Clinical trial NCT05131282: Maternal Serum Markers Predicting Preeclampsia At Early Gestations
Official title: An Observational Study of a Maternal Blood Protein Predictor for Case Finding of Pregnancies At Risk of Preeclampsia At Early Gestation
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Pre-eclampsia
Preterm Birth
Keywords: pre-eclampsia
maternal serum marker
preterm pre-eclampsia
Lead sponsor: HBI Solutions Inc.
Sponsor class: INDUSTRY
Collaborators: name: Shenzhen Maternity & Child Healthcare Hospital
name: Eighth Affiliated Hospital, Sun Yat-sen University
name: Women's Hospital, of Zhejiang University School of Medicine
name: Third Affiliated Hospital of Zhengzhou University
name: Qilu Hospital of Shandong University
name: Hunan Provincial Maternal and Child Health Care Hospital
First posted: 2021-11-23
Enrollment: 18000
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: A multiple-site prospective cohort of women who developed PE (i.e. the PE group) and women who had normal pregnancy (i.e. the Normal group) will be recruited. Maternal serum samples were collected between 11 weeks and 13 weeks+6 days of GA. The two group of women are matched by age, BMI, pregnant history, and other clinical information.

Brief summary: This observational study aims to assess the effectiveness of a maternal blood test as a prognostic tool for predicting early pregnancy risk of preeclampsia (PE).

We hypothesize that specific circulating protein markers may serve as reliable biomarkers for PE risk prediction. Our PE predictor is a standalone blood test designed for early gestation screening to identify pregnancies at risk. This test measures concentrations of four proteins between 11 weeks and 13 weeks+6 days of gestation.

Based on the levels of these analytes, the test generates a risk score to classify patients as either low or high risk for PE.

Detailed description: Background and rationale:

Preeclampsia (PE) is a severe medical condition that affects 2-4% of pregnant women globally and is characterized by high blood pressure along with organ damage, particularly to the liver and kidneys. It is one of the leading causes of maternal and fetal morbidity and mortality worldwide. Early detection and preventative management of PE, including the use of low-dose aspirin, are essential for safeguarding the health of both the mother and the developing fetus. The British National Institute for Health and Care Excellence (NICE) and the American College of Obstetricians and Gynecologists (ACOG) use risk factor-based guidelines to identify women at high risk for PE. These guidelines treat each risk factor independently, leading to additive detection rates but low overall sensitivity. NICE guidelines detect only 40% of preterm PE and 35% of all PE cases with an 11% false positive rate, while ACOG detects just 5% of preterm and 2% of term PE. ACOG recommends low-dose aspirin only for women with a history of preeclampsia in multiple pregnancies or preterm delivery before 34 weeks, covering just 0.3% of all pregnancies, 5% of preterm PE, and 2% of term PE. The Fetal Medicine Foundation (FMF) PE test is utilized in several studies for screening and assessing the risk of developing PE during the first trimester. This test measures biochemical markers, such as pregnancy associated plasma protein A (PAPP-A) and placental growth factor (PlGF), in maternal blood to calculate individual risk scores. However, its limitations have highlighted the need for more effective and reliable alternatives. Performance varies across clinical sites, with sensitivity reported as low as 39-40%, and its positive predictive value (PPV) is relatively low, typically around 10-20%. This results in a significant number of false positives and negatives, which can lead to unnecessary anxiety for pregnant women and may result in missed diagnoses for those at risk. Furthermore, the FMF test requires specialized equipment and techniques, such as ultrasound for measuring the uterine artery pulsatility index (UAPI), making it less accessible in resource-limited settings and inaccuracy due to variance from different operators. These constraints limit its widespread use, underscoring the urgent need for improved blood tests to enhance prediction accuracy and reduce false results.

Clinical significance and potential impact of the test:

Advancements in medical research and technology are paving the way for more effective blood tests to improve pre-eclampsia care management. By integrating additional biomarkers and employing cutting-edge diagnostic tools such as genomics, proteomics, and metabolomics, we aim to enhance the precision and reliability of preeclampsia predictions. Our current research showcases the use of four blood serum protein markers to assess the risk of pre-eclampsia in women during early gestation (11-13 weeks), well before clinical symptoms arise.

To further validate the prediction and diagnosis performance of the novel preeclampsia test, we will enroll patients and initiate a large, multi-center observational clinical trial, including four diverse Asia cohorts, to test whether this standalone solution could bypass the need for complex maternal assessments.

Objectives and primary hypothesis of the study:

The primary objective of this study is to evaluate the predictive performance of the test for preterm preeclampsia (PE), specifically assessing its sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Additionally, the study aims to examine the test's predictive performance for overall PE, using the same performance metrics. We hypothesize that specific circulating protein markers may serve as reliable biomarkers for identifying pregnancies at risk for PE.

TRIAL DESIGN:

This trial is a multicenter observational study conducted in real-world clinical settings.

OUTCOMES:

The primary outcome is the diagnosis of PE during pregnancy, following the America College of Obstetricians and Gynecologists (ACOG, 2019) criteria. This diagnosis will be based on a systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg, measured on multiple occasions after 20 weeks of gestation, alongside proteinuria (dipstick urinalysis ≥ 1+ or a protein/creatinine ratio ≥ 30 mg/mmol \[0.3 mg/mg\]) or other signs of maternal organ dysfunction. PE will be categorized by gestational age at delivery as early-onset (\<34 weeks), preterm (\<37 weeks), or term (≥37 weeks).

Eligibility criteria: Inclusion Criteria:

1. Female participants aged 18 to 40 years.
2. Gestational age between 11 weeks and 13 weeks+6 days of GA at the first visit, as confirmed by ultrasound.
3. Control group: Pregnancies with no risk factors for preterm delivery, preeclampsia, or fetal growth restriction, selected during routine prenatal care between 11 weeks and 13 weeks+6 days of GA.
4. Informed consent to participate in the study.

   Exclusion Criteria:
5. Multiple pregnancies.
6. Pregestational diabetes.
7. Chronic hypertension.
8. Systemic diseases (e.g., chronic kidney disease, autoimmune disorders).
9. Any maternal or fetal condition necessitating pregnancy termination.
10. Known major fetal anomalies or fetal demise.
11. Active vaginal bleeding.
12. Serious medical illnesses (e.g., renal insufficiency, congestive heart failure, chronic respiratory insufficiency).
13. Asthma requiring systemic corticosteroids.
14. Use of anti-platelet or non-steroidal anti-inflammatory drugs.
15. Active hepatitis.
16. Lack of informed consent.

Primary outcomes:
measure: diagnosis of PE during pregnancy
timeFrame: an average of up to 1 year
Secondary outcomes:
measure: Sensitivity, specificity, PPV and NPV
timeFrame: an average of up to 1 year
Other outcomes:
Locations:
city: Shenzhen
country: China
facility: Shenzhen Maternity & Child Healthcare Hospital
state: Guangdong
city: Shenzhen
country: China
facility: the Eighth Affiliated Hospital
state: Guangdong
city: Zhengzhou
country: China
facility: The Third Affiliated Hospital of Zhengzhou University
state: Henan
city: Changsha
country: China
facility: Hunan Provincial Maternal and Child Health Care Hospital
state: Hunan
city: Jinan
country: China
facility: Qilu Hospital of Shandong University
state: Shandong
city: Hangzhou
country: China
facility: Women's Hospital, of Zhejiang University School of Medicine
state: Zhejiang
Study officials:
affiliation: Shenzhen Maternity and Child Healthcare Hospital
name: Jianmin Niu, Master
role: PRINCIPAL_INVESTIGATOR
References: