Performance of a proteomic preterm delivery predictor in a large independent prospective cohort

Glenn R. Markenson; George R. Saade; Louise C. Laurent; Kent D. Heyborne; Dean V. Coonrod; Corina N. Schoen; Jason K. Baxter; David M. Haas; Sherri Longo; William A. Grobman; Scott A. Sullivan; Carol A. Major; Sarahn M. Wheeler; Leonardo M. Pereira; Emily J. Su; Kim A. Boggess; Angela F. Hawk; Amy H. Crockett; Angela C. Fox; Ashoka Polpitiya; Tracey C. Fleischer; Gregory C. Critchfield; Julja Burchard; J. Jay Boniface; Garrett K. Lam

doi:10.1016/j.ajogmf.2020.100140

Performance of a proteomic preterm delivery predictor in a large independent prospective cohort

Glenn R. Markenson, George R. Saade, Louise C. Laurent, Kent D. Heyborne, Dean V. Coonrod, Corina N. Schoen, Jason K. Baxter, David M. Haas, Sherri Longo, William A. Grobman, Scott A. Sullivan, Carol A. Major, Sarahn M. Wheeler, Leonardo M. Pereira, Emily J. Su, Kim A. Boggess, Angela F. Hawk, Amy H. Crockett, Angela C. Fox, Ashoka PolpitiyaTracey C. Fleischer, Gregory C. Critchfield, Julja Burchard, J. Jay Boniface, Garrett K. Lam

Obstetrics and Gynecology

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

Background: Preterm birth remains a common and devastating complication of pregnancy. There remains a need for effective and accurate screening methods for preterm birth. Using a proteomic approach, we previously discovered and validated (Proteomic Assessment of Preterm Risk study, NCT01371019) a preterm birth predictor comprising a ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin. Objective: To determine the performance of the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin to predict both spontaneous and medically indicated very preterm births, in an independent cohort distinct from the one in which it was developed. Study Design: This was a prospective observational study (Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor, NCT02787213) at 18 sites in the United States. Women had blood drawn at 17^0/7 to 21^6/7 weeks’ gestation. For confirmation, we planned to analyze a randomly selected subgroup of women having blood drawn between 19^1/7 and 20^6/7 weeks’ gestation, with the results of the remaining study participants blinded for future validation studies. Serum from participants was analyzed by mass spectrometry. Neonatal morbidity and mortality were analyzed using a composite score by a method from the PREGNANT trial (NCT00615550, Hassan et al). Scores of 0–3 reflect increasing numbers of morbidities or length of neonatal intensive care unit stay, and 4 represents perinatal mortality. Results: A total of 5011 women were enrolled, with 847 included in this planned substudy analysis. There were 9 preterm birth cases at <32^0/7 weeks’ gestation and 838 noncases at ≥32^0/7 weeks’ gestation; 21 of 847 infants had neonatal composite morbidity and mortality index scores of ≥3, and 4 of 21 had a score of 4. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was substantially higher in both preterm births at <32^0/7 weeks’ gestation and there were more severe neonatal outcomes. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was significantly predictive of birth at <32^0/7 weeks’ gestation (area under the receiver operating characteristic curve, 0.71; 95% confidence interval, 0.55–0.87; P=.016). Stratification by body mass index, optimized in the previous validation study (22<body mass index≤37 kg/m²), resulted in an area under the receiver operating characteristic curve of 0.76 (95% confidence interval, 0.59–0.93; P=.023). The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio predicted neonatal outcomes with respective area under the receiver operating characteristic curve of 0.67 (95% confidence interval, 0.57–0.77; P=.005) and 0.78 (95% confidence interval, 0.63–0.93; P=.026) for neonatal composite morbidity and mortality scores of ≥3 or 4. In addition, the ratio of insulin-like growth factor-binding protein 4 to sex hormone binding globulin significantly stratified neonates with increased length of hospital stay (log rank P=.023). Conclusion: We confirmed in an independent cohort the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio as a predictor of very preterm birth, with additional prediction of increased length of neonatal hospital stay and increased severity of adverse neonatal outcomes. Potential uses of the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin predictor may be to risk stratify patients for implementation of preterm birth preventive strategies and direct patients to appropriate levels of care.

