Performance of a Proteomic Preterm Delivery Predictor in a Large Independent Prospective Cohort


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 (PAPR study-NCT01371019) a preterm birth predictor comprising a ratio of insulin-like growth factor-binding protein 4/sex hormone-binding globulin (IBP4/SHBG).


To determine the performance of IBP4/SHBG 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 (TREETOP-NCT02787213) at eighteen US sites. Women had blood drawn at 170/7 – 216/7 weeks. For confirmation, we planned to analyze a randomly selected subgroup of women having blood drawn between 191/7-206/7 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 NICU stay, and 4 represents perinatal mortality.


A total of 5,011 women were enrolled, with 847 included in this planned sub-study analysis. There were 9 preterm birth cases <320/7 weeks and 838 non-cases ≥320/7 weeks. 21/847 infants had neonatal composite morbidity and mortality index scores of ≥3; 4/21 had a score of 4. The IBP4/SHBG ratio was significantly higher in both preterm births <320/7 weeks and more severe neonatal outcomes. The IBP4/SHBG ratio was significantly predictive of birth <320/7 weeks (AUC 0.71, 95%CI 0.55-0.87, p=.016). Stratification by BMI, optimized in the previous validation study (22 < BMI ≤37 kg/m2), resulted in an AUC of 0.76 (95% CI 0.59-0.93, p=.023). The IBP4/SHBG ratio predicted neonatal outcomes with respective AUCs of 0.67 (95% CI 0.57-0.77, p=.005) and 0.78 (95% CI 0.63-0.93, p=.026) for composite morbidity/mortality scores of ≥3 or 4. In addition, IBP4/SHBG significantly stratified neonates with increased length of hospital stay (log rank p-value 0.023).


We confirmed, in an independent cohort, the IBP4/SHBG 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 IBP4/SHBG predictor may be to risk-stratify patients for implementation of preterm birth preventive strategies and direct patients to appropriate levels of care.

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