Development and validation of a spontaneous preterm delivery predictor in asymptomatic women

George R. Saade, Kim A. Boggess, Scott A. Sullivan, Glenn R. Markenson, Jay D. Iams, Dean V. Coonrod, Leonardo Pereira, M. Sean Esplin, Larry M. Cousins, Garrett K. Lam, Matthew K. Hoffman, Robert D. Severinsen, Trina Pugmire, Jeff S. Flick, Angela C. Fox, Amir J. Lueth, Sharon R. Rust, Emanuele Mazzola, Chienting Hsu, Max T. DuffordChad L. Bradford, Ilia E. Ichetovkin, Tracey C. Fleischer, Ashoka D. Polpitiya, Gregory C. Critchfield, Paul E. Kearney, J. Jay Boniface, Durlin E. Hickok

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background Preterm delivery remains the leading cause of perinatal mortality. Risk factors and biomarkers have traditionally failed to identify the majority of preterm deliveries. Objective To develop and validate a mass spectrometry-based serum test to predict spontaneous preterm delivery in asymptomatic pregnant women. Study Design A total of 5501 pregnant women were enrolled between 170/7 and 286/7 weeks gestational age in the prospective Proteomic Assessment of Preterm Risk study at 11 sites in the United States between 2011 and 2013. Maternal blood was collected at enrollment and outcomes collected following delivery. Maternal serum was processed by a proteomic workflow, and proteins were quantified by multiple reaction monitoring mass spectrometry. The discovery and verification process identified 2 serum proteins, insulin-like growth factor-binding protein 4 (IBP4) and sex hormone-binding globulin (SHBG), as predictors of spontaneous preterm delivery. We evaluated a predictor using the log ratio of the measures of IBP4 and SHBG (IBP4/SHBG) in a clinical validation study to classify spontaneous preterm delivery cases (0/7 weeks gestational age) in a nested case-control cohort different from subjects used in discovery and verification. Strict blinding and independent statistical analyses were employed. Results The predictor had an area under the receiver operating characteristic curve value of 0.75 and sensitivity and specificity of 0.75 and 0.74, respectively. The IBP4/SHBG predictor at this sensitivity and specificity had an odds ratio of 5.04 for spontaneous preterm delivery. Accuracy of the IBP4/SHBG predictor increased using earlier case-vs-control gestational age cutoffs (eg, 0/7 vs ≥350/7 weeks gestational age). Importantly, higher-risk subjects defined by the IBP4/SHBG predictor score generally gave birth earlier than lower-risk subjects. Conclusion A serum-based molecular predictor identifies asymptomatic pregnant women at risk of spontaneous preterm delivery, which may provide utility in identifying women at risk at an early stage of pregnancy to allow for clinical intervention. This early detection would guide enhanced levels of care and accelerate development of clinical strategies to prevent preterm delivery.

Original languageEnglish (US)
Pages (from-to)633e1-633e24
JournalAmerican Journal of Obstetrics and Gynecology
Volume214
Issue number5
DOIs
StatePublished - May 1 2016

Fingerprint

Insulin-Like Growth Factor Binding Protein 4
Sex Hormone-Binding Globulin
Gestational Age
Pregnant Women
Proteomics
Mass Spectrometry
Serum
Mothers
Sensitivity and Specificity
Workflow
Validation Studies
Perinatal Mortality
ROC Curve
Blood Proteins
Biomarkers
Odds Ratio
Parturition
Pregnancy
Proteins

Keywords

  • biomarker
  • IBP4
  • IGFBP4
  • pregnancy
  • preterm birth
  • proteomics
  • SHBG

ASJC Scopus subject areas

  • Obstetrics and Gynecology

Cite this

Saade, G. R., Boggess, K. A., Sullivan, S. A., Markenson, G. R., Iams, J. D., Coonrod, D. V., ... Hickok, D. E. (2016). Development and validation of a spontaneous preterm delivery predictor in asymptomatic women. American Journal of Obstetrics and Gynecology, 214(5), 633e1-633e24. https://doi.org/10.1016/j.ajog.2016.02.001

Development and validation of a spontaneous preterm delivery predictor in asymptomatic women. / Saade, George R.; Boggess, Kim A.; Sullivan, Scott A.; Markenson, Glenn R.; Iams, Jay D.; Coonrod, Dean V.; Pereira, Leonardo; Esplin, M. Sean; Cousins, Larry M.; Lam, Garrett K.; Hoffman, Matthew K.; Severinsen, Robert D.; Pugmire, Trina; Flick, Jeff S.; Fox, Angela C.; Lueth, Amir J.; Rust, Sharon R.; Mazzola, Emanuele; Hsu, Chienting; Dufford, Max T.; Bradford, Chad L.; Ichetovkin, Ilia E.; Fleischer, Tracey C.; Polpitiya, Ashoka D.; Critchfield, Gregory C.; Kearney, Paul E.; Boniface, J. Jay; Hickok, Durlin E.

In: American Journal of Obstetrics and Gynecology, Vol. 214, No. 5, 01.05.2016, p. 633e1-633e24.

