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 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

20 Citations (Scopus)

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

Fingerprint

Premature Obstetric Labor
Interleukin-6
Membranes
Area Under Curve
Amniocentesis
Proteins
Insulin-Like Growth Factor Binding Protein 1
alpha-Fetoproteins
Ligands
Chemokine CXCL1
Ribosomal DNA
ROC Curve
Patient Selection
Biomarkers
Logistic Models
Enzyme-Linked Immunosorbent Assay
Mothers
Prospective Studies
Morbidity
Sensitivity and Specificity

Keywords

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

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Medicine(all)

Cite this

Detection of microbial invasion of the amniotic cavity by analysis of cervicovaginal proteins in women with preterm labor and intact membranes. / Combs, C. Andrew; Garite, Thomas J.; Lapidus, Jodi A.; Lapointe, Jerome P.; Gravett, Michael; Rael, Julie; Amon, Erol; Baxter, Jason K.; Brady, Kim; Clewell, William; Eddleman, Keith A.; Fortunato, Stephen; Franco, Albert; Haas, David; Heyborne, Kent; Hickok, Durlin E.; How, Helen Y.; Luthy, David; Miller, Hugh; Nageotte, Michael; Pereira, Leonardo; Porreco, Richard; Robilio, Peter A.; Simhan, Hyagriv; Sullivan, Scott A.; Trofatter, Kenneth; Westover, Thomas.

In: American Journal of Obstetrics and Gynecology, Vol. 212, No. 4, 01.04.2015, p. 482.e1-482.e12.

Research output: Contribution to journalArticle

Combs, CA, Garite, TJ, Lapidus, JA, Lapointe, JP, Gravett, M, Rael, J, Amon, E, Baxter, JK, Brady, K, Clewell, W, Eddleman, KA, Fortunato, S, Franco, A, Haas, D, Heyborne, K, Hickok, DE, How, HY, Luthy, D, Miller, H, Nageotte, M, Pereira, L, Porreco, R, Robilio, PA, Simhan, H, Sullivan, SA, Trofatter, K & 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, vol. 212, no. 4, pp. 482.e1-482.e12. https://doi.org/10.1016/j.ajog.2015.02.007
Combs, C. Andrew ; Garite, Thomas J. ; Lapidus, Jodi A. ; Lapointe, Jerome P. ; Gravett, Michael ; Rael, Julie ; Amon, Erol ; Baxter, Jason K. ; Brady, Kim ; Clewell, William ; Eddleman, Keith A. ; Fortunato, Stephen ; Franco, Albert ; Haas, David ; Heyborne, Kent ; Hickok, Durlin E. ; How, Helen Y. ; Luthy, David ; Miller, Hugh ; Nageotte, Michael ; Pereira, Leonardo ; Porreco, Richard ; Robilio, Peter A. ; Simhan, Hyagriv ; Sullivan, Scott A. ; Trofatter, Kenneth ; Westover, Thomas. / Detection of microbial invasion of the amniotic cavity by analysis of cervicovaginal proteins in women with preterm labor and intact membranes. In: American Journal of Obstetrics and Gynecology. 2015 ; Vol. 212, No. 4. pp. 482.e1-482.e12.
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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). 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.",
keywords = "biomarkers, cervicovaginal proteins, intraamniotic infection, microbial invasion of amniotic cavity, preterm labor",
author = "Combs, {C. Andrew} and Garite, {Thomas J.} and Lapidus, {Jodi A.} and Lapointe, {Jerome P.} and Michael Gravett and Julie Rael and Erol Amon and Baxter, {Jason K.} and Kim Brady and William Clewell and Eddleman, {Keith A.} and Stephen Fortunato and Albert Franco and David Haas and Kent Heyborne and Hickok, {Durlin E.} and How, {Helen Y.} and David Luthy and Hugh Miller and Michael Nageotte and Leonardo Pereira and Richard Porreco and Robilio, {Peter A.} and Hyagriv Simhan and Sullivan, {Scott A.} and Kenneth Trofatter and Thomas Westover",
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TY - JOUR

T1 - Detection of microbial invasion of the amniotic cavity by analysis of cervicovaginal proteins in women with preterm labor and intact membranes

AU - Combs, C. Andrew

AU - Garite, Thomas J.

AU - Lapidus, Jodi A.

AU - Lapointe, Jerome P.

AU - Gravett, Michael

AU - Rael, Julie

AU - Amon, Erol

AU - Baxter, Jason K.

AU - Brady, Kim

AU - Clewell, William

AU - Eddleman, Keith A.

AU - Fortunato, Stephen

AU - Franco, Albert

AU - Haas, David

AU - Heyborne, Kent

AU - Hickok, Durlin E.

AU - How, Helen Y.

AU - Luthy, David

AU - Miller, Hugh

AU - Nageotte, Michael

AU - Pereira, Leonardo

AU - Porreco, Richard

AU - Robilio, Peter A.

AU - Simhan, Hyagriv

AU - Sullivan, Scott A.

AU - Trofatter, Kenneth

AU - Westover, Thomas

PY - 2015/4/1

Y1 - 2015/4/1

N2 - 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.

AB - 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.

KW - biomarkers

KW - cervicovaginal proteins

KW - intraamniotic infection

KW - microbial invasion of amniotic cavity

KW - preterm labor

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