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