PRIME Trial Results: A New Evidence-Based Approach to Preterm Birth Risk Assessment

The PRIME Study is a multicenter randomized controlled trial of over 5,000 clinically low-risk singleton pregnancies.¹ The study evaluated the impact to moms and babies of screening with the PreTRM^® Test, a mid-trimester blood test measuring IGFBP4 and SHBG biomarkers, paired with accessible, commonly used interventions.  Pregnancies identified as higher risk were offered targeted interventions and experienced significant improvements in things like gestational age at birth, neonatal hospital length of stay, neonatal morbidity, and NICU admissions when compared with standard care. PRIME provides peer-reviewed clinical evidence supporting biomarker-based risk stratification to improve neonatal outcomes.

Why Preterm Birth Remains a Persistent Clinical and Public Health Challenge

Preterm birth, defined as delivery before 37 weeks’ gestation, remains one of the most significant and costly challenges in obstetric and neonatal care. Approximately 1 in 10 births in the United States are preterm, a rate that has remained largely unchanged for decades despite advances in prenatal and neonatal medicine.

Preterm birth is a major contributor to neonatal morbidity and mortality and is associated with long-term complications affecting neurodevelopment, respiratory health, and overall quality of life. Beyond clinical impact, preterm birth places a substantial burden on families, healthcare systems, and neonatal intensive care units. The annual economic cost in the United States alone is estimated to exceed $25 billion, reflecting both direct medical costs and longer-term societal impact.²

Limitations of Traditional Risk Factors in Identifying At-Risk Pregnancies

Traditional predictors of preterm birth include a history of prior preterm delivery, multiple gestation, and a shortened cervix. While clinically meaningful, these factors fail to capture a large number of pregnancies that ultimately result in spontaneous preterm birth.

Up to 50 percent of women who deliver preterm have no evident risk factors during pregnancy. Prior preterm birth, one of the strongest predictors, is not relevant for nulliparous patients.

Why Accurate Risk Assessment Is Foundational to Prevention

Preventing preterm birth requires identifying risk before symptoms develop. Evidence consistently shows that extending gestation, particularly among the earliest deliveries, is strongly associated with improved neonatal outcomes. While interventions such as vaginal progesterone and low-dose aspirin exist, their use depends on the ability to accurately identify patients who may benefit. Without reliable risk stratification, these interventions remain underutilized in the populations where most preterm births occur.

What Is the PRIME Study?

The recently published PRIME Study,  “Neonatal impact of maternal biomarker screening for risk of preterm birth with targeted interventions (PRIME): A multicenter, randomized, controlled trial,” was designed to evaluate whether biomarker-based risk identification combined with targeted interventions can improve neonatal outcomes compared with usual care.

Study Design and Population

The PRIME Study enrolled 5,018 singleton pregnancies across 19 clinical sites in the United States between 2020 and 2023. The study population consisted of clinically low-risk pregnancies, excluding patients with a prior history of preterm birth, short cervix, major maternal conditions, or known fetal anomalies. This design intentionally focused on the population where preterm birth risk is often undetected.

Primary Clinical Question Addressed by PRIME

The PRIME Study was designed to answer:

• Does pairing blood-based biomarker risk stratification with targeted interventions improve neonatal outcomes compared with usual care?

Biomarker-Based Risk Stratification in PRIME

Mid-Trimester Testing Window and Workflow

In PRIME, maternal blood samples were collected between 18 weeks 0 days and 20 weeks 6 days of gestation. Samples were processed by a CLIA-certified, CAP-accredited laboratory, with results returned to providers in approximately five business days. This workflow was designed to integrate into routine prenatal care at a clinically actionable point in pregnancy.

The IGFBP4 and SHBG Biomarker Ratio

The biomarker test used in PRIME measures insulin-like growth factor binding protein 4 (IGFBP4) and sex hormone-binding globulin (SHBG). The IGFBP4/SHBG ratio, combined with clinical variables in a validated algorithm, stratifies risk for spontaneous preterm birth in pregnancies otherwise considered clinically low risk.