Original language	English (US)
Article number	100140
Journal	American Journal of Obstetrics and Gynecology MFM
Volume	2
Issue number	3
DOIs	https://doi.org/10.1016/j.ajogmf.2020.100140
State	Published - Aug 2020

Keywords

IGFBP4
biomarker
insulin-like growth factor-binding protein 4
neonatal morbidity and mortality
pregnancy
prematurity
preterm birth
proteomics
sex hormone-binding globulin

ASJC Scopus subject areas

Obstetrics and Gynecology

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10.1016/j.ajogmf.2020.100140

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Markenson, G. R., Saade, G. R., Laurent, L. C., Heyborne, K. D., Coonrod, D. V., Schoen, C. N., Baxter, J. K., Haas, D. M., Longo, S., Grobman, W. A., Sullivan, S. A., Major, C. A., Wheeler, S. M., Pereira, L. M., Su, E. J., Boggess, K. A., Hawk, A. F., Crockett, A. H., Fox, A. C., ... Lam, G. K. (2020). Performance of a proteomic preterm delivery predictor in a large independent prospective cohort. American Journal of Obstetrics and Gynecology MFM, 2(3), Article 100140. https://doi.org/10.1016/j.ajogmf.2020.100140

Markenson, GR, Saade, GR, Laurent, LC, Heyborne, KD, Coonrod, DV, Schoen, CN, Baxter, JK, Haas, DM, Longo, S, Grobman, WA, Sullivan, SA, Major, CA, Wheeler, SM, Pereira, LM, Su, EJ, Boggess, KA, Hawk, AF, Crockett, AH, Fox, AC, Polpitiya, A, Fleischer, TC, Critchfield, GC, Burchard, J, Boniface, JJ & Lam, GK 2020, 'Performance of a proteomic preterm delivery predictor in a large independent prospective cohort', American Journal of Obstetrics and Gynecology MFM, vol. 2, no. 3, 100140. https://doi.org/10.1016/j.ajogmf.2020.100140

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title = "Performance of a proteomic preterm delivery predictor in a large independent prospective cohort",

abstract = "Background: Preterm birth remains a common and devastating complication of pregnancy. There remains a need for effective and accurate screening methods for preterm birth. Using a proteomic approach, we previously discovered and validated (Proteomic Assessment of Preterm Risk study, NCT01371019) a preterm birth predictor comprising a ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin. Objective: To determine the performance of the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin to predict both spontaneous and medically indicated very preterm births, in an independent cohort distinct from the one in which it was developed. Study Design: This was a prospective observational study (Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor, NCT02787213) at 18 sites in the United States. Women had blood drawn at 170/7 to 216/7 weeks{\textquoteright} gestation. For confirmation, we planned to analyze a randomly selected subgroup of women having blood drawn between 191/7 and 206/7 weeks{\textquoteright} gestation, with the results of the remaining study participants blinded for future validation studies. Serum from participants was analyzed by mass spectrometry. Neonatal morbidity and mortality were analyzed using a composite score by a method from the PREGNANT trial (NCT00615550, Hassan et al). Scores of 0–3 reflect increasing numbers of morbidities or length of neonatal intensive care unit stay, and 4 represents perinatal mortality. Results: A total of 5011 women were enrolled, with 847 included in this planned substudy analysis. There were 9 preterm birth cases at <320/7 weeks{\textquoteright} gestation and 838 noncases at ≥320/7 weeks{\textquoteright} gestation; 21 of 847 infants had neonatal composite morbidity and mortality index scores of ≥3, and 4 of 21 had a score of 4. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was substantially higher in both preterm births at <320/7 weeks{\textquoteright} gestation and there were more severe neonatal outcomes. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was significantly predictive of birth at <320/7 weeks{\textquoteright} gestation (area under the receiver operating characteristic curve, 0.71; 95% confidence interval, 0.55–0.87; P=.016). Stratification by body mass index, optimized in the previous validation study (222), resulted in an area under the receiver operating characteristic curve of 0.76 (95% confidence interval, 0.59–0.93; P=.023). The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio predicted neonatal outcomes with respective area under the receiver operating characteristic curve of 0.67 (95% confidence interval, 0.57–0.77; P=.005) and 0.78 (95% confidence interval, 0.63–0.93; P=.026) for neonatal composite morbidity and mortality scores of ≥3 or 4. In addition, the ratio of insulin-like growth factor-binding protein 4 to sex hormone binding globulin significantly stratified neonates with increased length of hospital stay (log rank P=.023). Conclusion: We confirmed in an independent cohort the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio as a predictor of very preterm birth, with additional prediction of increased length of neonatal hospital stay and increased severity of adverse neonatal outcomes. Potential uses of the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin predictor may be to risk stratify patients for implementation of preterm birth preventive strategies and direct patients to appropriate levels of care.",

keywords = "IGFBP4, biomarker, insulin-like growth factor-binding protein 4, neonatal morbidity and mortality, pregnancy, prematurity, preterm birth, proteomics, sex hormone-binding globulin",

author = "Markenson, {Glenn R.} and Saade, {George R.} and Laurent, {Louise C.} and Heyborne, {Kent D.} and Coonrod, {Dean V.} and Schoen, {Corina N.} and Baxter, {Jason K.} and Haas, {David M.} and Sherri Longo and Grobman, {William A.} and Sullivan, {Scott A.} and Major, {Carol A.} and Wheeler, {Sarahn M.} and Pereira, {Leonardo M.} and Su, {Emily J.} and Boggess, {Kim A.} and Hawk, {Angela F.} and Crockett, {Amy H.} and Fox, {Angela C.} and Ashoka Polpitiya and Fleischer, {Tracey C.} and Critchfield, {Gregory C.} and Julja Burchard and Boniface, {J. Jay} and Lam, {Garrett K.}",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = aug,

doi = "10.1016/j.ajogmf.2020.100140",

language = "English (US)",

volume = "2",

journal = "American Journal of Obstetrics and Gynecology MFM",

issn = "2589-9333",

publisher = "Elsevier BV",

number = "3",

}

TY - JOUR

T1 - Performance of a proteomic preterm delivery predictor in a large independent prospective cohort

AU - Markenson, Glenn R.

AU - Saade, George R.

AU - Laurent, Louise C.

AU - Heyborne, Kent D.

AU - Coonrod, Dean V.

AU - Schoen, Corina N.

AU - Baxter, Jason K.

AU - Haas, David M.

AU - Longo, Sherri

AU - Grobman, William A.

AU - Sullivan, Scott A.

AU - Major, Carol A.

AU - Wheeler, Sarahn M.

AU - Pereira, Leonardo M.

AU - Su, Emily J.

AU - Boggess, Kim A.

AU - Hawk, Angela F.

AU - Crockett, Amy H.

AU - Fox, Angela C.

AU - Polpitiya, Ashoka

AU - Fleischer, Tracey C.

AU - Critchfield, Gregory C.

AU - Burchard, Julja

AU - Boniface, J. Jay

AU - Lam, Garrett K.

PY - 2020/8

Y1 - 2020/8

N2 - Background: Preterm birth remains a common and devastating complication of pregnancy. There remains a need for effective and accurate screening methods for preterm birth. Using a proteomic approach, we previously discovered and validated (Proteomic Assessment of Preterm Risk study, NCT01371019) a preterm birth predictor comprising a ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin. Objective: To determine the performance of the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin to predict both spontaneous and medically indicated very preterm births, in an independent cohort distinct from the one in which it was developed. Study Design: This was a prospective observational study (Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor, NCT02787213) at 18 sites in the United States. Women had blood drawn at 170/7 to 216/7 weeks’ gestation. For confirmation, we planned to analyze a randomly selected subgroup of women having blood drawn between 191/7 and 206/7 weeks’ gestation, with the results of the remaining study participants blinded for future validation studies. Serum from participants was analyzed by mass spectrometry. Neonatal morbidity and mortality were analyzed using a composite score by a method from the PREGNANT trial (NCT00615550, Hassan et al). Scores of 0–3 reflect increasing numbers of morbidities or length of neonatal intensive care unit stay, and 4 represents perinatal mortality. Results: A total of 5011 women were enrolled, with 847 included in this planned substudy analysis. There were 9 preterm birth cases at <320/7 weeks’ gestation and 838 noncases at ≥320/7 weeks’ gestation; 21 of 847 infants had neonatal composite morbidity and mortality index scores of ≥3, and 4 of 21 had a score of 4. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was substantially higher in both preterm births at <320/7 weeks’ gestation and there were more severe neonatal outcomes. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was significantly predictive of birth at <320/7 weeks’ gestation (area under the receiver operating characteristic curve, 0.71; 95% confidence interval, 0.55–0.87; P=.016). Stratification by body mass index, optimized in the previous validation study (222), resulted in an area under the receiver operating characteristic curve of 0.76 (95% confidence interval, 0.59–0.93; P=.023). The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio predicted neonatal outcomes with respective area under the receiver operating characteristic curve of 0.67 (95% confidence interval, 0.57–0.77; P=.005) and 0.78 (95% confidence interval, 0.63–0.93; P=.026) for neonatal composite morbidity and mortality scores of ≥3 or 4. In addition, the ratio of insulin-like growth factor-binding protein 4 to sex hormone binding globulin significantly stratified neonates with increased length of hospital stay (log rank P=.023). Conclusion: We confirmed in an independent cohort the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio as a predictor of very preterm birth, with additional prediction of increased length of neonatal hospital stay and increased severity of adverse neonatal outcomes. Potential uses of the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin predictor may be to risk stratify patients for implementation of preterm birth preventive strategies and direct patients to appropriate levels of care.

