Preterm premature rupture of membranes (pPROM) is associated with a high risk of prematurity and complications of fetal inflammatory response syndrome (FIRS). The aim of the study is to determine any correlations between the concentration of selected cytokines contained in the cervicovaginal secretion eluates and in the umbilical cord plasma in patients with pPROM and to find the noninvasive markers of FIRS in order to pinpoint the optimal time of the delivery.
The study included 80 patients with pPROM between the 24th and 34th week of gestation. The cervicovaginal fluid and umbilical cord blood were collected. Interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 19 (IL-19) and tumor necrosis factor-α (TNF-α) concentrations were measured in both materials. For the statistical analysis, SigmaStat3.5 software was used.
There was no direct association in levels of IL-6, TNF-α, IL-10 and IL-19 between the cord blood and cervicovaginal secretions within the studied group. The cut-off point of IL-6 of 26.8 pg/mL in the vaginal fluid had high sensitivity and specificity in order to discriminate between newborns with and without FIRS (81.08%; 76.74%).
Further studies are needed on a larger group of participants to demonstrate that an elevated concentration of IL-6 above 26.8 pg/mL in the cervicovaginal secretion eluate is an indirect noninvasive marker of FIRS.
Mercer BM, Goldenberg RL, Meis PJ, Moawad AH, Shellhaas C, Das A, et al. The Preterm Prediction Study: prediction of preterm premature rupture of membranes through clinical findings and ancillary testing. Am J Obstet Gynecol 2000;183:738–45.
Gasparović VE, Ahmetasević SG, Beljan P. The role of antibiotic prophylaxis in preterm premature rupture of membranes. Coll Antropol 2014;38:653–7.
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;25:21–39.
Romero R, Gomez R, Ghezzi F, Yoon BH, Mazor M, Edwin SS, et al. A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol 1998;181:773–9.
Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol 1998;179:194–202.
Janeway C, Travers P, Walport M, Shlomchik M. Innate immunity. In: Janeway C, Travers P, Walport M, Shlomchik M. editors. Immunobiology, 6th ed. New York: Garland Science Publishing; 2005. p. 37–102.
Hofer N, Kothari R, Morris N, Müller W, Resch B. The fetal inflammatory response syndrome is a risk factor for morbidity in preterm neonates. Am J Obstet Gynecocol 2013;209:542.e1–11.
Beg AA. Endogenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol 2002;23:509–12.
Gotsch F, Romero R, Kusanovic JP, Mazaki-Tovi S, Pineles BL, Erez O, et al. The fetal inflammatory response syndrome. Clin Obstet Gynecol 2007;50:652–83.
Yoon BH, Romero R, Park JS, Kim M, Oh SY, Kim CJ, et al. The relationship among inflammatory lesions of the umbilical cord (funisitis), umbilical cord plasma interleukin 6 concentration, amniotic fluid infection, and neonatal sepsis. Am J Obstet Gynecol 2000;183:1124–9.
Savasan ZA, Chaiworapongsa T, Romero R, Hussein Y, Kusanovic JP, Xu Y, et al. Interleukin-19 in fetal systemic inflammation. J Matern Fetal Neonatal Med 2012;25:995–1005.
Kunze M, Klar M, Morfeld CA, Thorns B, Schild RL, Markfeld-Erol F, et al. Cytokines in noninvasively obtained amniotic fluid as predictors of fetal inflammatory response syndrome. Am J Obstet Gynecol 2016;215:96.e1–8.
Fortunato SJ, Menon R, Lombardi SJ. Role of tumor necrosis factor-[alpha] in the premature rupture of membranes and preterm labor pathways. Am J Obstet Gynecol 2002;187:1159–62.
Yoon BH, Romero R, Shim JY, Shim SS, Kim CJ, Jun JK. C-reactive protein in umbilical cord blood: a simple and widely available clinical method to assess the risk of amniotic fluid infection and funisitis. J Matern Fetal Neonatal Med 2003;14:85–90.
Shim SS, Romero R, Hong JS, Park CW, Jun JK, Kim BI, et al. Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes. Am J Obstet Gynecol 2004;191:1339–45.
Yoon BH, Romero R, Kim KS, Park JS, Ki SH, Kim BI, et al. A systemic fetal inflammatory response and the development of bronchopulmonary dysplasia. Am J Obstet Gynecol 1999;181:773–9.
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;182:675–81.
Kenyon SL, Taylor DJ, Tarnow-Mordi W. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. ORACLE Collaborative Group. Lancet 2001;357:979–88.
