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Research Article

Preterm labor with intact membranes: a simple noninvasive method to identify patients at risk for intra-amniotic infection and/or inflammation

ORCID Icon, , , , &
Pages 10514-10529 | Received 04 Mar 2022, Accepted 28 Sep 2022, Published online: 13 Oct 2022

References

  • Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014;345(6198):760–765.
  • Romero R, Gomez R, Chaiworapongsa T, et al. The role of infection in preterm labour and delivery. Paediatr Perinat Epidemiol. 2001;15(Suppl 2):41–56.
  • Goncalves LF, Chaiworapongsa T, Romero R. Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev. 2002;8(1):3–13.
  • Novy MJ, Duffy L, Axthelm MK, et al. Ureaplasma parvum or Mycoplasma hominis as sole pathogens cause chorioamnionitis, preterm delivery, and fetal pneumonia in rhesus macaques. Reprod Sci. 2009;16(1):56–70.
  • Morales WJ, Washington SR, 3rd, Lazar AJ. The effect of chorioamnionitis on perinatal outcome in preterm gestation. J Perinatol. 1987;7(2):105–110.
  • Sperling RS, Newton E, Gibbs RS. Intraamniotic infection in low-birth-weight infants. J Infect Dis. 1988;157(1):113–117.
  • Romero R, Sirtori M, Oyarzun E, et al. Infection and labor. V. Prevalence, microbiology, and clinical significance of intraamniotic infection in women with preterm labor and intact membranes. Am J Obstet Gynecol. 1989;161(3):817–824.
  • Yoon BH, Jun JK, Romero R, et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol. 1997;177(1):19–26.
  • Yoon BH, Chang JW, Romero R. Isolation of Ureaplasma urealyticum from the amniotic cavity and adverse outcome in preterm labor. Obstet Gynecol. 1998;92(1):77–82.
  • Hitti J, Tarczy-Hornoch P, Murphy J, et al. Amniotic fluid infection, cytokines, and adverse outcome among infants at 34 weeks’ gestation or less. Obstet Gynecol. 2001;98(6):1080–1088.
  • Kirchner L, Helmer H, Heinze G, et al. Amnionitis with Ureaplasma urealyticum or other microbes leads to increased morbidity and prolonged hospitalization in very low birth weight infants. Eur J Obstet Gynecol Reprod Biol. 2007;134(1):44–50.
  • Romero R, Gotsch F, Pineles B, et al. Inflammation in pregnancy: its roles in reproductive physiology, obstetrical complications, and fetal injury. Nutr Rev. 2007;65(12 Pt 2):S194–S202.
  • Korzeniewski SJ, Romero R, Cortez J, et al. A "multi-hit" model of neonatal white matter injury: cumulative contributions of chronic placental inflammation, acute fetal inflammation and postnatal inflammatory events. J Perinat Med. 2014;42(6):731–743.
  • Oh KJ, Park JY, Lee J, et al. The combined exposure to intra-amniotic inflammation and neonatal respiratory distress syndrome increases the risk of intraventricular hemorrhage in preterm neonates. J Perinat Med. 2018;46(1):9–20.
  • Al-Haddad BJS, Oler E, Armistead B, et al. The fetal origins of mental illness. Am J Obstet Gynecol. 2019;221(6):549–562.
  • Venkatesh KK, Leviton A, Hecht JL, et al. Histologic chorioamnionitis and risk of neurodevelopmental impairment at age 10 years among extremely preterm infants born before 28 weeks of gestation. Am J Obstet Gynecol. 2020;223(5):745.e1–745.e10.
  • Romero R, Miranda J, Chaemsaithong P, et al. Sterile and microbial-associated intra-amniotic inflammation in preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2015;28(12):1394–1409.
  • Gomez-Lopez N, Romero R, Plazyo O, et al. Intra-Amniotic administration of HMGB1 induces spontaneous preterm labor and birth. Am J Reprod Immunol. 2016;75(1):3–7.
  • Plazyo O, Romero R, Unkel R, et al. HMGB1 induces an inflammatory response in the chorioamniotic membranes that is partially mediated by the inflammasome. Biol Reprod. 2016;95(6):2.
  • Gomez-Lopez N, Romero R, Plazyo O, et al. Preterm labor in the absence of acute histologic chorioamnionitis is characterized by cellular senescence of the chorioamniotic membranes. Am J Obstet Gynecol. 2017;217(5):592.e1–592.e17.
  • Gomez-Lopez N, Romero R, Panaitescu B, et al. Inflammasome activation during spontaneous preterm labor with intra-amniotic infection or sterile intra-amniotic inflammation. Am J Reprod Immunol. 2018;80(5):e13049.
  • Gomez-Lopez N, Romero R, Garcia-Flores V, et al. Inhibition of the NLRP3 inflammasome can prevent sterile intra-amniotic inflammation, preterm labor/birth, and adverse neonatal outcomesdagger. Biol Reprod. 2019;100(5):1306–1318.
  • Garite TJ, Freeman RK. Chorioamnionitis in the preterm gestation. Obstet Gynecol. 1982;59(5):539–545.
  • Yoon BH, Romero R, Moon JB, et al. Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Obstet Gynecol. 2001;185(5):1130–1136.
  • Shim SS, Romero R, Hong JS, et al. Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes. Am J Obstet Gynecol. 2004;191(4):1339–1345.
  • Oh KJ, Lee KA, Sohn YK, et al. Intraamniotic infection with genital mycoplasmas exhibits a more intense inflammatory response than intraamniotic infection with other microorganisms in patients with preterm premature rupture of membranes. Am J Obstet Gynecol. 2010;203(3):211.e1-8–211.e8.
