Clinical Validation of a Proteomic Biomarker Threshold for Increased Risk of Spontaneous Preterm Birth

Burchard, Julja; Ad, Polpitiya; Ac, Fox; Randolph, Todd L.; Fleischer, Tracey C.; Dufford, Max T.; Tj, Garite; Gc, Critchfield; Jj, Boniface; Pe, Kearney

doi:10.1101/2021.01.23.21249902

Cited by 6 publications

(4 citation statements)

References 12 publications

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“…The proteomic biomarker measurements were assayed on all TREETOP serum samples as they were collected, using a standardized lab process previously validated and documented (11), consistent with clinical intended use. A previously validated probability threshold (34) was used to assign higher and lower preterm risk. As per Saade et al (9), proteomic measurements were translated into risk predictions for each subject and a threshold corresponding to 15% risk of sPTB < 37 weeks of gestation was employed to stratify higher vs. lower risk in each pregnancy.…”

Section: Methodsmentioning

confidence: 99%

Clinical and economic evaluation of a proteomic biomarker preterm birth risk predictor: Cost-effectiveness modeling of prenatal interventions applied to predicted higher-risk pregnancies within a large and diverse cohort

Burchard

Markenson

Saade

et al. 2021

Preprint

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Objective Evaluate clinical utility and cost effectiveness of identifying pregnancies at increased risk of preterm birth using a validated proteomic biomarker risk predictor to enable proactive intervention Study Design Pregnancies at elevated risk (≥15%) of preterm birth were identified in a cohort from TREETOP (NCT02787213), a study independent of biomarker development. In the screening arm, higher-risk subjects received simulated interventions based on published efficacy of multimodal treatment or care-management alone. Subjects in the non-screening arm received no interventions. Neonatal and maternal length of stay, neonatal mortality and morbidity and neonatal costs were compared between arms. Results Multimodal/care-management modeled treatments predicted reductions in neonatal (30%/22%) and maternal (9.2%/8.5%) hospital stays, neonatal morbidity and mortality (41%/29%), and neonatal costs (34%/16%) for the screening vs. non-screening arm. Conclusion Modeled interventions applied to pregnancies identified as higher-risk by a proteomic biomarker risk predictor demonstrate clinically and economically meaningful improvements in neonatal and maternal outcomes.

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Section: Methodsmentioning

confidence: 99%

Clinical and economic evaluation of a proteomic biomarker preterm birth risk predictor: Cost-effectiveness modeling of prenatal interventions applied to predicted higher-risk pregnancies within a large and diverse cohort

Burchard

Markenson

Saade

et al. 2021

Preprint

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“…These endpoints are better-powered continuous health-related outcomes than typical dichotomous surrogate endpoints (e.g., sPTB rate) 22,25 and have been reported to be enriched by the biomarker test. 20,21 Since the competing risk of death results in shorter stays, the protocol prespecified that NNLOS and NICULOS for fetuses or neonates who expired would be adjusted to be one day longer than the longest stay observed among all neonates. To avoid bias, calculations of mean days saved in the NICU between arms used the actual NICULOS for any neonates that expired in the NICU.…”

Section: Trial Outcomesmentioning

confidence: 99%

“…18,19 Biological links to spontaneous PTB (sPTB) have been proposed to involve IGFBP4 involvement in sensing fetal nutrient delivery and SHBG involvement in proinflammatory signaling within the placenta. 18,20 A risk score threshold corresponding to twice the U.S. population sPTB risk was subsequently validated 21 and shown to significantly stratify higher-and not-higher-risk participants in an extended window of 18 0/7 -20 6/7 weeks' gestation, with a sensitivity and specificity of 88% and 75%, respectively. 19 The objective of the AVERT PRETERM trial was to test whether targeting treatment improves neonatal outcomes for pregnancies deemed by the biomarker to be at elevated PTB risk but lacking traditional PTB risk factors.…”

Section: Introductionmentioning

confidence: 99%

“…Prior studies of the IGFBP4/SHBG predictor have demonstrated that it enriches strongly for severe sPTB and PTB-associated neonatal health outcomes such as hospital and neonatal intensive care unit (NICU) stays and neonatal morbitidy. 18,20,21 As described previously, 22 to avoid masking the clinical benefit of the test-and-treatment strategy by including the large excess of healthy births not expected to be altered by treatment, primary and secondary hypotheses were tested on quantiles of the population corresponding to the earliest births and the longest hospital and NICU stays.…”

Section: Introductionmentioning

confidence: 99%

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Neonatal outcomes after maternal biomarker-guided preterm birth intervention: the AVERT PRETERM trial

Hoffman,

Kitto,

Zhang

et al. 2023

Preprint

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1. 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. 2. 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. 3. Study Design The study 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 19 1/7-20 6/7 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. 4. 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%. 5. 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.

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Neonatal Outcomes after Maternal Biomarker-Guided Preterm Birth Intervention: The AVERT PRETERM Trial

Hoffman,

Kitto,

Zhang

et al. 2024

Diagnostics

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The AVERT PRETERM trial (NCT03151330) evaluated whether screening clinically low-risk pregnancies with a validated maternal blood biomarker test for spontaneous preterm birth (sPTB) risk, followed by preventive treatments for those screening positive, would improve neonatal outcomes compared to a clinically low-risk historical population that had received the usual care. Prospective arm participants with singleton non-anomalous pregnancies and no PTB history were tested for sPTB risk at 191/7–206/7 weeks’ gestation and followed up with after neonatal discharge. Screen-positive individuals (≥16% sPTB risk) were offered vaginal progesterone (200 mg) and aspirin (81 mg) daily, with twice-weekly nurse phone calls. Co-primary outcomes were neonatal morbidity and mortality, measured using a validated composite index (NMI), and neonatal hospital length of stay (NNLOS). Endpoints were assessed using survival analysis and logistic regression in a modified intent-to-treat population comprising screen-negative individuals and screen-positive individuals accepting treatment. Of 1460 eligible participants, 34.7% screened positive; of these, 56.4% accepted interventions and 43.6% declined. Compared to historical controls, prospective arm neonates comprising mothers accepting treatment had lower NMI scores (odds ratio 0.81, 95% CI, 0.67–0.98, p = 0.03) and an 18% reduction in severe morbidity. NNLOS was shorter (hazard ratio 0.73, 95% CI, 0.58–0.92, p = 0.01), with a 21% mean stay decrease among neonates having the longest stays. Sensitivity analyses in the entire intent-to-treat population supported these findings. These results suggest that biomarker sPTB risk stratification and preventive interventions can ameliorate PTB complications in singleton, often nulliparous, pregnancies historically deemed low risk.

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Clinical Validation of a Proteomic Biomarker Threshold for Increased Risk of Spontaneous Preterm Birth

Cited by 6 publications

References 12 publications

Clinical and economic evaluation of a proteomic biomarker preterm birth risk predictor: Cost-effectiveness modeling of prenatal interventions applied to predicted higher-risk pregnancies within a large and diverse cohort

Clinical and economic evaluation of a proteomic biomarker preterm birth risk predictor: Cost-effectiveness modeling of prenatal interventions applied to predicted higher-risk pregnancies within a large and diverse cohort

Neonatal outcomes after maternal biomarker-guided preterm birth intervention: the AVERT PRETERM trial

Neonatal Outcomes after Maternal Biomarker-Guided Preterm Birth Intervention: The AVERT PRETERM Trial

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