This biomarker-based approach has been validated in multiple independent cohorts and was used in the PRIME Study to guide care in the screen-guided care arm.^3,4,5

The biomarker strategy used in PRIME is implemented clinically through the PreTRM Test, which measures the IGFBP4 and SHBG ratio in a mid-trimester maternal blood sample.

Clinicians interested in the test used in the trial can review an overview of the PreTRM Test used in PRIME for additional context.

Targeted Interventions Evaluated in the PRIME Study

Components of the Intervention Bundle

Participants identified as higher risk in the screen-guided care arm were offered commonly used, accessible interventions, including:

• Daily vaginal progesterone at 200 mg until 36 weeks 6 days
• Daily low-dose aspirin at 81 mg until 36 weeks 6 days
• Weekly nurse-led care management calls

Participants identified as not at higher risk continued with standard prenatal care.

Care Management as a Key Component

Care management played an important role in PRIME. Weekly nurse outreach focused on patient education, recognition of early signs and symptoms of preterm labor, adherence to recommended interventions, and timely coordination of care. These interactions were delivered by trained obstetric clinicians and were designed to support both clinical and nonclinical factors that influence pregnancy outcomes.

Integration With Existing Clinical Practices

Cervical length screening was included as part of the PRIME protocol. Patients identified as higher risk were offered additional cervical length surveillance when clinically appropriate. Cerclage considerations aligned with existing clinical guidelines, reinforcing that the PRIME approach builds upon, rather than replaces, current standards of care.

Clinical Outcomes Measured in PRIME

Co-Primary Outcomes

The PRIME Study evaluated two co-primary outcomes:

• Composite Neonatal Morbidity and Mortality Index
• Neonatal hospital length of stay

These outcomes were selected to capture meaningful effects on neonatal health and healthcare utilization.

Additional Outcomes

Additional outcomes included:

• Gestational age at birth
• NICU admission
• NICU length of stay

Key Findings From the Published PRIME Trial

Reduction in Neonatal Morbidity

The PRIME trial demonstrated a statistically significant reduction in neonatal morbidity among pregnancies in the intervention arm. The Neonatal Morbidity Index, a validated measure of newborn complications and severity of impact, was reduced by approximately 20 percent, compared with standard of care.

Impact on Neonatal Outcomes

Infants in the intervention arm experienced meaningful improvements across several outcomes, including  

• 20 percent reduction in NICU admissions, 
• 56% reduction in <32 week deliveries
• 32% reduction in <35 week deliveries 
• 20% fewer health complications for newborns. 

These findings indicate that earlier risk identification paired with targeted interventions can translate into measurable neonatal benefit.

For clinicians interested in how the biomarker-guided approach utilized in PRIME is applied in practice, additional information on the PreTRM Test and associated care pathways is available as an educational resource.

Why the PRIME Results Matter for Clinical Practice

Addressing Risk in Clinically Low-Risk Pregnancies

PRIME specifically addresses the population in which many spontaneous preterm births occur: pregnancies classified as clinically low risk. Unlike the screening tools available today, this study demonstrates that preterm birth risk through PreTRM screening can be identified before clinical symptoms appear, enabling earlier, proactive care.

Implications for Population Health and Health Systems

At scale, reductions in neonatal morbidity and NICU utilization have important implications for population health and healthcare systems. PRIME aligns with ACOG’s emphasis on tailored prenatal care and shared decision making, supporting proactive strategies that may improve outcomes while optimizing resource use as part of a personalized treatment plan.

PRIME and the Future of Personalized Prenatal Care

Biomarkers as a Foundation for Precision Obstetrics

The PRIME Studysupports the role of biomarkers as a complement to clinical assessment, moving obstetric care beyond reactive management toward proactive risk assessment and mitigation.