  • Sung JH, Choi SJ, Oh SY, et al. Should the diagnostic criteria for suspected clinical chorioamnionitis be changed? J Matern Fetal Neonatal Med. 2019;3:1–10.
  • Galaz J, Romero R, Slutsky R, et al. Cellular immune responses in amniotic fluid of women with preterm prelabor rupture of membranes. J Perinat Med. 2020;48(3):222–233.
  • Galaz J, Romero R, Xu Y, et al. Cellular immune responses in amniotic fluid of women with preterm clinical chorioamnionitis. Inflamm Res. 2020;69(2):203–216.
  • Romero R, Quintero R, Nores J, et al. Amniotic fluid white blood cell count: a rapid and simple test to diagnose microbial invasion of the amniotic cavity and predict preterm delivery. Am J Obstet Gynecol. 1991;165(4 Pt 1):821–830.
  • Romero R, Yoon BH, Mazor M, 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. 1993;169(4):805–816.
  • Mönckeberg M, Valdés R, Kusanovic JP, et al. Patients with acute cervical insufficiency without intra-amniotic infection/inflammation treated with cerclage have a good prognosis. J Perinat Med. 2019;47(5):500–509.
  • Romero R, Avila C, Santhanam U, et al. Amniotic fluid interleukin 6 in preterm labor. Association with infection. J Clin Invest. 1990;85(5):1392–1400.
  • Santhanam U, Avila C, Romero R, et al. Cytokines in normal and abnormal parturition: elevated amniotic fluid interleukin-6 levels in women with premature rupture of membranes associated with intrauterine infection. Cytokine. 1991;3(2):155–163.
  • Romero R, Sepulveda W, Kenney JS, et al. Interleukin 6 determination in the detection of microbial invasion of the amniotic cavity. Ciba Found Symp. 1992;167:205–220.
  • Saito S, Kasahara T, Kato Y, et al. Elevation of amniotic fluid interleukin 6 (IL-6), IL-8 and granulocyte colony stimulating factor (G-CSF) in term and preterm parturition. Cytokine. 1993;5(1):81–88.
  • Romero R, Yoon BH, Kenney JS, et al. Amniotic fluid interleukin-6 determinations are of diagnostic and prognostic value in preterm labor. Am J Reprod Immunol. 1993;30(2–3):167–183.
  • Greig PC, Ernest JM, Teot L, et al. Amniotic fluid interleukin-6 levels correlate with histologic chorioamnionitis and amniotic fluid cultures in patients in premature labor with intact membranes. Am J Obstet Gynecol. 1993;169(4):1035–1044.
  • Romero R, Yoon BH, Mazor M, et al. A comparative study of the diagnostic performance of amniotic fluid glucose, white blood cell count, interleukin-6, and gram stain in the detection of microbial invasion in patients with preterm premature rupture of membranes. Am J Obstet Gynecol. 1993;169(4):839–851.
  • Dudley DJ, Hunter C, Mitchell MD, et al. Clinical value of amniotic fluid interleukin-6 determinations in the management of preterm labour. Br J Obstet Gynaecol. 1994;101(7):592–597.
  • Coultrip LL, Lien JM, Gomez R, et al. The value of amniotic fluid interleukin-6 determination in patients with preterm labor and intact membranes in the detection of microbial invasion of the amniotic cavity. Am J Obstet Gynecol. 1994;171(4):901–911.
  • Gomez R, Romero R, Galasso M, et al. The value of amniotic fluid interleukin-6, white blood cell count, and gram stain in the diagnosis of microbial invasion of the amniotic cavity in patients at term. Am J Reprod Immunol. 1994;32(3):200–210.
  • Yoon BH, Romero R, Kim CJ, et al. Amniotic fluid interleukin-6: a sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morbidity. Am J Obstet Gynecol. 1995;172(3):960–970.
  • Andrews WW, Hauth JC, Goldenberg RL, et al. Amniotic fluid interleukin-6: correlation with upper genital tract microbial colonization and gestational age in women delivered after spontaneous labor versus indicated delivery. Am J Obstet Gynecol. 1995;173(2):606–612.
  • Baud O, Emilie D, Pelletier E, et al. Amniotic fluid concentrations of interleukin-1beta, interleukin-6 and TNF-alpha in chorioamnionitis before 32 weeks of gestation: histological associations and neonatal outcome. Br J Obstet Gynaecol. 1999;106(1):72–77.
  • Hsu CD, Aversa K, Meaddough E. The role of amniotic fluid interleukin-6, and cell adhesion molecules, intercellular adhesion molecule-1 and leukocyte adhesion molecule-1, in intra-amniotic infection. Am J Reprod Immunol. 2000;43(5):251–254.
  • Jacobsson B, Mattsby-Baltzer I, Hagberg H. Interleukin-6 and interleukin-8 in cervical and amniotic fluid: relationship to microbial invasion of the chorioamniotic membranes. BJOG: Int J O&G. 2005;112(6):719–724.
  • Combs CA, Gravett M, Garite TJ, et al. Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes. Am J Obstet Gynecol. 2014;210(2):125 e1–125 e15.
  • Romero R, Kadar N, Miranda J, et al. The diagnostic performance of the mass restricted (MR) score in the identification of microbial invasion of the amniotic cavity or intra-amniotic inflammation is not superior to amniotic fluid interleukin-6. J Matern Fetal Neonatal Med. 2014;27(8):757–769.
  • Kacerovsky M, Musilova I, Hornychova H, et al. Bedside assessment of amniotic fluid interleukin-6 in preterm prelabor rupture of membranes. Am J Obstet Gynecol. 2014;211(4):385.e1-9–385.e9.
  • Chaemsaithong P, Romero R, Korzeniewski SJ, et al. A rapid interleukin-6 bedside test for the identification of intra-amniotic inflammation in preterm labor with intact membranes. J Matern Fetal Neonatal Med. 2016;29(3):349–359.
