PubMed

Kacerovsky, M. et al. Antibiotic administration reduces the rate of intraamniotic inflammation in preterm prelabor rupture of the membranes. Am. J. Obstet. Gynecol.223 (1), 114e1–114e20 (2020). PubMed PMC

Ikeda, M. et al. Antibiotic administration reduced intra-amniotic inflammation 7 days after preterm premature rupture of the membranes with intra-amniotic infection. J. Maternal-Fetal Neonatal Med.36 (2), 2286189 (2023). PubMed

Yoon, B. H. et al. Antibiotic administration can eradicate intra-amniotic infection or intra-amniotic inflammation in a subset of patients with preterm labor and intact membranes. Am. J. Obstet. Gynecol. 221 (2), 142.e1-142.e22. (2019). PubMed PMC

Lee, J., Romero, R., Kim, S. M., Chaemsaithong, P. & Yoon, B. H. A new antibiotic regimen treats and prevents intra-amniotic inflammation/infection in patients with preterm PROM. J. Maternal-Fetal Neonatal Med.29 (17), 2727–2737 (2016). PubMed PMC

Nien, J. K. et al. A rapid MMP-8 bedside test for the detection of intra-amniotic inflammation identifies patients at risk for imminent preterm delivery. Am. J. Obstet. Gynecol.195 (4), 1025–1030 (2006). PubMed

Buhimschi, I. A. et al. The receptor for advanced glycation end products (RAGE) system in women with intraamniotic infection and inflammation. Am. J. Obstet. Gynecol.196 (2), 181e1–18113 (2007). PubMed

Vajrychova, M., Kacerovsky, M., Tambor, V., Hornychova, H. & Lenco, J. Microbial invasion and histological chorioamnionitis upregulate neutrophil-gelatinase associated Lipocalin in preterm prelabor rupture of membranes. J. Matern Fetal Neonatal Med.29 (1), 12–21 (2016). PubMed

Seliger, G. et al. Daily monitoring of vaginal Interleukin 6 as a predictor of intraamniotic inflammation after preterm premature rupture of membranes - a new method of sampling studied in a prospective multicenter trial. J. Perinat. Med.49 (5), 572–582 (2021). PubMed

Martinez-Portilla, R. J. et al. Maternal serum Interleukin-6: A Non-Invasive predictor of histological chorioamnionitis in women with Preterm-Prelabor rupture of membranes. Fetal Diagn. Ther.45 (3), 168–175 (2019). PubMed

Armstrong-Wells, J. et al. Inflammatory predictors of neurologic disability after preterm premature rupture of membranes. Am. J. Obstet. Gynecol.212 (2), 212e1–212e9 (2015). PubMed PMC

Kacerovsky, M. et al. Preterm prelabor rupture of membranes between 34 and 37 weeks: A Point-of-Care test of vaginal fluid Interleukin-6 concentrations for a noninvasive detection of Intra-Amniotic inflammation. Fetal Diagn. Ther.43 (3), 175–183 (2018). PubMed