title: Detection of microbial invasion of the amniotic cavity by analysis of cervicovaginal proteins in women with preterm labor and intact membranes.
abstract: OBJECTIVE
  Microbial invasion of the amniotic cavity (MIAC) is common in early preterm labor and is associated with maternal and neonatal infectious morbidity. MIAC is usually occult and is reliably detected only with amniocentesis. We sought to develop a noninvasive test to predict MIAC based on protein biomarkers in cervicovaginal fluid (CVF) in a cohort of women with preterm labor (phase 1) and to validate the test in an independent cohort (phase 2).
  
  
  METHODS
  This was a prospective study of women with preterm labor who had amniocentesis to screen for MIAC. MIAC was defined by positive culture and/or 16S ribosomal DNA results. Nine candidate CVF proteins were analyzed by enzyme-linked immunosorbent assay. Logistic regression was used to identify combinations of up to 3 proteins that could accurately classify the phase 1 cohort (N = 108) into those with or without MIAC. The best models, selected by area under the curve (AUC) of the receiver operating characteristic curve in phase 1, included various combinations of interleukin (IL)-6, chemokine (C-X-C motif) ligand 1 (CXCL1), alpha fetoprotein, and insulin-like growth factor binding protein-1. Model performance was then tested in the phase 2 cohort (N = 306).
  
  
  RESULTS
  MIAC was present in 15% of cases in phase 1 and 9% in phase 2. A 3-marker CVF model using IL-6 plus CXCL1 plus insulin-like growth factor binding protein-1 had AUC 0.87 in phase 1 and 0.78 in phase 2. Two-marker models using IL-6 plus CXCL1 or alpha fetoprotein plus CXCL1 performed similarly in phase 2 (AUC 0.78 and 0.75, respectively), but were not superior to CVF IL-6 alone (AUC 0.80). A cutoff value of CVF IL-6 ≥463 pg/mL (which had 81% sensitivity in phase 1) predicted MIAC in phase 2 with sensitivity 79%, specificity 78%, positive predictive value 38%, and negative predictive value 97%.
  
  
  CONCLUSIONS
  High levels of IL-6 in CVF are strongly associated with MIAC. If developed into a bedside test or rapid laboratory assay, cervicovaginal IL-6 might be useful in selecting patients in whom the probability of MIAC is high enough to warrant amniocentesis or transfer to a higher level of care. Such a test might also guide selection of potential subjects for treatment trials.
authors: Center for Research, Education, and Quality, Mednax Inc, Sunrise, FL; Obstetrix Medical Group, San Jose, CA. Electronic address: andrewcombs@me.com.
authors: C Andrew
authors: CA
authors: Combs
authors: Center for Research, Education, and Quality, Mednax Inc, Sunrise, FL; University of California, Irvine, School of Medicine, Irvine, CA.
authors: Thomas J
authors: TJ
authors: Garite
authors: Oregon Health and Science University, Portland, OR.
authors: Jodi A
authors: JA
authors: Lapidus
authors: Hologic Inc, Sunnyvale, CA.
authors: Jerome P
authors: JP
authors: Lapointe
authors: University of Washington Medical Center, Seattle, WA; Global Alliance to Prevent Prematurity and Stillbirth, Seattle, WA.
authors: Michael
authors: M
authors: Gravett
authors: Center for Research, Education, and Quality, Mednax Inc, Sunrise, FL; Obstetrix Medical Group, Denver, CO.
authors: Julie
authors: J
authors: Rael
authors: St Louis University School of Medicine, St Louis, MO.
authors: Erol
authors: E
authors: Amon
authors: Thomas Jefferson University, Philadelphia, PA.
authors: Jason K
authors: JK
authors: Baxter
authors: TriHealth Hatton Institute for Research, Cincinnati, OH.
authors: Kim
authors: K
authors: Brady
authors: Obstetrix Medical Group, Phoenix Perinatal Associates, Phoenix, AZ.
authors: William
authors: W
authors: Clewell
authors: Mount Sinai School of Medicine, New York, NY.
authors: Keith A
authors: KA
authors: Eddleman
authors: Perinatal Research Group, Nashville, TN.
authors: Stephen
authors: S
authors: Fortunato
authors: Carolinas Medical Center, Charlotte, NC.
authors: Albert
authors: A
authors: Franco
authors: Indiana University School of Medicine, Indianapolis, IN.
authors: David M
authors: DM
authors: Haas
authors: Obstetrix Medical Group, Denver, CO.
authors: Kent
authors: K
authors: Heyborne
authors: ProteoGenix Inc, Costa Mesa, CA.
authors: Durlin E
authors: DE
authors: Hickok
authors: Norton Healthcare, Louisville, KY.
authors: Helen Y
authors: HY
authors: How
authors: Obstetrix Medical Group, Seattle, WA.
authors: David
authors: D
authors: Luthy
authors: Obstetrix Medical Group, Tucson, AZ.
authors: Hugh
authors: H
authors: Miller
authors: Obstetrix Medical Group, Long Beach, CA.
authors: Michael
authors: M
authors: Nageotte
authors: Oregon Health and Science University, Portland, OR.
authors: Leonardo
authors: L
authors: Pereira
authors: Obstetrix Medical Group, Denver, CO.
authors: Richard
authors: R
authors: Porreco
authors: University of Washington Medical Center, Seattle, WA.
authors: Peter A
authors: PA
authors: Robilio
authors: University of Pittsburgh, Pittsburgh, PA.
authors: Hyagriv
authors: H
authors: Simhan
authors: Medical University of South Carolina, Charleston, SC.
authors: Scott A
authors: SA
authors: Sullivan
authors: University Medical Center, Greenville, SC.
authors: Kenneth
authors: K
authors: Trofatter
authors: Cooper Perinatology Associates, Camden, NJ.
authors: Thomas
authors: T
authors: Westover
mesh_terms: D000328:Adult; D000649:Amniocentesis; D015415:Biomarkers / Q000378:metabolism; D001826:Body Fluids / Q000378:metabolism* / Q000382:microbiology; D002584:Cervix Uteri / Q000378:metabolism* / Q000382:microbiology; D002821:Chorioamnionitis / Q000175:diagnosis* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016015:Logistic Models; D007752:Obstetric Labor, Premature / Q000378:metabolism / Q000382:microbiology*; D011247:Pregnancy; D011446:Prospective Studies; D012372:ROC Curve; D012680:Sensitivity and Specificity; D014621:Vagina / Q000378:metabolism* / Q000382:microbiology
chemical_list: D015415:Biomarkers; C508600:IL6 protein, human; D015850:Interleukin-6
keywords: biomarkers; cervicovaginal proteins; intraamniotic infection; microbial invasion of amniotic cavity; preterm labor