  • Chaemsaithong P, Romero R, Korzeniewski SJ, 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 Matern Fetal Neonatal Med. 2016;29(3):360–367.
  • Musilova I, Andrys C, Holeckova M, 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 Matern Fetal Neonatal Med. 2020;33(11):1919–1926.
  • Yoon BH, Oh SY, Romero R, et al. An elevated amniotic fluid matrix metalloproteinase-8 level at the time of mid-trimester genetic amniocentesis is a risk factor for spontaneous preterm delivery. Am J Obstet Gynecol. 2001;185(5):1162–1167.
  • Park JS, Romero R, Yoon BH, et al. The relationship between amniotic fluid matrix metalloproteinase-8 and funisitis. Am J Obstet Gynecol. 2001;185(5):1156–1161.
  • Nien JK, Yoon BH, Espinoza J, 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. 2006;195(4):1025–1030.
  • Kim KW, Romero R, Park HS, et al. A rapid matrix metalloproteinase-8 bedside test for the detection of intraamniotic inflammation in women with preterm premature rupture of membranes. Am J Obstet Gynecol. 2007;197(3):292.e1-5–292.e5.
  • Park CW, Lee SM, Park JS, et al. The antenatal identification of funisitis with a rapid MMP-8 bedside test. J Perinat Med. 2008;36(6):497–502.
  • Chaemsaithong P, Romero R, Docheva N, et al. Comparison of rapid MMP-8 and interleukin-6 point-of-care tests to identify intra-amniotic inflammation/infection and impending preterm delivery in patients with preterm labor and intact membranes. J Matern Fetal Neonatal Med. 2018;31(2):228–244.
  • Gultekin-Elbir EE, Genc MR. Tinker, tailor, infection, inflammation. J Perinat Med. 2019;47(3):259–261.
  • Mazor M, Kassis A, Horowitz S, et al. Relationship between C-reactive protein levels and intraamniotic infection in women with preterm labor. J Reprod Med. 1993;38(10):799–803.
  • Watts DH, Krohn MA, Hillier SL, et al. Characteristics of women in preterm labor associated with elevated C-reactive protein levels. Obstet Gynecol. 1993;82(4 Pt 1):509–514.
  • Vogel I, Thorsen P, Curry A, et al. Biomarkers for the prediction of preterm delivery. Acta Obstet Gynecol Scand. 2005;84(6):516–525.
  • Trochez-Martinez RD, Smith P, Lamont RF. Use of C-reactive protein as a predictor of chorioamnionitis in preterm prelabour rupture of membranes: a systematic review. BJOG. 2007;114(7):796–801.
  • Kayem G, Maillard F, Schmitz T, et al. Prediction of clinical infection in women with preterm labour with intact membranes: a score based on ultrasonographic, clinical and biological markers. Eur J Obstet Gynecol Reprod Biol. 2009;145(1):36–40.
  • van de Laar R, van der Ham DP, Oei SG, et al. Accuracy of C-reactive protein determination in predicting chorioamnionitis and neonatal infection in pregnant women with premature rupture of membranes: a systematic review. Eur J Obstet Gynecol Reprod Biol. 2009;147(2):124–129.
  • Popowski T, Goffinet F, Batteux F, et al. [Prediction of maternofetal infection in preterm premature rupture of membranes: serum maternal markers]. Gynecol Obstet Fertil. 2011;39(5):302–308.
  • Oh KJ, Park KH, Kim SN, et al. Predictive value of intra-amniotic and serum markers for inflammatory lesions of preterm placenta. Placenta. 2011;32(10):732–736.
  • Cobo T, Tsiartas P, Kacerovsky M, et al. Maternal inflammatory response to microbial invasion of the amniotic cavity: analyses of multiple proteins in the maternal serum. Acta Obstet Gynecol Scand. 2013;92(1):61–68.
  • Dulay AT, Buhimschi IA, Zhao G, et al. Compartmentalization of acute phase reactants interleukin-6, C-Reactive protein and procalcitonin as biomarkers of intra-amniotic infection and chorioamnionitis. Cytokine. 2015;76(2):236–243.
  • Stepan M, Cobo T, Musilova I, et al. Maternal serum C-Reactive protein in women with preterm prelabor rupture of membranes. PLOS One. 2016;11(3):e0150217.
  • Musilova I, Kacerovsky M, Stepan M, et al. Maternal serum C-reactive protein concentration and intra-amniotic inflammation in women with preterm prelabor rupture of membranes. PLoS ONE. 2017;12(8):e0182731.
  • Rizzo G, Capponi A, Vlachopoulou A, et al. The diagnostic value of interleukin-8 and fetal fibronectin concentrations in cervical secretions in patients with preterm labor and intact membranes. J Perinat Med. 1997;25(6):461–468.
  • Rizzo G, Capponi A, Vlachopoulou A, et al. Ultrasonographic assessment of the uterine cervix and interleukin-8 concentrations in cervical secretions predict intrauterine infection in patients with preterm labor and intact membranes. Ultrasound Obstet Gynecol. 1998;12(2):86–92.
  • Jun JK, Yoon BH, Romero R, et al. Interleukin 6 determinations in cervical fluid have diagnostic and prognostic value in preterm premature rupture of membranes. Am J Obstet Gynecol. 2000;183(4):868–873.
  • Hitti J, Hillier SL, Agnew KJ, et al. Vaginal indicators of amniotic fluid infection in preterm labor. Obstet Gynecol. 2001;97(2):211–219.
  • Di Naro E, Ghezzi F, Raio L, et al. C-reactive protein in vaginal fluid of patients with preterm premature rupture of membranes. Acta Obstet Gynecol Scand. 2003;82(12):1072–1079.