Research output: Contribution to journalArticle

Saade, GR, Boggess, KA, Sullivan, SA, Markenson, GR, Iams, JD, Coonrod, DV, Pereira, L, Esplin, MS, Cousins, LM, Lam, GK, Hoffman, MK, Severinsen, RD, Pugmire, T, Flick, JS, Fox, AC, Lueth, AJ, Rust, SR, Mazzola, E, Hsu, C, Dufford, MT, Bradford, CL, Ichetovkin, IE, Fleischer, TC, Polpitiya, AD, Critchfield, GC, Kearney, PE, Boniface, JJ & Hickok, DE 2016, 'Development and validation of a spontaneous preterm delivery predictor in asymptomatic women', American Journal of Obstetrics and Gynecology, vol. 214, no. 5, pp. 633e1-633e24. https://doi.org/10.1016/j.ajog.2016.02.001
Saade, George R. ; Boggess, Kim A. ; Sullivan, Scott A. ; Markenson, Glenn R. ; Iams, Jay D. ; Coonrod, Dean V. ; Pereira, Leonardo ; Esplin, M. Sean ; Cousins, Larry M. ; Lam, Garrett K. ; Hoffman, Matthew K. ; Severinsen, Robert D. ; Pugmire, Trina ; Flick, Jeff S. ; Fox, Angela C. ; Lueth, Amir J. ; Rust, Sharon R. ; Mazzola, Emanuele ; Hsu, Chienting ; Dufford, Max T. ; Bradford, Chad L. ; Ichetovkin, Ilia E. ; Fleischer, Tracey C. ; Polpitiya, Ashoka D. ; Critchfield, Gregory C. ; Kearney, Paul E. ; Boniface, J. Jay ; Hickok, Durlin E. / Development and validation of a spontaneous preterm delivery predictor in asymptomatic women. In: American Journal of Obstetrics and Gynecology. 2016 ; Vol. 214, No. 5. pp. 633e1-633e24.
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abstract = "Background Preterm delivery remains the leading cause of perinatal mortality. Risk factors and biomarkers have traditionally failed to identify the majority of preterm deliveries. Objective To develop and validate a mass spectrometry-based serum test to predict spontaneous preterm delivery in asymptomatic pregnant women. Study Design A total of 5501 pregnant women were enrolled between 170/7 and 286/7 weeks gestational age in the prospective Proteomic Assessment of Preterm Risk study at 11 sites in the United States between 2011 and 2013. Maternal blood was collected at enrollment and outcomes collected following delivery. Maternal serum was processed by a proteomic workflow, and proteins were quantified by multiple reaction monitoring mass spectrometry. The discovery and verification process identified 2 serum proteins, insulin-like growth factor-binding protein 4 (IBP4) and sex hormone-binding globulin (SHBG), as predictors of spontaneous preterm delivery. We evaluated a predictor using the log ratio of the measures of IBP4 and SHBG (IBP4/SHBG) in a clinical validation study to classify spontaneous preterm delivery cases (0/7 weeks gestational age) in a nested case-control cohort different from subjects used in discovery and verification. Strict blinding and independent statistical analyses were employed. Results The predictor had an area under the receiver operating characteristic curve value of 0.75 and sensitivity and specificity of 0.75 and 0.74, respectively. The IBP4/SHBG predictor at this sensitivity and specificity had an odds ratio of 5.04 for spontaneous preterm delivery. Accuracy of the IBP4/SHBG predictor increased using earlier case-vs-control gestational age cutoffs (eg, 0/7 vs ≥350/7 weeks gestational age). Importantly, higher-risk subjects defined by the IBP4/SHBG predictor score generally gave birth earlier than lower-risk subjects. Conclusion A serum-based molecular predictor identifies asymptomatic pregnant women at risk of spontaneous preterm delivery, which may provide utility in identifying women at risk at an early stage of pregnancy to allow for clinical intervention. This early detection would guide enhanced levels of care and accelerate development of clinical strategies to prevent preterm delivery.",
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author = "Saade, {George R.} and Boggess, {Kim A.} and Sullivan, {Scott A.} and Markenson, {Glenn R.} and Iams, {Jay D.} and Coonrod, {Dean V.} and Leonardo Pereira and Esplin, {M. Sean} and Cousins, {Larry M.} and Lam, {Garrett K.} and Hoffman, {Matthew K.} and Severinsen, {Robert D.} and Trina Pugmire and Flick, {Jeff S.} and Fox, {Angela C.} and Lueth, {Amir J.} and Rust, {Sharon R.} and Emanuele Mazzola and Chienting Hsu and Dufford, {Max T.} and Bradford, {Chad L.} and Ichetovkin, {Ilia E.} and Fleischer, {Tracey C.} and Polpitiya, {Ashoka D.} and Critchfield, {Gregory C.} and Kearney, {Paul E.} and Boniface, {J. Jay} and Hickok, {Durlin E.}",
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T1 - Development and validation of a spontaneous preterm delivery predictor in asymptomatic women

AU - Saade, George R.

AU - Boggess, Kim A.

AU - Sullivan, Scott A.