AB - Background: Preterm birth remains a common and devastating complication of pregnancy. There remains a need for effective and accurate screening methods for preterm birth. Using a proteomic approach, we previously discovered and validated (Proteomic Assessment of Preterm Risk study, NCT01371019) a preterm birth predictor comprising a ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin. Objective: To determine the performance of the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin to predict both spontaneous and medically indicated very preterm births, in an independent cohort distinct from the one in which it was developed. Study Design: This was a prospective observational study (Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor, NCT02787213) at 18 sites in the United States. Women had blood drawn at 170/7 to 216/7 weeks’ gestation. For confirmation, we planned to analyze a randomly selected subgroup of women having blood drawn between 191/7 and 206/7 weeks’ gestation, with the results of the remaining study participants blinded for future validation studies. Serum from participants was analyzed by mass spectrometry. Neonatal morbidity and mortality were analyzed using a composite score by a method from the PREGNANT trial (NCT00615550, Hassan et al). Scores of 0–3 reflect increasing numbers of morbidities or length of neonatal intensive care unit stay, and 4 represents perinatal mortality. Results: A total of 5011 women were enrolled, with 847 included in this planned substudy analysis. There were 9 preterm birth cases at <320/7 weeks’ gestation and 838 noncases at ≥320/7 weeks’ gestation; 21 of 847 infants had neonatal composite morbidity and mortality index scores of ≥3, and 4 of 21 had a score of 4. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was substantially higher in both preterm births at <320/7 weeks’ gestation and there were more severe neonatal outcomes. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was significantly predictive of birth at <320/7 weeks’ gestation (area under the receiver operating characteristic curve, 0.71; 95% confidence interval, 0.55–0.87; P=.016). Stratification by body mass index, optimized in the previous validation study (222), resulted in an area under the receiver operating characteristic curve of 0.76 (95% confidence interval, 0.59–0.93; P=.023). The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio predicted neonatal outcomes with respective area under the receiver operating characteristic curve of 0.67 (95% confidence interval, 0.57–0.77; P=.005) and 0.78 (95% confidence interval, 0.63–0.93; P=.026) for neonatal composite morbidity and mortality scores of ≥3 or 4. In addition, the ratio of insulin-like growth factor-binding protein 4 to sex hormone binding globulin significantly stratified neonates with increased length of hospital stay (log rank P=.023). Conclusion: We confirmed in an independent cohort the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio as a predictor of very preterm birth, with additional prediction of increased length of neonatal hospital stay and increased severity of adverse neonatal outcomes. Potential uses of the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin predictor may be to risk stratify patients for implementation of preterm birth preventive strategies and direct patients to appropriate levels of care.

KW - IGFBP4

KW - biomarker

KW - insulin-like growth factor-binding protein 4

KW - neonatal morbidity and mortality

KW - pregnancy

KW - prematurity

KW - preterm birth

KW - proteomics

KW - sex hormone-binding globulin

UR - http://www.scopus.com/inward/record.url?scp=85099442215&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85099442215&partnerID=8YFLogxK

U2 - 10.1016/j.ajogmf.2020.100140

DO - 10.1016/j.ajogmf.2020.100140

M3 - Article

C2 - 33345877

AN - SCOPUS:85099442215

SN - 2589-9333

VL - 2

JO - American Journal of Obstetrics and Gynecology MFM

JF - American Journal of Obstetrics and Gynecology MFM

IS - 3

M1 - 100140

ER -

Performance of a proteomic preterm delivery predictor in a large independent prospective cohort

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