  • Holst RM, Mattsby-Baltzer I, Wennerholm UB, et al. Interleukin-6 and interleukin-8 in cervical fluid in a population of swedish women in preterm labor: relationship to microbial invasion of the amniotic fluid, intra-amniotic inflammation, and preterm delivery. Acta Obstet Gynecol Scand. 2005;84(6):551–557.
  • Shim SS, Romero R, Jun JK, et al. C-reactive protein concentration in vaginal fluid as a marker for intra-amniotic inflammation/infection in preterm premature rupture of membranes. J Matern Fetal Neonatal Med. 2005;18(6):417–422.
  • Kacerovsky M, Musilova I, Jacobsson B, et al. Cervical fluid IL-6 and IL-8 levels in pregnancies complicated by preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2015;28(2):134–140.
  • Kunze M, Klar M, Morfeld CA, et al. Cytokines in noninvasively obtained amniotic fluid as predictors of fetal inflammatory response syndrome. Am J Obstet Gynecol. 2016;215(1):96.e1-8–96.e8.
  • Andrys C, Musilova I, Drahosova M, et al. Cervical fluid calreticulin and cathepsin-G in pregnancies complicated by preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2018;31(4):481–488.
  • Janku P, Kacerovsky M, Zednikova B, et al. Pentraxin 3 in noninvasively obtained cervical fluid samples from pregnancies complicated by preterm prelabor rupture of membranes. Fetal Diagn Ther. 2019 May;46(6):402–410.
  • Parry S, Leite R, Esplin MS, et al. Cervicovaginal fluid proteomic analysis to identify potential biomarkers for preterm birth. Am J Obstet Gynecol. 2020;222(5):493 e1–493 e13.
  • Oh KJ, Lee JH, Romero R, et al. A new rapid bedside test to diagnose and monitor intra-amniotic inflammation in preterm PROM using transcervically collected fluid. Am J Obstet Gynecol. 2020;223(3):423.e1–423.e15.
  • Polat IH, Marin S, Ríos J, et al. Exploratory and confirmatory analysis to investigate the presence of vaginal metabolome expression of microbial invasion of the amniotic cavity in women with preterm labor using high-performance liquid chromatography. Am J Obstet Gynecol. 2021;224(1):90.e1-90–e9.
  • Benattar C, Taieb J, Fernandez H, et al. Rapid fetal fibronectin swab-test in preterm labor patients treated by betamimetics. Eur J Obstet Gynecol Reprod Biol. 1997;72(2):131–135.
  • Lu GC, Goldenberg RL, Cliver SP, et al. Vaginal fetal fibronectin levels and spontaneous preterm birth in symptomatic women. Obstet Gynecol. 2001;97(2):225–228.
  • Abbott DS, Radford SK, Seed PT, et al. Evaluation of a quantitative fetal fibronectin test for spontaneous preterm birth in symptomatic women. Am J Obstet Gynecol. 2013;208(2):122 e1–6.
  • Kuhrt K, Hezelgrave N, Foster C, et al. Development and validation of a tool incorporating quantitative fetal fibronectin to predict spontaneous preterm birth in symptomatic women. Ultrasound Obstet Gynecol. 2016;47(2):210–216.
  • Levine LD, Downes KL, Romero JA, et al. Quantitative fetal fibronectin and cervical length in symptomatic women: results from a prospective blinded cohort study. J Matern Fetal Neonatal Med. 2018;15:1–9.
  • Ravi M, Beljorie M, El Masry K. Evaluation of the quantitative fetal fibronectin test and PAMG-1 test for the prediction of spontaneous preterm birth in patients with signs and symptoms suggestive of preterm labor. J Matern Fetal Neonatal Med. 2019;32(23):3909–3914.
  • Conde-Agudelo A, Romero R. Prediction of preterm birth in twin gestations using biophysical and biochemical tests. Am J Obstet Gynecol. 2014;211(6):583–595.
  • Dawes LK, Prentice LR, Huang Y, et al. The biomarkers for preterm birth Study-A prospective observational study comparing the impact of vaginal biomarkers on clinical practice when used in women with symptoms of preterm labor. Acta Obstet Gynecol Scand. 2020;99(2):249–258.
  • Mahomed K, Ibiebele I, Fraser C, et al. Predictive value of the quantitative fetal fibronectin levels for the management of women presenting with threatened preterm labour – a revised cut off level: a retrospective cohort study. European Journal of Obstetrics & Gynecology and Reproductive Biology: X. 2019;4:100079.
  • Oh KJ, Romero R, Park JY, et al. A high concentration of fetal fibronectin in cervical secretions increases the risk of intra-amniotic infection and inflammation in patients with preterm labor and intact membranes. J Perinat Med. 2019;47(3):288–303.
  • Skrablin S, Lovric H, Banovic V, et al. Maternal plasma interleukin-6, interleukin-1beta and C-reactive protein as indicators of tocolysis failure and neonatal outcome after preterm delivery. J Matern Fetal Neonatal Med. 2007;20(4):335–341.
  • Park KH, Lee SY, Kim SN, et al. Prediction of imminent preterm delivery in women with preterm premature rupture of membranes. J Perinat Med. 2011;40(2):151–157.
  • Kwak DW, Cho HY, Kwon JY, et al. Usefulness of maternal serum C-reactive protein with vaginal Ureaplasma urealyticum as a marker for prediction of imminent preterm delivery and chorioamnionitis in patients with preterm labor or preterm premature rupture of membranes. J Perinat Med. 2015;43(4):409–415.
  • Hadzi-Legal M, Markova AD, Stefanovic M, et al. Combination of selected biochemical markers and cervical length in the prediction of impending preterm delivery in symptomatic patients. Clin Exp Obstet Gynecol. 2016;43(1):154–160.
