Aspirin Supplementation for Pregnancy Indicated Risk Reduction In Nulliparas (ASPIRIN)

Background: Preterm birth (PTB) remains the leading cause of neonatal mortality and long term
disability throughout the developed and developing world. Though complex in its origins, a
growing body of evidence suggests that first trimester administration of low dose aspirin
(LDA) holds promise to reduce the rate of PTB substantially.

Hypothesis: The investigators' primary hypothesis is that nulliparous women with no more than
two previous first trimester pregnancy losses who are treated with LDA daily beginning
between 6 0/7 weeks and 13 6/7 weeks gestational age (GA) through 36 0/7 weeks GA will reduce
the risk of preterm birth from all causes.

Study Design Type: Prospective randomized, placebo-controlled, double-blinded multicenter
clinical trial (patient level 1:1).

Population: Nulliparous women between the ages of 18 (or local age of majority) and 40 with
no more than two previous first trimester pregnancy losses or any second trimester
spontaneous pregnancy loss, a singleton pregnancy between 6 0/7 weeks and 13 6/7 weeks GA
confirmed by ultrasound, and no contraindications to aspirin. Other medical conditions, such
as sickle-cell anemia, may be considered a contraindication per the judgment of the site
investigator.

Intervention: Daily administration of low dose (81 mg) aspirin [also known as acetylsalicylic
acid (ASA)], initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks
GA compared to an identical appearing placebo. Compliance and outcomes will be assessed
biweekly.

Outcomes:

The primary outcome is to determine whether daily LDA initiated between 6 0/7 weeks and 13
6/7 weeks and continued to 36 0/7 weeks reduces the risk of preterm birth (birth prior to 37
0/7 weeks of pregnancy) by 20%. This will be determined based on assessed date of delivery in
comparison to the projected estimated date of delivery, independent of whether or not the
preterm delivery is indicated or spontaneous.

Secondary outcomes include:

- Preeclampsia and eclampsia (hypertensive disorders of pregnancy)

- Small for gestational age

- Perinatal mortality

Other secondary outcomes of interest are:

Maternal outcomes:

- Vaginal bleeding

- Antepartum hemorrhage

- Postpartum hemorrhage

- Maternal mortality

- Late abortion

- Change in maternal hemoglobin

- Preterm, preeclampsia

Fetal outcomes:

- Preterm birth <34 0/7 weeks of pregnancy

- Birth weight <2500g and <1500g

- Fetal loss

- Spontaneous abortion

- Stillbirth

- Medical termination of pregnancy

Inclusion Criteria:

- Nulliparous women between 18 - 40 years of age. Minors who are ≥ 14 years of age may
be enrolled if permitted by the country's ethical guidelines.

- No more than two previous first trimester pregnancy losses

- No medical contraindications to aspirin;

- Single live intrauterine pregnancy (IUP) between 6 0/7 and 13 6/7 weeks GA
corroborated by an early dating ultrasound and with presence of a heartbeat.

Exclusion Criteria:

- Women prescribed daily aspirin for more than 7 days;

- Multiple gestations;

- Fetal anomaly by ultrasound (Note most fetal anomalies are not detectable by
ultrasounds done at this early gestation. Subsequent discovery of a fetal anomaly is
not viewed as an exclusion.);

- Hemoglobin < 7.0 gm/dl at screening;

- Any other medical conditions that may be considered a contraindication per the
judgment of the site investigator (e.g., Lupus, Type 1 Diabetes, or any other known
significant disease)

- Blood pressure ≥ 140/90 (Systolic blood pressure ≥ 140 and diastolic ≥ 90 at
screening)