Screen-and-Treat Strategies Backed by Peer-Reviewed Evidence

Unlike observational prediction models, PRIME links risk identification to improved outcomes using randomized, controlled evidence. The interventions evaluated were commonly used and widely accessible, underscoring the feasibility of translating biomarker-guided strategies into real-world care.  And by supporting a 20% reduction in NICU admissions, more babies can stay with mom postpartum supporting patient centered care delivery.

Frequently Asked Questions About the PRIME Study

What makes the PRIME study different from prior preterm birth trials?
PRIME is a large, randomized controlled trial that confirmed findings from multiple peer-reviewed publications, pairing biomarker-based risk stratification with targeted interventions in clinically low-risk pregnancies. ^1,6,7

Was the PRIME population representative of routine obstetric care?
Yes. The study recruited a representative sample of participants, focused on clinically low-risk singleton pregnancies, reflecting the majority of patients seen in everyday practice.

Which neonatal outcomes improved most significantly in PRIME?
Neonatal morbidity, NICU admissions, reduction in risk of delivery before 32 and 35 weeks, and neonatal hospital length of stay were all improved in the intervention arm.

How was neonatal morbidity defined and measured?
Neonatal morbidity was assessed using a composite Neonatal Morbidity Index, an established measure designed to capture clinically meaningful outcomes.⁸

Why is biomarker-based risk stratification important in clinically low risk pregnancies?
Because most spontaneous preterm births occur in pregnancies without traditional risk factors, blood-based biomarkers can reveal risk that would otherwise remain undetected. The PreTRM test also supports identification of risk prior to symptom onset, enabling proactive care.

Conclusion: Clinical Significance of the Published PRIME Study

The PRIME Study provides peer-reviewed, randomized controlled evidence supporting biomarker-based risk stratification paired with targeted interventions. The trial demonstrates meaningful improvements in neonatal outcomes and represents an important step toward more personalized, proactive prenatal care.

Additional clinical resources for interested clinicians include:

• Review the full PRIME peer-reviewed publication
• Explore additional educational resources on preterm birth risk assessment

References:

1.Iriye BK, O’Brien JM, Ennen CS, et al. Neonatal impact of maternal biomarker screening for risk of preterm birth with targeted interventions (PRIME): A multicenter, randomized, controlled trial. Pregnancy 2026;2(1):e70202. DOI: https://doi.org/10.1002/pmf2.702022. 2.Waitzman NJ, et al. Updating National Preterm Birth Costs to 2016 with Separate Estimates for Individual States: Final Report to the March of Dimes. Available from: https://www.marchofdimes.org/peristats/documents/Cost_of_Prematurity_2019.pdf3. Saade GR, et al. Development and validation of a spontaneous preterm delivery predictor in asymptomatic women. Am J Obstet Gynecol. 2016;214(5):633.e1-24 4.Burchard J, Saade GR, Boggess KA, et al. Better estimation of spontaneous preterm birth prediction performance through improved gestational age dating. J Clin Med. 2022;11(10):2885. doi:10.3390/jcm11102885 5. Burchard J, Polpitiya AD, Fox AC, et al. Clinical validation of a proteomic biomarker threshold for increased risk of spontaneous preterm birth and associated clinical outcomes: a replication study. J Clin Med. 2021;10(21):5088. doi:10.3390/jcm10215088 6.Hoffman MK, Kitto C, Zhang Z, Shi J, Walker MG, Shahbaba B, Ruhstaller K. Neonatal Outcomes after Maternal Biomarker-Guided Preterm Birth Intervention: The AVERT PRETERM Trial. Diagnostics. 2024; 14(14):1462. https://doi.org/10.3390/diagnostics14141462 7.Branch DW, VanBuren JM, Porter TF, Holmgren C, Holubkov R, Page K, Burchard J, Lam GK, Esplin MS. Prediction and prevention of preterm birth: a prospective, randomized intervention trial. Am J Perinatol. 2023;40(10):1071-1080. doi:10.1055/s-0041-1732339 8.Hassan SS, Romero R, Vidyadhari D, et al. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2011;38(1):18-31. doi:10.1002/uog.9017