  • Lucaroni F, Morciano L, Rizzo G, et al. Biomarkers for predicting spontaneous preterm birth: an umbrella systematic review. J Matern Fetal Neonatal Med. 2018;31(6):726–734.
  • Higgins RD, Saade G, Polin RA, Chorioamnionitis Workshop Participants, et al. Evaluation and management of women and newborns with a maternal diagnosis of chorioamnionitis: Summary of a workshop. Obstet Gynecol. 2016;127(3):426–436.
  • Costa-Castro T, Zhao DP, Lipa M, et al. Velamentous cord insertion in dichorionic and monochorionic twin pregnancies – does it make a difference? Placenta. 2016;42:87–92.
  • Yoon BH, Yang SH, Jun JK, et al. Maternal blood C-reactive protein, white blood cell count, and temperature in preterm labor: a comparison with amniotic fluid white blood cell count. Obstet Gynecol. 1996;87(2):231–237.
  • Yoon BH, Romero R, Moon JB, et al. The frequency and clinical significance of intra-amniotic inflammation in patients with a positive cervical fetal fibronectin. Am J Obstet Gynecol. 2001;185(5):1137–1142.
  • Kim SM, Romero R, Lee J, et al. Gastric fluid versus amniotic fluid analysis for the identification of intra-amniotic infection due to ureaplasma species. J Matern Fetal Neonatal Med. 2016;29(16):2579–2587.
  • Park JY, Romero R, Lee J, et al. An elevated amniotic fluid prostaglandin F2alpha concentration is associated with intra-amniotic inflammation/infection, and clinical and histologic chorioamnionitis, as well as impending preterm delivery in patients with preterm labor and intact membranes. J Matern Fetal Neonatal Med. 2016;29(16):2563–2572.
  • Oh KJ, Hong JS, Romero R, et al. The frequency and clinical significance of intra-amniotic inflammation in twin pregnancies with preterm labor and intact membranes. J Matern Fetal Neonatal Med. 2017;11:1–15.
  • Yoon BH, Jun JK, Park KH, et al. Serum C-reactive protein, white blood cell count, and amniotic fluid white blood cell count in women with preterm premature rupture of membranes. Obstet Gynecol. 1996;88(6):1034–1040.
  • Lee SE, Romero R, Kim CJ, et al. Funisitis in term pregnancy is associated with microbial invasion of the amniotic cavity and intra-amniotic inflammation. J Matern Fetal Neonatal Med. 2006;19(11):693–697.
  • Gibbs RS, Castillo MS, Rodgers PJ. Management of acute chorioamnionitis. Am J Obstet Gynecol. 1980;136(6):709–713.
  • Gibbs RS, Blanco JD, St Clair PJ, et al. Quantitative bacteriology of amniotic fluid from women with clinical intraamniotic infection at term. J Infect Dis. 1982;145(1):1–8.
  • Romero R, Miranda J, Kusanovic JP, et al. Clinical chorioamnionitis at term I: microbiology of the amniotic cavity using cultivation and molecular techniques. J Perinat Med. 2015;43(1):19–36.
  • Romero R, Chaemsaithong P, Korzeniewski SJ, et al. Clinical chorioamnionitis at term II: the intra-amniotic inflammatory response. J Perinat Med. 2016;44(1):5–22.
  • Romero R, Chaemsaithong P, Docheva N, et al. Clinical chorioamnionitis at term V: umbilical cord plasma cytokine profile in the context of a systemic maternal inflammatory response. J Perinat Med. 2016;44(1):53–76.
  • Romero R, Chaemsaithong P, Docheva N, et al. Clinical chorioamnionitis at term VI: acute chorioamnionitis and funisitis according to the presence or absence of microorganisms and inflammation in the amniotic cavity. J Perinat Med. 2016;44(1):33–51.
  • Martinez-Varea A, Romero R, Xu Y, et al. Clinical chorioamnionitis at term VII: the amniotic fluid cellular immune response. J Perinat Med. 2017;45(5):523–538.
  • Chaiyasit N, Romero R, Chaemsaithong P, et al. Clinical chorioamnionitis at term VIII: a rapid MMP-8 test for the identification of intra-amniotic inflammation. J Perinat Med. 2017;45(5):539–550.
  • Gallen RS, Gambino SR. Evaluation of laboratory tests: Comparing sensitivity and specificity data. In: Beyond normality: the predictive value and efficiency of medical diagnoses. New York: John Wiley. 1975. p. 131–140.
  • Feinberg RF, Kliman HJ, Lockwood CJ. Is oncofetal fibronectin a trophoblast glue for human implantation? Am J Pathol. 1991;138(3):537–543.
  • Lockwood CJ, Senyei AE, Dische MR, et al. Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery. N Engl J Med. 1991;325(10):669–674.
  • Casey ML, MacDonald PC. Biomolecular processes in the initiation of parturition: decidual activation. Clin Obstet Gynecol. 1988;31(3):533–552.
  • Romero R, Espinoza J, Kusanovic JP, et al. The preterm parturition syndrome. BJOG. 2006;113(Suppl 3):17–42.
  • Menon R, Fortunato SJ. Infection and the role of inflammation in preterm premature rupture of the membranes. Best Pract Res Clin Obstet Gynaecol. 2007;21(3):467–478.
  • van der Krogt L, Ridout AE, Seed PT, et al. Placental inflammation and its relationship to cervicovaginal fetal fibronectin in preterm birth. Eur J Obstet Gynecol Reprod Biol. 2017;214:173–177.
  • Leeson SC, Maresh MJ, Martindale EA, et al. Detection of fetal fibronectin as a predictor of preterm delivery in high risk asymptomatic pregnancies. Br J Obstet Gynaecol. 1996;103(1):48–53.
