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

George Saade, Kim A. Boggess, Scott A. Sullivan, Glenn R. Markenson, Jay D. Iams, Dean V. Coonrod, Leonardo M. 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. Dufford & 8 others Chad 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

    18 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., 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; Boggess, Kim A.; Sullivan, Scott A.; Markenson, Glenn R.; Iams, Jay D.; Coonrod, Dean V.; Pereira, Leonardo M.; 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, G, Boggess, KA, Sullivan, SA, Markenson, GR, Iams, JD, Coonrod, DV, Pereira, LM, 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 ; Boggess, Kim A. ; Sullivan, Scott A. ; Markenson, Glenn R. ; Iams, Jay D. ; Coonrod, Dean V. ; Pereira, Leonardo M. ; 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.",
    keywords = "biomarker, IBP4, IGFBP4, pregnancy, preterm birth, proteomics, SHBG",
    author = "George Saade and Boggess, {Kim A.} and Sullivan, {Scott A.} and Markenson, {Glenn R.} and Iams, {Jay D.} and Coonrod, {Dean V.} and Pereira, {Leonardo M.} 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

    AU - Boggess, Kim A.

    AU - Sullivan, Scott A.

    AU - Markenson, Glenn R.

    AU - Iams, Jay D.

    AU - Coonrod, Dean V.

    AU - Pereira, Leonardo M.

    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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