Neonatal impact of maternal biomarker screening for risk of preterm birth with targeted interventions (PRIME): A multicenter, randomized, controlled trial

Abstract Background Preterm birth remains a leading cause of neonatal morbidity and mortality, yet clinicians possess limited tools to identify at‐risk pregnancies and implement effective interventions. This study evaluated whether knowledge of a mid‐second‐trimester maternal blood biomarker test result, combined with an intervention bundle for those identified as being at higher risk, improves neonatal outcomes in a population at low overall risk for spontaneous preterm birth. Methods PRIME was a multicenter, randomized, controlled trial at 19 US sites. Participants with singleton pregnancies at 18–20 6/7 weeks’ gestation underwent biomarker testing with the previously validated insulin‐like growth factor‐binding protein 4 to sex hormone‐binding globulin (IGFBP4/SHBG) ratio and were randomized to an open‐label screen‐guided care arm or a blinded routine care arm. Higher‐risk participants in the screen‐guided care arm received a bundled intervention consisting of daily vaginal progesterone, low‐dose aspirin, and weekly telephonic nurse support. The co‐primary outcomes, analyzed in an intent‐to‐treat population, were: (1) a composite index of neonatal morbidity and mortality and (2) neonatal hospital length of stay. Additional outcomes were gestational age at birth, neonatal intensive care unit (NICU) admissions, and NICU length of stay. Outcomes were adjusted for parity, pre‐enrollment aspirin use, and COVID positivity. Recruitment was halted for efficacy at the interim analysis, and all enrolled participants were followed to delivery and neonatal outcome assessment. Results The enrolled population included 5018 participants with delivery data available for 4806, comprising the intent‐to‐treat population (2416 screen‐guided care, 2390 routine care). Screen‐guided care was associated with reduced composite neonatal morbidity (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.66–0.96; p = 0.015), shortened neonatal hospital stays (incidence rate ratio [IRR], 0.95; 95% CI, 0.92–0.98; p = 0.004), and fewer NICU admissions. Conclusion In low‐risk pregnancies, care guided by a maternal IGFBP4/SHBG blood test with targeted interventions improved neonatal outcomes. These findings suggest a potential role for IGFBP4/SHBG screen‐guided care in enhancing early risk detection and informing strategies to reduce events related to preterm birth. Trial Registration ClinicalTrials.gov identifier: NCT04301518