  • Tolino A, Ronsini S, Zullo F, et al. Fetal fibronectin as a screening test for premature delivery in multiple pregnancies. Int J Gynaecol Obstet. 1996;52(1):3–7.
  • Goldenberg RL, Mercer BM, Meis PJ, et al. The preterm prediction study: fetal fibronectin testing and spontaneous preterm birth. NICHD maternal fetal medicine units network. Obstet Gynecol. 1996;87(5 Pt 1):643–648.
  • Morrison JC, Naef RW, 3rd, Botti JJ, et al. Prediction of spontaneous preterm birth by fetal fibronectin and uterine activity. Obstet Gynecol. 1996;87(5 Pt 1):649–655.
  • Di Stefano L, Carta G, Di Paolantonio L, et al. Preterm delivery: predictive value of cervico-vaginal fetal fibronectin. Clin Exp Obstet Gynecol. 1999;26(3–4):187–189.
  • Goldenberg RL, Iams JD, Das A, et al. The preterm prediction study: sequential cervical length and fetal fibronectin testing for the prediction of spontaneous preterm birth. National institute of child health and human development maternal-fetal medicine units network. Am J Obstet Gynecol. 2000;182(3):636–643.
  • Goldenberg RL, Iams JD, Mercer BM, et al. The preterm prediction study: toward a multiple-marker test for spontaneous preterm birth. Am J Obstet Gynecol. 2001;185(3):643–651.
  • Morrison JC, Allbert JR, McLaughlin BN, et al. Oncofetal fibronectin in patients with false labor as a predictor of preterm delivery. Am J Obstet Gynecol. 1993;168(2):538–542.
  • Iams JD, Casal D, McGregor JA, et al. Fetal fibronectin improves the accuracy of diagnosis of preterm labor. Am J Obstet Gynecol. 1995;173(1):141–145.
  • Parker J, Bell R, Brennecke S. Fetal fibronectin in the cervicovaginal fluid of women with threatened preterm labour as a predictor of delivery before 34 weeks’ gestation. Aust N Z J Obstet Gynaecol. 1995;35(3):257–261.
  • Goldenberg RL, Thom E, Moawad AH, et al. The preterm prediction study: fetal fibronectin, bacterial vaginosis, and peripartum infection. NICHD maternal fetal medicine units network. Obstet Gynecol. 1996;87(5 Pt 1):656–660.
  • Malak TM, Sizmur F, Bell SC, et al. Fetal fibronectin in cervicovaginal secretions as a predictor of preterm birth. BJOG. 1996;103(7):648–653.
  • Greenhagen JB, Van Wagoner J, Dudley D, et al. Value of fetal fibronectin as a predictor of preterm delivery for a low-risk population. Am J Obstet Gynecol. 1996;175(4):1054–1056.
  • Langer B, Boudier E, Schlaeder G. Cervico-vaginal fetal fibronectin: predictive value during false labor. Acta Obstet Gynecol Scand. 1997;76(3):218–221.
  • Chuileannain FN, Bell R, Brennecke S. Cervicovaginal fetal fibronectin testing in threatened preterm labour–translating research findings into clinical practice. Aust N Z J Obstet Gynaecol. 1998;38(4):399–402.
  • Goepfert AR, Goldenberg RL, Mercer B, et al. The preterm prediction study: quantitative fetal fibronectin values and the prediction of spontaneous preterm birth. The national institute of child health and human development maternal-fetal medicine units network. Am J Obstet Gynecol. 2000;183(6):1480–1483.
  • Kurtzman J, Chandiramani M, Briley A, et al. Quantitative fetal fibronectin screening in asymptomatic high-risk patients and the spectrum of risk for recurrent preterm delivery. Am J Obstet Gynecol. 2009;200(3):263 e1–6.
  • Foster C, Shennan AH. Fetal fibronectin as a biomarker of preterm labor: a review of the literature and advances in its clinical use. Biomark Med. 2014;8(4):471–484.
  • Abbott DS, Hezelgrave NL, Seed PT, et al. Quantitative fetal fibronectin to predict preterm birth in asymptomatic women at high risk. Obstet Gynecol. 2015;125(5):1168–1176.
  • Hezelgrave NL, Abbott DS, Radford SK, et al. Quantitative fetal fibronectin at 18 weeks of gestation to predict preterm birth in asymptomatic high-risk women. Obstet Gynecol. 2016;127(2):255–263
  • Centra M, Coata G, Picchiassi E, et al. Evaluation of quantitative fFn test in predicting the risk of preterm birth. J Perinat Med. 2017;45(1):91–98.
  • Esplin MS, Elovitz MA, Iams JD, nuMoM2b Network, et al. Predictive accuracy of serial transvaginal cervical lengths and quantitative vaginal fetal fibronectin levels for spontaneous preterm birth among nulliparous women. JAMA. 2017;317(10):1047–1056.
  • Ridout AE, Ibeto LA, Ross GN, et al. Cervical length and quantitative fetal fibronectin in the prediction of spontaneous preterm birth in asymptomatic women with congenital uterine anomaly. Am J Obstet Gynecol. 2019;221(4):341 e1–341 e9.
  • Nguyen AD, Liu CZ, Lehner C, et al. The efficacy of quantitative fetal fibronectin in predicting spontaneous preterm birth in symptomatic women: a retrospective cohort study. Aust NZ J Obst Gynaeco. 2019;59(5):656–661.
  • Towers CV, Yates A, Zite N, et al. Incidence of fever in labor and risk of neonatal sepsis. Am J Obstet Gynecol. 2017;216(6):596 e1–596 e5.
