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The clinical management of pregnancy and spontaneous preterm birth (sPTB) relies on estimates of gestational age (GA). Our objective was to evaluate the effect of GA dating uncertainty on the observed performance of a validated proteomic biomarker risk predictor, and then to test the generalizability of that effect in a broader range of GA at blood draw. In a secondary analysis of a prospective clinical trial (PAPR; NCT01371019), we compared two GA dating categories: both ultrasound and dating by last menstrual period (LMP) (all subjects) and excluding dating by LMP (excluding LMP). The risk predictor's performance was observed at the validated risk predictor threshold both in weeks 19 1/7 -20 6/7 and extended to weeks 18 0/7 -20 6/7 . Strict blinding and independent statistical analyses were employed. The validated biomarker risk predictor showed greater observed sensitivity of 88% at 75% specificity (increases of 17% and 1%) in more reliably dated (excluding-LMP) subjects, relative to all subjects. Excluding dating by LMP significantly improved the sensitivity in weeks 19 1/7 -20 6/7 . In the broader blood draw window, the previously validated risk predictor threshold significantly stratified higher and lower risk of sPTB, and the risk predictor again showed significantly greater observed sensitivity in excluding-LMP subjects. These findings have implications for testing the performance of models aimed at predicting PTB.

Preterm births are the leading cause of neonatal death in the United States. Previously, a spontaneous preterm birth (sPTB) predictor based on the ratio of two proteins, IBP4/SHBG, was validated as a predictor of sPTB in the Proteomic Assessment of Preterm Risk (PAPR) study. In particular, a proteomic biomarker threshold of -1.37, corresponding to a ~two-fold increase or ~15% risk of sPTB, significantly stratified earlier deliveries. Guidelines for molecular tests advise replication in a second independent study. Here we tested whether the significant association between proteomic biomarker scores above the threshold and sPTB, and associated adverse outcomes, was replicated in a second independent study, the Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor (TREETOP). The threshold significantly stratified subjects in PAPR and TREETOP for sPTB ( p = 0.041, p = 0.041, respectively). Application of the threshold in a Kaplan-Meier analysis demonstrated significant stratification in each study, respectively, for gestational age at birth ( p < 001, p = 0.0016) and rate of hospital discharge for both neonate ( p < 0.001, p = 0.005) and mother ( p < 0.001, p < 0.001). Above the threshold, severe neonatal morbidity/mortality and mortality alone were 2.2 ( p = 0.0083,) and 7.4-fold higher ( p = 0.018), respectively, in both studies combined. Thus, higher predictor scores were associated with multiple adverse pregnancy outcomes.