Role of ASpirin in Placental and Maternal Endothelial Cell Regulation IN Pre-eclampsia

Overview

Endothelial dysfunction and defective placental vascularization are hypothesized to be significant causes of preeclampsia. In preeclampsia, due to vascular endothelial dysfunction, vasoconstriction and platelet activation can result in severe features which alter pregnancy outcomes. However, studies have shown that acetylsalicylic acid (Aspirin) can decrease endothelial dysfunction leading to decreased platelet aggregation which reduces adverse outcomes. The objective of our study is to determine if Aspirin has a dose-dependent response for modifying biomarkers reflective of maternal endothelial dysfunction when indicated for preeclampsia prevention in a cohort of women identified at risk for developing preeclampsia. Pregnant women who are at risk for preeclampsia will be randomized to receive either 81mg Aspirin or 162mg Aspirin daily starting from 11-16 weeks of gestation until 36 weeks of gestation. A third, control group of women at low risk for preeclampsia will not receive aspirin. All women will be assessed with uterine artery Doppler studies and mean arterial blood pressures at three time points during pregnancy. Blood, urine, and cord blood samples will also be collected.

Full Title of Study: “Role of Aspirin in Maternal Endothelial Dysfunction and Uterine Artery Blood Flow in Women at Risk for Preeclampsia”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 2023

Detailed Description

Eligible women will be identified in the late first or early second trimesters. Once recruited, women will be randomly assigned to either 81 mg or 162 mg per day dosing schedules. The randomization scheme will vary based on the body mass index (BMI) with separate schemes for women <=30 kg/m2 versus >30 kg/m2. Ultrasonographic assessment of biophysical biomarkers will be obtained at 11-16 weeks, 18-22 weeks, and 28-32 weeks gestation. Biologic samples of serum and urine will be obtained at the 11-16 week and 28-32 week visit. Upon delivery, cord blood and a placental specimen will also be obtained. Medication treatment will continue until 36 weeks gestation. Pregnancy and neonatal outcome data will be recorded.

Interventions

  • Drug: Acetylsalicylic Acid 81 mg
    • Patients will receive 81mg acetylsalicylic acid daily, initiated between 11 and 16 weeks of gestation and continued until 36 weeks of gestation.
  • Drug: Acetylsalicylic Acid 162 mg
    • Patients will receive 162mg acetylsalicylic acid daily, initiated between 11 and 16 weeks of gestation and continued until 36 weeks of gestation.
  • Other: Control
    • Standard of Care

Arms, Groups and Cohorts

  • Active Comparator: Control Group
    • Patients will receive standard of care.
  • Experimental: Acetylsalicylic Acid 81mg
    • Patients will receive low dose (81mg) acetylsalicylic acid (Aspirin).
  • Experimental: Acetylsalicylic Acid 162mg
    • Patients will receive low dose (162mg) acetylsalicylic acid (Aspirin).

Clinical Trial Outcome Measures

Primary Measures

  • Change in Pulsatility Index (PI)
    • Time Frame: Three times between 11 and 32 weeks of gestation.
    • Uterine artery doppler will be used to assess impedance to flow in the uterine artery three times: at 11-16 weeks gestation, 18-22 weeks gestation, and 28-32 weeks gestation.

Secondary Measures

  • Onset of Pre-eclampsia
    • Time Frame: Throughout pregnancy and postpartum ( 6 weeks after delivery)
    • Frequency of Disease during pregnancy and postpartum as defined by American College of Obstetrics and Gynecology (ACOG) criteria
  • Severity of Pre-eclampsia
    • Time Frame: Throughout pregnancy and immediate postpartum ( 6 weeks after delivery)
    • Frequency women are identified with Severe Features of the disease
  • Composite Neonatal outcomes including frequency of Intraventricular hemorrhage (IVH), Bronchopulmonary dysplasia (BPD), Respiratory distress syndrome (RDS), Necrotising enterocolitis(NEC)
    • Time Frame: Neonatal period ( first 28 days after birth)
    • Frequency of adverse neonatal outcomes
  • Change in s-ICAM levels over time
    • Time Frame: Three times between 11 and 32 weeks of gestation
    • Serial biologic samples will be obtained in the first, second, and third trimesters to measure changes in soluble Intercellular Adhesion Molecule (s-ICAM) levels over time.
  • Change in PIGF levels over time
    • Time Frame: Three times between 11 and 32 weeks of gestation
    • Serial biologic samples will be obtained in the first, second, and third trimesters to measure changes in placental growth factor (PIGF) levels over time.
  • Change in CRP levels over time
    • Time Frame: Three times between 11 and 32 weeks of gestation
    • Serial biologic samples will be obtained in the first, second, and third trimesters to measure changes in C-reactive protein (CRP) levels over time.
  • Change in IL-6 over time
    • Time Frame: Three times between 11 and 32 weeks of gestation
    • Serial biologic samples will be obtained in the first, second, and third trimesters to measure changes in interleukin 6 (IL-6) levels over time.
  • Change in TNF over time
    • Time Frame: Three times between 11 and 32 weeks of gestation
    • Serial biologic samples will be obtained in the first, second, and third trimesters to measure changes in tumor necrosis factor (TNFα) levels over time.

Participating in This Clinical Trial

Inclusion Criteria (control) • No risk factors for preeclampsia Inclusion Criteria (pre-eclampsia)

  • History of preterm preeclampsia – Chronic hypertension – Type 1 and Type 2 diabetes – Renal diseases – Autoimmune disease Exclusion Criteria – Pregnant women younger than 18 years or older than 45 years – Multiple gestations – History of allergy (urticaria or anaphylaxis) to aspirin or aspirin-related products asthma that worsens after aspirin use – Patients with gastrointestinal or genitourinary bleeding – Patients with peptic ulcer disease – Patients with severe liver dysfunction – Patients who have undergone bypass surgery – Patients on anticoagulant medication(s) – Women with anomalous fetus

Gender Eligibility: Female

Minimum Age: 18 Years

Maximum Age: 45 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • John O’Brien, MD
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: John O’Brien, MD, Professor – University of Kentucky
  • Overall Official(s)
    • John M O’Brien, MD, Principal Investigator, University of Kentucky
    • Katherine Vignes, MD, Study Chair, University of Kentucky
  • Overall Contact(s)
    • Aarthi Srinivasan, MD, MS, 8592180765, asr224@uky.edu

References

Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco Matallana C, Akolekar R, Cicero S, Janga D, Singh M, Molina FS, Persico N, Jani JC, Plasencia W, Papaioannou G, Tenenbaum-Gavish K, Meiri H, Gizurarson S, Maclagan K, Nicolaides KH. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med. 2017 Aug 17;377(7):613-622. doi: 10.1056/NEJMoa1704559. Epub 2017 Jun 28.

Askie LM, Duley L, Henderson-Smart DJ, Stewart LA; PARIS Collaborative Group. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007 May 26;369(9575):1791-1798. doi: 10.1016/S0140-6736(07)60712-0.

Roberge S, Bujold E, Nicolaides KH. Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol. 2018 Mar;218(3):287-293.e1. doi: 10.1016/j.ajog.2017.11.561. Epub 2017 Nov 11.

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