  • Committee on Obstetric P. Committee opinion no. 712: intrapartum management of intraamniotic infection. Obstet Gynecol. 2017;130(2):e95–e101.
  • Hameed C, Tejani N, Verma UL, et al. Silent chorioamnionitis as a cause of preterm labor refractory to tocolytic therapy. Am J Obstet Gynecol. 1984;149(7):726–730.
  • Murtha AP, Sinclair T, Hauser ER, et al. Maternal serum cytokines in preterm premature rupture of membranes. Obstet Gynecol. 2007;109(1):121–127.
  • Gulati S, Agrawal S, Raghunandan C, et al. Maternal serum interleukin-6 and its association with clinicopathological infectious morbidity in preterm premature rupture of membranes: a prospective cohort study. J Matern Fetal Neonatal Med. 2012;25(8):1428–1432.
  • Gulati S, Bhatnagar S, Raghunandan C, et al. Interleukin-6 as a predictor of subclinical chorioamnionitis in preterm premature rupture of membranes. Am J Reprod Immunol. 2012;67(3):235–240.
  • Canzoneri BJ, Grotegut CA, Swamy GK, et al. Maternal serum interleukin-6 levels predict impending funisitis in preterm premature rupture of membranes after completion of antibiotics. J Matern Fetal Neonatal Med. 2012;25(8):1329–1332.
  • Park H, Park KH, Kim YM, et al. Plasma inflammatory and immune proteins as predictors of intra-amniotic infection and spontaneous preterm delivery in women with preterm labor: a retrospective study. BMC Pregnancy Childbirth. 2018;18(1):146.
  • Romero R, Chaemsaithong P, Korzeniewski SJ, et al. Clinical chorioamnionitis at term III: how well do clinical criteria perform in the identification of proven intra-amniotic infection? J Perinat Med. 2016;44(1):23–32.
  • Romero R, Chaemsaithong P, Docheva N, et al. Clinical chorioamnionitis at term IV: the maternal plasma cytokine profile. J Perinat Med. 2016;44(1):77–98.
  • Musilova I, Pliskova L, Gerychova R, 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 One. 2017;12(12):e0189394.
  • Maki Y, Furukawa S, Nakayama T, et al. Clinical chorioamnionitis criteria are not sufficient for predicting intra-amniotic infection. J Matern Fetal Neonatal Med. 2020;8:1–6.
  • Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous premature delivery. National institute of child health and human development maternal fetal medicine unit network. N Engl J Med. 1996;334(9):567–573.
  • Colombo DF, Iams JD. Cervical length and preterm labor. Clin Obstet Gynecol. 2000;43(4):735–745.
  • Hibbard JU, Tart M, Moawad AH. Cervical length at 16-22 weeks’ gestation and risk for preterm delivery. Obstet Gynecol. 2000;96(6):972–978.
  • Heath VC, Daskalakis G, Zagaliki A, et al. Cervicovaginal fibronectin and cervical length at 23 weeks of gestation: relative risk of early preterm delivery. BJOG. 2000;107(10):1276–1281.
  • Hassan SS, Romero R, Berry SM, et al. Patients with an ultrasonographic cervical length < or =15 mm have nearly a 50% risk of early spontaneous preterm delivery. Am J Obstet Gynecol. 2000;182(6):1458–1467.
  • Gomez R, Romero R, Nien JK, et al. A short cervix in women with preterm labor and intact membranes: a risk factor for microbial invasion of the amniotic cavity. Am J Obstet Gynecol. 2005;192(3):678–689.
  • Iams JD, Cebrik D, Lynch C, et al. The rate of cervical change and the phenotype of spontaneous preterm birth. Am J Obstet Gynecol. 2011;205(2):130 e1–6.
  • Conde-Agudelo A, Romero R. Predictive accuracy of changes in transvaginal sonographic cervical length over time for preterm birth: a systematic review and metaanalysis. Am J Obstet Gynecol. 2015;213(6):789–801.
  • Hernandez-Andrade E, Garcia M, Ahn H, et al. Strain at the internal cervical os assessed with quasi-static elastography is associated with the risk of spontaneous preterm delivery at </=34 weeks of gestation. J Perinat Med. 2015;43(6):657–666.
  • Hadzi-Lega M, Markova AD, Stefanovic M, et al. Correlation of cervical length, fetal fibronectin, phIGFBP-1, and cytokines in spontaneous preterm birth up to 14 days from sampling. J Perinat Med. 2015;43(5):545–551.
  • Nikolova T, Bayev O, Nikolova N, et al. Comparison of a novel test for placental alpha microglobulin-1 with fetal fibronectin and cervical length measurement for the prediction of imminent spontaneous preterm delivery in patients with threatened preterm labor. J Perinat Med. 2015;43(4):395–402.
  • Kiefer DG, Peltier MR, Keeler SM, et al. Efficacy of midtrimester short cervix interventions is conditional on intraamniotic inflammation. Am J Obstet Gynecol. 2016;214(2):276.e1-276–e6.
  • Vintzileos AM, Visser GH. Interventions for women with mid-trimester short cervix: which ones work? Ultrasound Obstet Gynecol. 2017;49(3):295–300.
  • Sharvit M, Weiss R, Ganor Paz Y, et al. Vaginal examination vs. cervical length - which is superior in predicting preterm birth? J Perinat Med. 2017;45(8):977–983.
  • Berghella V, Palacio M, Ness A, et al. Cervical length screening for prevention of preterm birth in singleton pregnancy with threatened preterm labor: systematic review and Meta-analysis of randomized controlled trials using individual patient-level data. Ultrasound Obstet Gynecol. 2017;49(3):322–329.
