Detection of microbial invasion of the amniotic cavity by analysis of cervicovaginal proteins in women with preterm labor and intact membranes

C. Andrew Combs, Thomas J. Garite, Jodi A. Lapidus, Jerome P. Lapointe, Michael Gravett, Julie Rael, Erol Amon, Jason K. Baxter, Kim Brady, William Clewell, Keith A. Eddleman, Stephen Fortunato, Albert Franco, David M. Haas, Kent Heyborne, Durlin E. Hickok, Helen Y. How, David Luthy, Hugh Miller, Michael NageotteLeonardo Pereira, Richard Porreco, Peter A. Robilio, Hyagriv Simhan, Scott A. Sullivan, Kenneth Trofatter, Thomas Westover

Research output: Contribution to journalArticle

34 Scopus citations

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). Study Design 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%. Conclusion 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.

Original languageEnglish (US)
Pages (from-to)482.e1-482.e12
JournalAmerican Journal of Obstetrics and Gynecology
Volume212
Issue number4
DOIs
StatePublished - Apr 1 2015

Keywords

  • biomarkers
  • cervicovaginal proteins
  • intraamniotic infection
  • microbial invasion of amniotic cavity
  • preterm labor

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Medicine(all)

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    Combs, C. A., Garite, T. J., Lapidus, J. A., Lapointe, J. P., Gravett, M., Rael, J., Amon, E., Baxter, J. K., Brady, K., Clewell, W., Eddleman, K. A., Fortunato, S., Franco, A., Haas, D. M., Heyborne, K., Hickok, D. E., How, H. Y., Luthy, D., Miller, H., ... Westover, T. (2015). Detection of microbial invasion of the amniotic cavity by analysis of cervicovaginal proteins in women with preterm labor and intact membranes. American Journal of Obstetrics and Gynecology, 212(4), 482.e1-482.e12. https://doi.org/10.1016/j.ajog.2015.02.007