Cervical fluid interleukin 6 and intra-amniotic complications of preterm prelabor rupture of membranes

Abstract Objective: To determine if cervical fluid interleukin (IL)-6 concentrations in women with preterm prelabor rupture of membranes (PPROM) allows identification of microbial invasion of the amniotic cavity (MIAC) and/or intra-amniotic inflammation (IAI). Methods: One hundred forty-four women with singleton pregnancies complicated by PPROM were included in this prospective cohort study. Cervical and amniotic fluids were collected at the time of admission and concentrations of IL-6 were measured using an ELISA and point-of-care test, respectively. Cervical fluid was obtained using a Dacron polyester swab and amniotic fluid was obtained by transabdominal amniocentesis. MIAC was diagnosed based on a positive PCR result for Ureaplasma species, M. hominis, and/or C. trachomatis and/or by positivity for the 16 S rRNA gene. IAI was defined as amniotic fluid point-of-care IL-6 concentrations ≥745 pg/mL. The women were assigned to four subgroups based on the presence of MIAC and/or IAI: microbial-associated IAI (both MIAC and IAI), sterile IAI (IAI alone), MIAC alone, and without either MIAC or IAI. Results: (1) Women with microbial-associated IAI had higher cervical fluid IL-6 concentrations (median 560 pg/mL) than did women with sterile IAI (median 303 pg/mL; p = .001), women with MIAC alone (median 135 pg/mL; p = .0004), and women without MIAC and IAI (median 180 pg/mL; p = .0001). (2) No differences were found in cervical fluid IL-6 concentrations among women with sterile IAI, with MIAC alone, and without MIAC and IAI. (3) A positive correlation was observed between cervical fluid IL-6 concentrations and the amount of Ureaplasma species in amniotic fluid (copies DNA/mL; rho = 0.57, p < .0001). (4) A weak positive correlation was detected between cervical and amniotic fluid IL-6 concentrations (rho = 0.33, p < .0001). Conclusions: The presence of microbial-associated IAI is associated with the highest cervical fluid IL-6 concentrations. Cervical IL-6 can be helpful in the identification of microbial-associated IAI.

[1]  B. Jacobsson,et al.  Amniotic fluid cathepsin-G in pregnancies complicated by the preterm prelabor rupture of membranes , 2017, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[2]  B. Jacobsson,et al.  Intraamniotic inflammation and umbilical cord blood interleukin-6 concentrations in pregnancies complicated by preterm prelabor rupture of membranes , 2017, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[3]  B. Jacobsson,et al.  Amniotic fluid calreticulin in pregnancies complicated by the preterm prelabor rupture of membranes , 2016, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[4]  R. Romero,et al.  HMGB1 Induces an Inflammatory Response in the Chorioamniotic Membranes That Is Partially Mediated by the Inflammasome1 , 2016, Biology of reproduction.

[5]  B. Jacobsson,et al.  Vaginal fluid interleukin-6 concentrations as a point-of-care test is of value in women with preterm prelabor rupture of membranes. , 2016, American journal of obstetrics and gynecology.

[6]  V. Bhandari,et al.  Limiting the Exposure of Select Fetuses to Intrauterine Infection/Inflammation Improves Short-Term Neonatal Outcomes in Preterm Premature Rupture of Membranes , 2016, Fetal Diagnosis and Therapy.

[7]  B. Jacobsson,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 , 2016, Acta obstetricia et gynecologica Scandinavica.

[8]  R. Romero,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 , 2016, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[9]  R. Romero,et al.  A rapid interleukin-6 bedside test for the identification of intra-amniotic inflammation in preterm labor with intact membranes , 2015, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[10]  R. Romero,et al.  Sterile and microbial-associated intra-amniotic inflammation in preterm prelabor rupture of membranes , 2015, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[11]  B. Jacobsson,et al.  Intraamniotic Inflammation in Women with Preterm Prelabor Rupture of Membranes , 2015, PloS one.

[12]  R. Menon,et al.  Cervical Microbiota in Women with Preterm Prelabor Rupture of Membranes , 2015, PloS one.

[13]  Ó. O’Sullivan,et al.  The Effects of Freezing on Faecal Microbiota as Determined Using MiSeq Sequencing and Culture-Based Investigations , 2015, PloS one.