  • Nikolova T, Uotila J, Nikolova N, et al. Prediction of spontaneous preterm delivery in women presenting with premature labor: a comparison of placenta alpha microglobulin-1, phosphorylated insulin-like growth factor binding protein-1, and cervical length. Am J Obstet Gynecol. 2018;219(6):610.e1–610.e9.
  • Maia MC, Nomura R, Mendonca F, et al. Is cervical length evaluated by transvaginal ultrasonography helpful in detecting true preterm labor? J Matern Fetal Neonatal Med. 2020;33(17):2902–2908.
  • Gudicha DW, Romero R, Kabiri D, et al. Personalized assessment of cervical length improves prediction of spontaneous preterm birth: a standard and a percentile calculator. Am J Obstet Gynecol. 2021;224(3):288.e1–288.e17.
  • Hassan S, Romero R, Hendler I, et al. A sonographic short cervix as the only clinical manifestation of intra-amniotic infection. J Perinat Med. 2006;34(1):13–19.
  • Vaisbuch E, Hassan SS, Mazaki-Tovi S, et al. Patients with an asymptomatic short cervix (<or = 15 mm) have a high rate of subclinical intraamniotic inflammation: implications for patient counseling. Am J Obstet Gynecol. 2010;202(5):433 e1–8.
  • Jung EY, Park KH, Lee SY, et al. Non-invasive prediction of intra-amniotic infection and/or inflammation in patients with cervical insufficiency or an asymptomatic short cervix (</=15 mm). Arch Gynecol Obstet. 2015;292(3):579–587.
  • Tarca AL, Fitzgerald W, Chaemsaithong P, et al. The cytokine network in women with an asymptomatic short cervix and the risk of preterm delivery. Am J Reprod Immunol. 2017;78(3):e12686.
  • Iams JD, Goldenberg RL, Mercer BM, et al. The preterm prediction study: recurrence risk of spontaneous preterm birth. National institute of child health and human development maternal-fetal medicine units network. Am J Obstet Gynecol. 1998;178(5):1035–1040.
  • Gomez R, Romero R, Medina L, et al. Cervicovaginal fibronectin improves the prediction of preterm delivery based on sonographic cervical length in patients with preterm uterine contractions and intact membranes. Am J Obstet Gynecol. 2005;192(2):350–359.
  • Bruijn M, Vis JY, Wilms FF, et al. Quantitative fetal fibronectin testing in combination with cervical length measurement in the prediction of spontaneous preterm delivery in symptomatic women. BJOG. 2016;123(12):1965–1971.
  • Bruijn MM, Kamphuis EI, Hoesli IM, et al. The predictive value of quantitative fibronectin testing in combination with cervical length measurement in symptomatic women. Am J Obstet Gynecol. 2016;215(6):793.e1-793–e8.
  • Tran TL, Jwala S, Terenna C, et al. Evaluation of additive effect of quantitative fetal fibronectin to cervical length for prediction of spontaneous preterm birth among asymptomatic high-risk women. J Matern Fetal Neonatal Med. 2019;7:1–7.
  • Kacerovsky M, Musilova I, Khatibi A, 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(10):2014–2019.
  • Oh KJ, Romero R, Park JY, et al. The earlier the gestational age, the greater the intensity of the intra-amniotic inflammatory response in women with preterm premature rupture of membranes and amniotic fluid infection by ureaplasma species. J Perinat Med. 2019;47(5):516–527.
  • Yoon BH, Romero R, Park JY, 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. 2019;221(2):142.e1-142–e22.
  • Lee J, Romero R, Kim SM, et al. A new anti-microbial combination prolongs the latency period, reduces acute histologic chorioamnionitis as well as funisitis, and improves neonatal outcomes in preterm PROM. J Matern Fetal Neonatal Med. 2016;29(5):707–720.
  • Lee J, Romero R, Kim SM, et al. A new antibiotic regimen treats and prevents intra-amniotic inflammation/infection in patients with preterm PROM. J Matern Fetal Neonatal Med. 2016;29(17):2727–2737.
  • Kacerovsky M, Romero R, Stepan M, et al. Antibiotic administration reduces the rate of intraamniotic inflammation in preterm prelabor rupture of the membranes. American Journal of Obstetrics and Gynecology. 2020;223(1):114 e1–114 e20.
  • Oh KJ, Romero R, Park JY, et al. Evidence that antibiotic administration is effective in the treatment of a subset of patients with intra-amniotic infection/inflammation presenting with cervical insufficiency. Am J Obstet Gynecol. 2019;221(2):140 e1–140 e18.
  • Espinoza J, Goncalves LF, Romero R, et al. The prevalence and clinical significance of amniotic fluid 'sludge’ in patients with preterm labor and intact membranes. Ultrasound Obstet Gynecol. 2005;25(4):346–352.
  • Kiefer DG, Keeler SM, Rust OA, et al. Is midtrimester short cervix a sign of intraamniotic inflammation? Am J Obstet Gynecol. 2009;200(4):374 e1–5.
  • Yoneda N, Yoneda S, Niimi H, et al. Sludge reflects intra-amniotic inflammation with or without microorganisms. Am J Reprod Immunol. 2018;79(2):e12807.
  • Kusanovic JP, Romero R, Martinovic C, et al. Transabdominal collection of amniotic fluid "sludge" and identification of Candida albicans intra-amniotic infection. J Matern Fetal Neonatal Med. 2018;31(10):1279–1284.
  • Pustotina O. Effects of antibiotic therapy in women with the amniotic fluid "sludge" at 15-24 weeks of gestation on pregnancy outcomes. J Matern Fetal Neonatal Med. 2020;33(17):3016–3027.
  • Dinglas C, Chavez M, Vintzileos A. Resolution of intra-amniotic sludge after antibiotic administration in a patient with short cervix and recurrent mid-trimester loss. Am J Obstet Gynecol. 2019;221(2):159.

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