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

Study Overview
=================
Brief Summary
-----------------
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.

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.

Official Title
-----------------
Role of Aspirin in Maternal Endothelial Dysfunction and Uterine Artery Blood Flow in Women at Risk for Preeclampsia

Conditions
-----------------
Pre-Eclampsia

Intervention / Treatment
-----------------
* Drug: Acetylsalicylic Acid 81 mg
* Drug: Acetylsalicylic Acid 162 mg
* Other: Control


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control Group<br>Patients will receive standard of care. | Other: Control<br>* Standard of Care<br>|
| Experimental: Acetylsalicylic Acid 81mg<br>Patients will receive low dose (81mg) acetylsalicylic acid (Aspirin). | Drug: Acetylsalicylic Acid 81 mg<br>* Patients will receive 81mg acetylsalicylic acid daily, initiated between 11 and 16 weeks of gestation and continued until 36 weeks of gestation.<br>* Other names: Aspirin;|
| Experimental: Acetylsalicylic Acid 162mg<br>Patients will receive low dose (162mg) acetylsalicylic acid (Aspirin). | Drug: Acetylsalicylic Acid 162 mg<br>* Patients will receive 162mg acetylsalicylic acid daily, initiated between 11 and 16 weeks of gestation and continued until 36 weeks of gestation.<br>* Other names: Aspirin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Pulsatility Index (PI) | 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. | Three times between 11 and 32 weeks of gestation. | 

Secondary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
aspirin, pulsatility index, doppler, uterine, acetylsalicylic acid, preeclampsia, blood pressure