Aspirin (ASA) Therapy and Preeclampsia Prevention
Aspirin (ASA) Therapy and Preeclampsia Prevention
According to U.S. Pharmacist® "low-dose aspirin refers to dosages between 81 mg and 325 mg
 taken every day to prevent heart attacks, strokes, and colon cancer." It has been found
 through research that low-dose aspirin also decreases the risk of preeclampsia. The American
 College of Obstetrics and Gynecologists (ACOG) recommends low-dose aspirin (81mg/day) for
 women at high risk of preeclampsia. However, some researchers report that a dose of aspirin <
 100 mg/day does not seem to decrease the risk of preeclampsia. Another trial studying
 patients who are at a high risk for preterm preeclampsia, reported a reduction in the
 occurrence of preeclampsia among patients taking aspirin at a dose of 150 mg.

 The purpose of this pragmatic randomized study is to compare the difference in the
 effectiveness of two doses of aspirin: 81 mg versus 162 mg in the prevention of preeclampsia
 in pregnant women who are at a moderate to high risk for developing preeclampsia.
Rationale - The risk factors associated with preeclampsia (early-onset and late-onset,
 singleton deliveries) include the following maternal characteristics and clinical factors
 (Washington State, 2003-2008; ACOG 2018): age < 20 years, age >34 years, African-American
 race, marital status-single, first pregnancy, diabetes mellitus, chronic hypertension,
 infertility treatment, infant sex male, and congenital anomalies.

 Low dose aspirin decreases the risk of preeclampsia. The 2018 ACOG Committee Opinion on
 "Low-dose aspirin use during pregnancy" recommends the use of 81mg/day of aspirin for
 patients with risk factors for preeclampsia. However, it has been reported that a dose of
 aspirin < 100 mg/day does not seem to decrease the risk of preeclampsia.

 Rolnick et al., studying patients at high risk for preterm preeclampsia, reported a 63%
 relative risk reduction among patients taking aspirin at 150mg per day versus placebo. We
 anticipate a more conservative rate of 40% relative risk reduction, from 35% to 21%, for
 patients taking 162mg per day.

 Study/Project Population - We will include pregnant women up to 28.0 weeks gestation coming
 to the Regional One Health Obstetric (OB) Clinic for prenatal care, who meet ACOG's
 definition of high or moderate risk of developing preeclampsia during their current pregnancy
 (Low risk subjects will not be included).

 Those risk factors are:

 High Rish [ACOG recommends low-dose aspirin if the patient has one or more of these high-risk
 factors.]

 1. History of preeclampsia, especially when accompanied by an adverse outcome

 2. Multifetal gestation

 3. Chronic hypertension

 4. Type 1 or 2 Diabetes mellitus

 5. Renal disease [>300 mg/24-hour urine; protein creatinine ratio > 0.3; 1+ proteinuria;
 creatinine >1.2]

 6. Autoimmune disease (for example, systemic lupus erythematosus, antiphospholipid
 syndrome)

 Moderate Risk [ACOG recommends consideration of low-dose aspirin if the patient has more
 than one of these moderate-risk factors. Moderate-risk factors vary in their association
 with increased risk of preeclampsia.]

 7. Nulliparity

 8. Obesity (body mass index greater than 30)

 9. Family history of preeclampsia (mother or sister)

 10. Sociodemographic characteristics (African American race, low socioeconomic status)

 11. Age 35 years or older

 12. Personal history factors (e.g., low birthweight or small for gestational age, previous
 adverse pregnancy outcome, more than 10-year pregnancy interval)

 Low Risk [ACOG does not recommend low-dose aspirin.]

 13. Previous uncomplicated full-term delivery

 Research Design - This is a prospective clinical trial with binomial outcome and random
 assignment to two independent study groups, with a 1:1 ratio of assignment to 162mg versus
 81mg of aspirin recommended daily.

 For our sample size calculation, we use a one-sided Likelihood Ratio Chi-square Test for two
 proportions, with a Type I error rate of 5%, and power of 80%. To detect a 40% relative risk
 reduction in term preeclampsia prevalence, from 15% to 9%, requires a total (N)umber of 720
 patients. We estimate a 20% attrition due to causes including non-compliance, delivering at
 other hospitals, and non-hospital deliver; and therefore, plan to recruit 900 patients (450
 patients per group).

