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Background <p>Spontaneous preterm birth (sPTB) remains a major contributor to neonatal morbidity and mortality, with limited reliable early prediction tools. Existing biomarkers, such as the insulin-like growth factor-binding protein 4 (IBP4) to sex hormone-binding globulin (SHBG) ratio, offer modest predictive performance and are restricted to mid-gestation use (18–20&#xa0;weeks), limiting their utility for timely intervention. We aimed to develop and validate a novel serological test based on early-gestational sampling to predict the risk of sPTB.</p> Methods <p>We conducted a meta-analysis of 18 placental transcriptomic datasets to identify candidate genes associated with sPTB, resulting in 21 protein candidates tested by targeted proteomics. We developed a three-protein panel (glutathione peroxidase 3, GPX3; nidogen-1, NID1; and pappalysin-2, PAPPA2) and validated it in four independent cohorts (456 subjects and 1048 serum specimens) from the USA and Asia. Longitudinal serum samples were collected from 5&#xa0;weeks and were analyzed using mass spectrometry and ELISA platforms. Predictor performance was compared to the IBP4/SHBG ratio.</p> Results <p>The three-protein predictor (GPX3, NID1, and PAPPA2) demonstrated reproducible and superior performance across cohorts: <i>AUC</i> 0.74 (95% <i>CI</i> 0.59–0.88) in Alabama, 0.93 (95% <i>CI</i> 0.88–0.99) in California, 0.80 (95% <i>CI</i> 0.75–0.85) in Asia 1, and 0.83 (95% <i>CI</i> 0.70–0.95) in Asia 2. This outperformed the IBP4/SHBG ratio, which achieved AUCs of 0.68 (95% <i>CI</i> 0.50–0.89), 0.77 (95% <i>CI</i> 0.67–0.88), 0.59 (95% <i>CI</i> 0.52–0.65), and 0.61 (95% <i>CI</i> 0.50–0.75), respectively. Across obstetric trimesters, the three-protein panel maintained high predictive accuracy in the first and second trimesters (<i>AUROC</i> 0.82–0.97), the window when preventive interventions such as progesterone, cerclage, and low-dose aspirin are most effective. Kaplan–Meier analyses confirmed significantly earlier delivery among high-risk pregnancies identified by the three-protein panel.</p> Conclusions <p>This maternal serum test provides a reliable approach for early risk assessment of sPTB. The three-protein panel demonstrated reproducible performance across cohorts and across PPROM-positive and PPROM-negative phenotypes, with the strongest discrimination in the first and second trimesters, when preventive therapies such as progesterone or cerclage are most effective. These findings support its potential as an early, clinically actionable screening tool for improving pregnancy outcomes.</p>

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Early gestational prediction of spontaneous preterm birth using a validated three-protein serum biomarker panel

  • 期刊论文

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  • 发表日期：

    2026年2月2日

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  • Qiong Luo,
  • Juan Wei,
  • Yun Ding,
  • Yixuan Chen,
  • Linlin Wu,
  • C. James Chou,
  • Xiaohua Luo,
  • Negin Ghafourian,
  • Jian Tao,
  • Bo Jin,
  • Kuo-Jung Su,
  • Richard D. Mortensen,
  • James Schilling,
  • Zhi Han,
  • Naoto Ozawa,
  • Takumi Ichikawa,
  • Ruben Y. Luo,
  • Karl G. Sylvester,
  • Scott R. Ceresnak,
  • Ronald J. Wong,
  • Lu Tian,
  • Ivana Marić,
  • Nima Aghaeepour,
  • Brice Gaudilliere,
  • Martin S. Angst,
  • Gary M. Shaw,
  • Doff McElhinney,
  • Harvey J. Cohen,
  • Gary L. Darmstadt,
  • Jianmin Niu,
  • David K. Stevenson,
  • Xuefeng B. Ling

摘要

Background

Spontaneous preterm birth (sPTB) remains a major contributor to neonatal morbidity and mortality, with limited reliable early prediction tools. Existing biomarkers, such as the insulin-like growth factor-binding protein 4 (IBP4) to sex hormone-binding globulin (SHBG) ratio, offer modest predictive performance and are restricted to mid-gestation use (18–20 weeks), limiting their utility for timely intervention. We aimed to develop and validate a novel serological test based on early-gestational sampling to predict the risk of sPTB.

Methods

We conducted a meta-analysis of 18 placental transcriptomic datasets to identify candidate genes associated with sPTB, resulting in 21 protein candidates tested by targeted proteomics. We developed a three-protein panel (glutathione peroxidase 3, GPX3; nidogen-1, NID1; and pappalysin-2, PAPPA2) and validated it in four independent cohorts (456 subjects and 1048 serum specimens) from the USA and Asia. Longitudinal serum samples were collected from 5 weeks and were analyzed using mass spectrometry and ELISA platforms. Predictor performance was compared to the IBP4/SHBG ratio.

Results

The three-protein predictor (GPX3, NID1, and PAPPA2) demonstrated reproducible and superior performance across cohorts: AUC 0.74 (95% CI 0.59–0.88) in Alabama, 0.93 (95% CI 0.88–0.99) in California, 0.80 (95% CI 0.75–0.85) in Asia 1, and 0.83 (95% CI 0.70–0.95) in Asia 2. This outperformed the IBP4/SHBG ratio, which achieved AUCs of 0.68 (95% CI 0.50–0.89), 0.77 (95% CI 0.67–0.88), 0.59 (95% CI 0.52–0.65), and 0.61 (95% CI 0.50–0.75), respectively. Across obstetric trimesters, the three-protein panel maintained high predictive accuracy in the first and second trimesters (AUROC 0.82–0.97), the window when preventive interventions such as progesterone, cerclage, and low-dose aspirin are most effective. Kaplan–Meier analyses confirmed significantly earlier delivery among high-risk pregnancies identified by the three-protein panel.

Conclusions

This maternal serum test provides a reliable approach for early risk assessment of sPTB. The three-protein panel demonstrated reproducible performance across cohorts and across PPROM-positive and PPROM-negative phenotypes, with the strongest discrimination in the first and second trimesters, when preventive therapies such as progesterone or cerclage are most effective. These findings support its potential as an early, clinically actionable screening tool for improving pregnancy outcomes.