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

Available data suggest that low dose aspirin may be a safe, widely available and inexpensive intervention that may significantly reduce the risk of preterm birth. However, this possibility needs to be proven in a properly designed randomized controlled trial (RCT) with preterm birth as the primary outcome. Such a clinical trial in a racially, ethnically and geographically diverse population could best be accomplished by the established infrastructure of the Global Network for Women's and Children's Health Research (GN).

Study Overview

• Status: Completed
• Conditions: Premature Birth
• Intervention / Treatment: Drug: Placebo; Drug: Low dose aspirin

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 11976
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Congo, The Democratic Republic of the
  • Kinshasa, Congo, The Democratic Republic of the
    • Kinshasa School of Public Health
• Guatemala
  • Guatemala City, Guatemala, 01015
    • Institute of Nutrition of Central America and Panama (INCAP)
• India
  • Nagpur, India
    • Lata Medical Research Foundation
  • Karnataka
    • Belgaum, Karnataka, India
      • KLE University's Jawaharlal Nehru Medical College
• Kenya
  • Eldoret, Kenya, 30100
    • Moi University School of Medicine
• Pakistan
  • Karachi, Pakistan, 74800
    • The Aga Khan University
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama, Birmingham
  • Colorado
    • Denver, Colorado, United States, 80045
      • University of Colorado, Denver
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Boston University
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina, Chapel Hill
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
• Zambia
  • Lusaka, Zambia
    • University Teaching Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 38 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intervention Arm; Women will be randomized equally to receive daily low dose aspirin (LDA) [also known as acetylsalicylic acid (ASA)] of 81 mg beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.	Drug: Low dose aspirin; 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.; Other Names: Acetylsalicylic acid (ASA)
Placebo Comparator: Placebo Arm; Women will be randomized equally to receive an identical appearing placebo beginning between 6 0/7 weeks and 13 6/7 weeks GA and continuing until 36 0/7 weeks GA or delivery.	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Preterm Birth	The primary outcome of this study is incidence of preterm birth, which will be defined as delivery at or after 20 0/7 weeks and prior to 37 0/7 weeks. This will be determined based on actual date of delivery in comparison to the projected estimated due date (EDD), independent of whether or not the preterm delivery is indicated or spontaneous.	At delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Hypertensive Disorders of Pregnancy	- Hypertensive disorders of pregnancy is defined by the characterization of evidence of a hypertensive disorder, including either preeclampsia or eclampsia occurring during the pregnancy.	Evidence of hypertensive disorder during the pregnancy (prior to delivery/birth)
Incidence of Small for Gestational Age (SGA)	- Small for gestational age (SGA) as defined by the INTERGROWTH-21st standard	At delivery or at Day 42 after delivery
Incidence of Perinatal Mortality	- Incidence of Perinatal Mortality	At delivery or at Day 42 after delivery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maternal Outcome 1 - Incidence of Vaginal Bleeding	- Vaginal bleeding	At delivery or at Day 42 after delivery
Maternal Outcome 2 - Incidence of Antepartum Hemorrhage	- Antepartum hemorrhage	At delivery or at Day 42 after delivery
Maternal Outcome 3 - Incidence of Postpartum Hemorrhage	- Postpartum hemorrhage	At delivery or at Day 42 after delivery
Maternal Outcome 4 - Incidence of Maternal Mortality	- Incidence of Maternal Mortality	At delivery or at Day 42 after delivery
Maternal Outcome 5 - Incidence of Late Abortion	- Incidence of Late Abortion	At delivery or at Day 42 after delivery
Maternal Outcome 6 - Change in Maternal Hemoglobin	Hemoglobin < 7.0 gm/dl at 26-30 weeks gestation or a drop of 3.5+ gm/dl from screening to 26-30 weeks gestation	At enrollment, 4 weeks post enrollment, and 26-30 weeks GA.
Maternal Outcome 7 - Incidence of Preterm, Preeclampsia	Early preterm delivery (<34 weeks) and hypertensive disorders (i.e.: preeclampsia)	At delivery or at Day 42 after delivery
Fetal Outcome 1 - Incidence of Early Preterm Delivery (<34 Weeks)	- Early preterm delivery (<34 weeks)	At delivery
Fetal Outcome 2 - Incidence of Actual Birth Weight <2500g	- Birth weight <2500g	At delivery
Fetal Outcome 3 - Incidence of Actual Birth Weight <1500g	- Birth weight <1500g	At delivery
Fetal Outcome 4 - Incidence of Fetal Loss	- Incidence of Fetal Loss	At delivery
Fetal Outcome 5 - Incidence of Spontaneous Abortion	- Incidence of Spontaneous Abortion	At delivery
Fetal Outcome 6 - Incidence of All Stillbirth	- Incidence of All stillbirth	At delivery
Fetal Outcome 7 - Incidence of Medical Termination of Pregnancy	- Incidence of Medical Termination of Pregnancy	At delivery

Collaborators and Investigators

• Sponsor: NICHD Global Network for Women's and Children's Health
• Collaborators: Thomas Jefferson University; Jawaharlal Nehru Medical College
• Investigators: Study Director: Marion Koso-Thomas, MD, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Publications and helpful links

General Publications

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• Hoffman MK, Goudar SS, Kodkany BS, Metgud M, Somannavar M, Okitawutshu J, Lokangaka A, Tshefu A, Bose CL, Mwapule A, Mwenechanya M, Chomba E, Carlo WA, Chicuy J, Figueroa L, Garces A, Krebs NF, Jessani S, Zehra F, Saleem S, Goldenberg RL, Kurhe K, Das P, Patel A, Hibberd PL, Achieng E, Nyongesa P, Esamai F, Liechty EA, Goco N, Hemingway-Foday J, Moore J, Nolen TL, McClure EM, Koso-Thomas M, Miodovnik M, Silver R, Derman RJ; ASPIRIN Study Group. Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial. Lancet. 2020 Jan 25;395(10220):285-293. doi: 10.1016/S0140-6736(19)32973-3. Erratum In: Lancet. 2020 Mar 21;395(10228):e53.
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Study record dates

Study Major Dates

• Study Start (Actual): March 23, 2016
• Primary Completion (Actual): April 11, 2019
• Study Completion (Actual): April 11, 2019

Study Registration Dates

• First Submitted: March 30, 2015
• First Submitted That Met QC Criteria: April 6, 2015
• First Posted (Estimate): April 7, 2015

Study Record Updates

• Last Update Posted (Actual): September 8, 2021
• Last Update Submitted That Met QC Criteria: August 11, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Preterm birth; Low dose aspirin
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin
• Other Study ID Numbers: CP ASPIRIN