 To compare the ratios of preeclampsia incidence between two assigned groups, assigned to
 162mg or 81mg of daily aspirin, we plan to use a Likelihood Ratio Chi-square Test or Fisher's
 exact test.

 We anticipate a 12-month recruitment period for this study. The number of deliveries at
 Regional One Health (ROH) for the years 2017 and 2018 were 3325 and 3031 respectively.
 However, for this same period, the number of patients receiving prenatal care through
 Regional One Health Outpatient Center (MedPlex) were 1564 and 1651 respectively. This reveals
 that approximately 50% of those patients delivering at ROH did not receive prenatal care
 through Regional One Health.

 Study/Project Procedures - We will screen for eligibility by reviewing the clinic appointment
 lists, matching patient's reason for visit with key words indicating they are likely
 candidates. Subjects meeting inclusion criteria will be further screened for eligibility
 during their OB clinic visit. The willing subjects will have the informed consent presented,
 thoroughly explained, and given an opportunity to ask questions.

 Consented subjects will be randomly assigned and prescribed a daily dosage of 81 mg or 162 mg
 of aspirin to be taken each evening at bedtime. (See additional description below). Study
 drug bottles will be dispensed on the day of enrollment. Subjects will be instructed to
 continue taking the aspirin according to their randomization through the end of their
 pregnancy.

 Subjects will be randomized in consecutive order, entering their basic information (name,
 date of birth, medical record number, date/time of randomization, randomization number) on a
 master log.

 Patients recruited in the study will undergo a standard treatment ultrasound during the first
 trimester. At the time of consent, study subjects will be asked about their willingness to
 have a maternal uterine artery doppler ultrasound performed specifically for research. The
 maternal uterine artery doppler ultrasound will require an additional 3 minutes of the
 subject's time. If the subject agrees to participate in this portion of the study, they will
 initial the affirmative response line of the consent form.

 The additional information collected during the maternal uterine artery doppler ultrasound
 will add to the body of knowledge used as predictors of preeclampsia. This information will
 not be used for clinical management.

 We will collect data from the patient's electronic medical record (EMR) and the patient's
 fetus'/newborn's EMR, established at Regional One Health (clinic and hospital). This will
 include information pertaining to health history, current medical treatment, medications,
 pregnancy ultrasound scans, labor, delivery, and birth information.

 Collected paper records will be maintained in the research office under locked conditions.
 Electronic data will be retrieved, entered and stored in a study titled REDCap Data File,
 utilizing password protection for access. We will request the guidance and assistance of the
 Center for Biomedical Informatics (CBMI) personnel as is needed.

 Outcome Measures - Our primary outcome will be the occurrence of preeclampsia. Preeclampsia
 will be defined according to the 2018 American College of Obstetricians and Gynecologists
 recommendations.

 Interim analysis will be conducted after 318 enrolled subjects have delivered, evaluating the
 outcomes of: 'no preeclampsia,' 'preterm preeclampsia,' and 'term preeclampsia.' Enrollment
 will continue if the results of the first interim analysis are inconclusive. At that time,
 continuation of enrollment to 646 subjects delivered with a second interim analysis, or up to
 enrollment of 900 subjects delivered for a third, final analysis.
Inclusion Criteria:

 -  Pregnant females ages 14 to 50 years old

 -  Up to 28.0 weeks gestation (may initially base on last menstrual period (LMP), but
 confirmed with ultrasound (US)

 -  Be at high risk or moderate risk for developing preeclampsia as defined by the
 American College of Obstetrics and Gynecologists (ACOG-2018), the Society for
 Maternal-Fetal Medicine (SMFM-2018), and the United States Preventive Services Task
 Force (USPSTF-2017)

 Exclusion Criteria:

 -  Less than 14 years old or greater than 50 years old

 -  Allergy or contraindication to taking aspirin (i.e. nasal polyps, asthma with
 aspirin-induced bronchoconstriction)

 -  History of gastrointestinal bleeding

 -  Active peptic ulcer disease

 -  Other sources of active Gastrointestinal/Genitourinary bleeding

 -  Physician or provider refusal

 -  Patient refusal

 -  History of bleeding or clotting disorder (i.e. Factor V, von Willebrand, hemophilia)

 -  Severe renal failure (Glomerular Filtration Rate < 10 ml/min)

 -  Taking aspirin prior to pregnancy