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

John O'Brien, MD208 enrolled

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Interventions

Acetylsalicylic Acid 81 mgDRUG

Patients will receive 81mg acetylsalicylic acid daily, initiated between 11 and 16 weeks of gestation and continued until 36 weeks of gestation.

Acetylsalicylic Acid 162 mgDRUG

Patients will receive 162mg acetylsalicylic acid daily, initiated between 11 and 16 weeks of gestation and continued until 36 weeks of gestation.

ControlOTHER

Standard of Care

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Change in Pulsatility Index (PI)

Uterine artery doppler is used to assess impedance to flow in the uterine artery three times: 11-16 weeks gestation(baseline), 18-22 weeks gestation (event 2), 28-32 weeks gestation (event 3). Data reported as change between 11-16 weeks gestation (baseline) and either 18-22 weeks gestation (event 2) or 28-32 weeks gestation (event 3). difference in uterine artery pulsatility index (PI) is calculated as the difference in PI for each patient between each trimester visit. PI at each visit will be calculated by averaging left-side and right-side PIs from each of three (or all available) images on each side for each patient using ultrasound technology. Unit of measure is a ratio: difference between the peak systolic and end-diastolic velocities divided by the mean flow velocity Relative change in uterine artery pulsatility index is a measure of flow to the uterus. A greater difference from the baseline value represents a greater improvement in placental perfusion.

Time frame: Three times between 11 and 32 weeks of gestation.

Secondary Outcomes

Onset of Pre-eclampsia

Frequency of Disease during pregnancy and postpartum as defined by American College of Obstetrics and Gynecology (ACOG) criteria

Time frame: From enrollment at 11 weeks throughout pregnancy and postpartum ( 6 weeks after delivery), approximately 35 weeks

Severity of Pre-eclampsia

Frequency women are identified with Severe Features of the disease

Time frame: From enrollment at 11 weeks throughout pregnancy and immediate postpartum ( 6 weeks after delivery), approximately 35 weeks

Composite Neonatal Outcomes Including Frequency of Intraventricular Hemorrhage (IVH), Bronchopulmonary Dysplasia (BPD), Respiratory Distress Syndrome (RDS), Necrotising Enterocolitis(NEC)

Frequency of adverse neonatal outcomes

Time frame: Neonatal period ( first 28 days after birth)

Change in s-ICAM Levels Over Time

Serial biologic samples will be obtained in the first (baseline), second (event 2), and third (event 3) trimesters to measure changes in soluble Intercellular Adhesion Molecule (s-ICAM) levels over time.