AU - Markenson, Glenn R.

AU - Iams, Jay D.

AU - Coonrod, Dean V.

AU - Pereira, Leonardo

AU - Esplin, M. Sean

AU - Cousins, Larry M.

AU - Lam, Garrett K.

AU - Hoffman, Matthew K.

AU - Severinsen, Robert D.

AU - Pugmire, Trina

AU - Flick, Jeff S.

AU - Fox, Angela C.

AU - Lueth, Amir J.

AU - Rust, Sharon R.

AU - Mazzola, Emanuele

AU - Hsu, Chienting

AU - Dufford, Max T.

AU - Bradford, Chad L.

AU - Ichetovkin, Ilia E.

AU - Fleischer, Tracey C.

AU - Polpitiya, Ashoka D.

AU - Critchfield, Gregory C.

AU - Kearney, Paul E.

AU - Boniface, J. Jay

AU - Hickok, Durlin E.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Background Preterm delivery remains the leading cause of perinatal mortality. Risk factors and biomarkers have traditionally failed to identify the majority of preterm deliveries. Objective To develop and validate a mass spectrometry-based serum test to predict spontaneous preterm delivery in asymptomatic pregnant women. Study Design A total of 5501 pregnant women were enrolled between 170/7 and 286/7 weeks gestational age in the prospective Proteomic Assessment of Preterm Risk study at 11 sites in the United States between 2011 and 2013. Maternal blood was collected at enrollment and outcomes collected following delivery. Maternal serum was processed by a proteomic workflow, and proteins were quantified by multiple reaction monitoring mass spectrometry. The discovery and verification process identified 2 serum proteins, insulin-like growth factor-binding protein 4 (IBP4) and sex hormone-binding globulin (SHBG), as predictors of spontaneous preterm delivery. We evaluated a predictor using the log ratio of the measures of IBP4 and SHBG (IBP4/SHBG) in a clinical validation study to classify spontaneous preterm delivery cases (0/7 weeks gestational age) in a nested case-control cohort different from subjects used in discovery and verification. Strict blinding and independent statistical analyses were employed. Results The predictor had an area under the receiver operating characteristic curve value of 0.75 and sensitivity and specificity of 0.75 and 0.74, respectively. The IBP4/SHBG predictor at this sensitivity and specificity had an odds ratio of 5.04 for spontaneous preterm delivery. Accuracy of the IBP4/SHBG predictor increased using earlier case-vs-control gestational age cutoffs (eg, 0/7 vs ≥350/7 weeks gestational age). Importantly, higher-risk subjects defined by the IBP4/SHBG predictor score generally gave birth earlier than lower-risk subjects. Conclusion A serum-based molecular predictor identifies asymptomatic pregnant women at risk of spontaneous preterm delivery, which may provide utility in identifying women at risk at an early stage of pregnancy to allow for clinical intervention. This early detection would guide enhanced levels of care and accelerate development of clinical strategies to prevent preterm delivery.

AB - Background Preterm delivery remains the leading cause of perinatal mortality. Risk factors and biomarkers have traditionally failed to identify the majority of preterm deliveries. Objective To develop and validate a mass spectrometry-based serum test to predict spontaneous preterm delivery in asymptomatic pregnant women. Study Design A total of 5501 pregnant women were enrolled between 170/7 and 286/7 weeks gestational age in the prospective Proteomic Assessment of Preterm Risk study at 11 sites in the United States between 2011 and 2013. Maternal blood was collected at enrollment and outcomes collected following delivery. Maternal serum was processed by a proteomic workflow, and proteins were quantified by multiple reaction monitoring mass spectrometry. The discovery and verification process identified 2 serum proteins, insulin-like growth factor-binding protein 4 (IBP4) and sex hormone-binding globulin (SHBG), as predictors of spontaneous preterm delivery. We evaluated a predictor using the log ratio of the measures of IBP4 and SHBG (IBP4/SHBG) in a clinical validation study to classify spontaneous preterm delivery cases (0/7 weeks gestational age) in a nested case-control cohort different from subjects used in discovery and verification. Strict blinding and independent statistical analyses were employed. Results The predictor had an area under the receiver operating characteristic curve value of 0.75 and sensitivity and specificity of 0.75 and 0.74, respectively. The IBP4/SHBG predictor at this sensitivity and specificity had an odds ratio of 5.04 for spontaneous preterm delivery. Accuracy of the IBP4/SHBG predictor increased using earlier case-vs-control gestational age cutoffs (eg, 0/7 vs ≥350/7 weeks gestational age). Importantly, higher-risk subjects defined by the IBP4/SHBG predictor score generally gave birth earlier than lower-risk subjects. Conclusion A serum-based molecular predictor identifies asymptomatic pregnant women at risk of spontaneous preterm delivery, which may provide utility in identifying women at risk at an early stage of pregnancy to allow for clinical intervention. This early detection would guide enhanced levels of care and accelerate development of clinical strategies to prevent preterm delivery.

KW - biomarker

KW - IBP4

KW - IGFBP4

KW - pregnancy

KW - preterm birth

KW - proteomics

KW - SHBG

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