C Andrew Combs1, Thomas J Garite2, Jodi A Lapidus3, Jerome P Lapointe4, Michael Gravett5, Julie Rael6, Erol Amon7, Jason K Baxter8, Kim Brady9, William Clewell10, Keith A Eddleman11, Stephen Fortunato12, Albert Franco13, David M Haas14, Kent Heyborne15, Durlin E Hickok16, Helen Y How17, David Luthy18, Hugh Miller19, Michael Nageotte20, Leonardo Pereira3, Richard Porreco15, Peter A Robilio21, Hyagriv Simhan22, Scott A Sullivan23, Kenneth Trofatter24, Thomas Westover25. 1. Center for Research, Education, and Quality, Mednax Inc, Sunrise, FL; Obstetrix Medical Group, San Jose, CA. Electronic address: andrewcombs@me.com. 2. Center for Research, Education, and Quality, Mednax Inc, Sunrise, FL; University of California, Irvine, School of Medicine, Irvine, CA. 3. Oregon Health and Science University, Portland, OR. 4. Hologic Inc, Sunnyvale, CA. 5. University of Washington Medical Center, Seattle, WA; Global Alliance to Prevent Prematurity and Stillbirth, Seattle, WA. 6. Center for Research, Education, and Quality, Mednax Inc, Sunrise, FL; Obstetrix Medical Group, Denver, CO. 7. St Louis University School of Medicine, St Louis, MO. 8. Thomas Jefferson University, Philadelphia, PA. 9. TriHealth Hatton Institute for Research, Cincinnati, OH. 10. Obstetrix Medical Group, Phoenix Perinatal Associates, Phoenix, AZ. 11. Mount Sinai School of Medicine, New York, NY. 12. Perinatal Research Group, Nashville, TN. 13. Carolinas Medical Center, Charlotte, NC. 14. Indiana University School of Medicine, Indianapolis, IN. 15. Obstetrix Medical Group, Denver, CO. 16. ProteoGenix Inc, Costa Mesa, CA. 17. Norton Healthcare, Louisville, KY. 18. Obstetrix Medical Group, Seattle, WA. 19. Obstetrix Medical Group, Tucson, AZ. 20. Obstetrix Medical Group, Long Beach, CA. 21. University of Washington Medical Center, Seattle, WA. 22. University of Pittsburgh, Pittsburgh, PA. 23. Medical University of South Carolina, Charleston, SC. 24. University Medical Center, Greenville, SC. 25. Cooper Perinatology Associates, Camden, NJ.
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.
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.
Authors: Roberto Romero; Nardhy Gomez-Lopez; Andrew D Winters; Eunjung Jung; Majid Shaman; Janine Bieda; Bogdan Panaitescu; Percy Pacora; Offer Erez; Jonathan M Greenberg; Madison M Ahmad; Chaur-Dong Hsu; Kevin R Theis Journal: J Perinat Med Date: 2019-11-26 Impact factor: 1.901
Authors: Andrew D Winters; Roberto Romero; Emma Graffice; Nardhy Gomez-Lopez; Eunjung Jung; Tomi Kanninen; Kevin R Theis Journal: J Reprod Immunol Date: 2021-12-08 Impact factor: 4.054
Authors: Lisa M Christian; Lisa M Blair; Kyle Porter; Mary Lower; Rachel M Cole; Martha A Belury Journal: PLoS One Date: 2016-02-09 Impact factor: 3.240