Neonatal outcomes after proteomic biomarker-guided intervention: the AVERT PRETERM TRIAL

Background Vaginal progesterone, low dose aspirin and care management (comprising increased outreach and education) has been shown to reduce the rate of prematurity in select populations, but identifying at-risk pregnancies has been problematic. Objective(s) Test the hypothesis that screening singleton, non-anomalous pregnancies lacking traditional clinical risk factors with a validated blood test for preterm birth risk prediction, then targeting those with elevated risk for preventive treatment, would improve neonatal outcomes as compared to a large historical population. Study Design The AVERT PRETERM trial took place from June 2018-September 2020 at ChristianaCare Hospital (Newark, DE). Singleton non-anomalous pregnancies with no history of preterm birth were enrolled in a prospective study arm and followed through neonatal hospital discharge. Participants were screened using a serum proteomic test for spontaneous preterm birth risk during a gestational age window spanning 191/7-206/7 weeks. Pregnancies identified by the test to be at elevated risk for preterm birth (≥16.0%, approximately twice the U.S. population risk) were offered aspirin 81 mg daily, open-label vaginal progesterone 200 mg daily and care management. We compared outcomes for women who screened either low-risk or higher-risk accepting treatment with those in a historical study arm of 10,000 pregnancies. Our co-primary outcomes were neonatal hospital length of stay and an ordinal neonatal morbidity index score based on the occurrence of grade III/IV interventricular hemorrhage, necrotizing enterocolitis (Bell stage II/III), respiratory distress syndrome, bronchopulmonary dysplasia, retinopathy of prematurity (stage III), sepsis, and neonatal death or neonatal intensive care unit length of stay. Cox proportional hazards survival analysis and ordinal logistic regression were utilized to evaluate outcomes and control for population differences. Results A total of 1463 women were screened and tested before research operations were ceased due to the advent of the COVID-19 pandemic, and three women were subsequently deemed ineligible after screening. Of these, 34.72% (507/1460) were deemed high-risk, with 56.41% (286/507) accepting intervention and 43.59% (221/507) forgoing intervention. The remaining 65.3% (953/1460) were designated as low-risk. Women in the prospective arm were older, more obese, more likely to have hypertension and smoke, and less likely to use opioids compared to women in the historical arm. The primary analyses found that neonates in the prospective arm were discharged from the hospital earlier ( P =0.01; hazard ratio, 1.35; 95% confidence interval, 1.08-1.70) and had lower neonatal morbidity index scores ( P =0.031; odds ratio, 0.81; 95% confidence interval, 0.67-0.98). Average neonatal hospital length of stay decreased by 21%, and severe neonatal morbidity (neonatal morbidity index ≥3) was reduced on average by 18%. Conclusions Identifying singleton, non-anomalous pregnancies lacking traditional risk factors with a validated proteomic blood test for preterm birth risk and providing treatment to those at risk resulted in improved neonatal outcomes compared to controls in a racially diverse cohort. This test-and-treatment strategy shows promise for ameliorating the impacts of premature birth among individuals in this previously unidentified patient population. ### Competing Interest Statement BS, JS, and MGW are paid consultants of Sera Prognostics, Inc. For the purposes of this study, JS and MGW reported to MKH and were paid consultants of ChristianaCare, and BS was supported by Sera Prognostics, Inc. MKH received an investigator-initiated grant from Sera Prognostics, Inc., to conduct this study. ### Clinical Trial NCT02901626 ### Clinical Protocols ### Funding Statement This study was funded by Sera Prognostics, Inc. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol ([NCT02901626][1]) was approved by the ChristianaCare institutional review board prior to participant enrollment. An independent data safety monitoring board convened prior to study initiation, approved the protocol, and provided oversight of adverse events. All subjects provided written informed consent to participate in the study. The listed authors accept responsibility for the accuracy and completeness of the data and for fidelity in the conduct of the trial. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data supporting the results presented here are available on request from the corresponding author. Data will not be made publicly available or in any format that may violate a subject’s right to privacy. For example, dating information or identifiers that could allow data integration, thereby enabling potential identification of study subjects, are protected. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02901626&atom=%2Fmedrxiv%2Fearly%2F2023%2F09%2F14%2F2023.09.13.23295503.atom