Gravett MG, Sadowsky D, Witkin M, Novy M. Immunomodulators plus antibiotics to prevent preterm delivery in experimental intra-amniotic infection (IAI). Am J Obstet Gynecol 2003;189:S56.
Archabald KL, Buhimschi IA, Bahtiyar MO, Dulay AT, Abdel-Razeq SS, Pettker CM, et al. Limiting the exposure of select fetuses to intrauterine infection/inflammation improves short-term neonatal outcomes in preterm premature rupture of membranes. Fetal Diagn Ther 2017;42:99–110.
Rodríguez-Trujillo A, Cobo T, Vives I, Bosch J, Kacerovsky M, Posadas DE, et al. Gestational age is more important for short-term neonatal outcome than microbial invasion of the amniotic cavity or intra-amniotic inflammation in preterm prelabor rupture of membranes. Acta Obstet Gynecol Scand 2016;95:926–33.
Lee SE, Park JS, Norwitz ER, Kim KW, Park HS, Jun JK. Measurement of placental alpha-microglobulin-1 in cervicovaginal discharge to diagnose rupture of membranes. Obstet Gynecol 2007;109:634–40.
Cousins LM, Smok DP, Lovett SM, Poeltler DM. AmniSure placental alpha microglobulin-1 rapid immunoassay versus standard diagnostic methods for detection of rupture of membranes. Am J Perinatol 2005;22:317–20.
Cobo T, Kacerovsky M, Holst RM, Hougaard DM, Skogstrand K, Wennerholm UB, et al. Intra-amniotic inflammation predicts microbial invasion of the amniotic cavity but not spontaneous preterm delivery in preterm prelabor membrane rupture. Acta Obstet Gynecol Scand 2012;91:930–5.
Musilova I, Kutová R, Pliskova L, Stepan M, Menon R, Jacobsson B, et al. Intraamniotic inflammation in women with preterm prelabor rupture of membranes. PLoS One 2015;10:e0133929.
Kacerovsky M, Musilova I, Khatibi A, Skogstrand K, Hougaard DM, Tambor V, et al. Intraamniotic inflammatory response to bacteria: analysis of multiple amniotic fluid proteins in women with preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med 2012;25:2014–9.
Kacerovsky M, Musilova I, Andrys C, Hornychova H, Pliskova L, Kostal M, et al. Prelabor rupture of membranes between 34 and 37 weeks: the intraamniotic inflammatory response and neonatal outcomes. Am J Obstet Gynecol 2014;210:325.e1–10.
Skrzypczak J, Wirstlein PK, Wróbel M, Mikołajczyk M. Concentration of pro-inflammatory interleukins in cervical secretions of women with PROM and in the umbilical cord blood of their newborns. Ginekol Pol 2015;86:434–41.
Keel M, Ungethüm U, Steckholzer U, Niederer E, Hartung T, Trentz O, et al. Interleukin-10 counterregulates proinflammatory cytokine induced inhibition of neutrophil apoptosis during severe sepsis. Blood 1997;90:3356–63.
Jordan WJ, Eskdale J, Boniotto M, Lennon GP, Peat J, Campbell JD, et al. Human IL-19 regulates immunity through autoinduction of IL-19 and production of IL-10. Eur J Immunol 2005;35:1576–8.
Ryu A, Park KH, Oh KJ, Lee SY, Jeong EH, Park JW. Predictive value of combined cervicovaginal cytokines and gestational age at sampling for intra-amniotic infection in preterm premature rupture of membranes. Acta Obstet Gynecol Scand 2013;92:517–24.
Kayem G, Batteux F, Girard N, Schmitz T, Willaime M, Maillard F, et al. Predictive value of vaginal IL-6 and TNF-α bedside tests repeated until delivery for the prediction of maternal-fetal infection in cases of premature rupture of membranes. Eur J Obstet Gynecol Reprod Biol 2017;211:8–14.
The Journal of Perinatal Medicine is a truly international forum covering the entire field of perinatal medicine. It is an essential news source for all those obstetricians, neonatologists, perinatologists and allied health professionals who wish to keep abreast of progress in perinatal and related research.
01 Jan 1973
Eduardo Bancalari, Joseph Chappelle, Frank A. Chervenak, Vincenzo D'Addario, Mehmet R. Genc, Anne Greenough, Amos Grunebaum, Justin C. Konje, Asim Kurjak M.D., Roberto Romero and Ivica Zalud, MD PhD