[14]  B. Jacobsson,et al.  Cervical fluid IL-6 and IL-8 levels in pregnancies complicated by preterm prelabor rupture of membranes , 2015, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[15]  G. Saade,et al.  HMGB1 Promotes a p38MAPK Associated Non-Infectious Inflammatory Response Pathway in Human Fetal Membranes , 2014, PloS one.

[16]  B. Jacobsson,et al.  Bedside assessment of amniotic fluid interleukin-6 in preterm prelabor rupture of membranes. , 2014, American journal of obstetrics and gynecology.

[17]  R. Romero,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 , 2014, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[18]  K. Park,et al.  Predictive value of combined cervicovaginal cytokines and gestational age at sampling for intra‐amniotic infection in preterm premature rupture of membranes , 2013, Acta obstetricia et gynecologica Scandinavica.

[19]  R. Romero,et al.  Clinical chorioamnionitis is characterized by changes in the expression of the alarmin HMGB1 and one of its receptors, sRAGE , 2012, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[20]  D. Hougaard,et al.  The impact of the microbial load of genital mycoplasmas and gestational age on the intensity of intraamniotic inflammation. , 2012, American journal of obstetrics and gynecology.

[21]  R. Romero,et al.  Damage-associated molecular patterns (DAMPs) in preterm labor with intact membranes and preterm PROM: a study of the alarmin HMGB1 , 2011, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[22]  B. Jacobsson,et al.  The microbial load with genital mycoplasmas correlates with the degree of histologic chorioamnionitis in preterm PROM. , 2011, American journal of obstetrics and gynecology.

[23]  B. Mercer,et al.  Preterm PROM: prediction, prevention, principles. , 2011, Clinical obstetrics and gynecology.

[24]  Daniel B. DiGiulio,et al.  Prevalence and Diversity of Microbes in the Amniotic Fluid, the Fetal Inflammatory Response, and Pregnancy Outcome in Women with Preterm Pre‐Labor Rupture of Membranes , 2010, American journal of reproductive immunology.

[25]  Thomas P. Mechtler,et al.  The bacterial load of Ureaplasma parvum in amniotic fluid is correlated with an increased intrauterine inflammatory response. , 2010, Diagnostic microbiology and infectious disease.

[26]  Mi Jeong Kim,et al.  Widespread microbial invasion of the chorioamniotic membranes is a consequence and not a cause of intra-amniotic infection , 2009, Laboratory Investigation.

[27]  B. Jacobsson,et al.  Quantification of Ureaplasma urealyticum DNA in the amniotic fluid from patients in PTL and pPROM and its relation to inflammatory cytokine levels , 2009, Acta obstetricia et gynecologica Scandinavica.

[28]  Daniel B. DiGiulio,et al.  Microbial Prevalence, Diversity and Abundance in Amniotic Fluid During Preterm Labor: A Molecular and Culture-Based Investigation , 2008, PloS one.

[29]  Roberto Romero,et al.  The fetal inflammatory response syndrome. , 1998, American journal of obstetrics and gynecology.

[30]  B. Mercer.  Preterm premature rupture of the membranes: current approaches to evaluation and management. , 2005, Obstetrics and gynecology clinics of North America.

[31]  R. Romero,et al.  Interleukin 6 determinations in cervical fluid have diagnostic and prognostic value in preterm premature rupture of membranes. , 2000, American journal of obstetrics and gynecology.

[32]  G. Rizzo,et al.  Interleukin-6 Concentrations in Cervical Secretions in the Prediction of Intrauterine Infection in Preterm Premature Rupture of the Membranes , 1998, Gynecologic and Obstetric Investigation.

[33]  S. Kenyon,et al.  Preterm premature rupture of membranes. , 2012, Archivos argentinos de pediatria.

[34]  M. Loeffelholz,et al.  PCR primers and probes for the 16S rRNA gene of most species of pathogenic bacteria, including bacteria found in cerebrospinal fluid , 1994, Journal of clinical microbiology.

[35]  R. Romero,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. , 1993, American journal of obstetrics and gynecology.

[36]  R. Romero,et al.  Intraamniotic infection and the onset of labor in preterm premature rupture of the membranes. , 1988, American journal of obstetrics and gynecology.