Assessing placental endocrine and vascular function for prenatal prediction of adverse pregnancy outcomes in advanced‑maternal‑age pregnancies

Abstract

Background: Advanced-maternal-age pregnancies carry a heightened risk of pre-eclampsia and fetal growth restriction (FGR), yet current first-trimester screening has limited predictive accuracy. We hypothesized that combining mid-pregnancy placental endocrine biomarkers with a Doppler-based vascular index would improve early identification of women at risk for these complications. Methods: In a prospective cohort at Zibo Central Hospital (January 2022–June 2024), 420 singleton pregnancies in women ≥35 years (first antenatal visit <14 weeks) underwent serum assays for human chorionic gonadotrophin (hCG), pregnancy-associated plasma protein A (PAPP-A) and the soluble fms-like tyrosine kinase-1/placental growth factor ratio (sFlt-1/PlGF), plus transabdominal Doppler measurement of mean uterine-artery pulsatility index (UtA-PI) at 20–24 weeks. Sequential logistic-regression models—baseline clinical, + vascular (UtA-PI), + endocrine (biomarkers), and an integrated model—were internally validated with 1,000-bootstrap resampling; discrimination (AUC), calibration, net reclassification improvement (NRI) and decision-curve net benefit were assessed. The composite adverse pregnancy outcome (APO) was pre-eclampsia and/or SGA (defined post‑natally by INTERGROWTH‑21st birth‑weight standards). Results: Eighty-three women (19.8%) developed the APO: 45 PE cases (10.7 %), 51 SGA cases (12.1%; 38 < 3rd centile, 13 3rd–< 10th centile + abnormal Doppler), including 13 concurrent PE +SGA. Compared with unaffected pregnancies, cases showed higher median hCG, lower PAPP-A, higher sFlt-1/PlGF ratio and elevated UtA-PI. Model AUC rose from 0.62 (baseline) to 0.70 (+vascular), 0.78 (+endocrine) and 0.80 (95% CI: 0.75–0.85) for the integrated model, with good calibration and NRI + 0.18. Decision-curve analysis showed the integrated model yielded the greatest net benefit across 5–25% risk thresholds; at a 10% threshold it correctly flagged nine additional high-risk pregnancies and avoided five unnecessary interventions per 100 women screened. Performance remained strong in women ≥40 years (AUC 0.78) and nulliparas (AUC 0.82). Conclusion: Simultaneous mid-pregnancy assessment of endocrine (hCG, PAPP-A, sFlt-1/PlGF) and vascular (UtA-PI) placental function markedly improves prediction of pre-eclampsia and SGA in women of advanced maternal age, outperforming clinical or single-domain models and demonstrating practical decision-curve gains; integrating this dual-domain profile into routine prenatal care could facilitate targeted surveillance and prophylactic strategies to mitigate adverse outcomes.