APPLE: Aspirin to Prevent Pregnancy Loss and Preeclampsia (APPLE)

The goal of this clinical trial is to investigate the effects of early initiation of double low-dose aspirin in pregnant women. The main questions it aims to answer are:

Does this dose and timing of aspirin reduce the risk of pre-eclampsia compared to standard recommendations? Does this dose and timing of aspirin reduce the risk of pregnancy loss compared to standard recommendations? Participants will begin taking at no later than 6 weeks 6 days gestational age, either 162mg of aspirin through delivery or placebo until 12 weeks and then 81mg of aspirin through delivery.

Study Overview

• Status: Recruiting
• Conditions: Pre-Eclampsia; Pregnancy Loss
• Intervention / Treatment: Drug: Aspirin 162 mg; Drug: Aspirin 81mg

• Study Type: Interventional
• Enrollment (Estimated): 1150
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Kurt T Barnhart, MD; Phone Number: 215-662-2974; Email: kbarnhart@pennmedicine.upenn.edu
• Study Contact Backup: Name: Enrique Schisterman, PhD; Email: enrique.schisterman@pennmedicine.upenn.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • University of Pennsylvania
      • Contact: Theresa Delahanty; Email: theresa.delahanty@pennmedicine.upenn.edu
      • Contact: Andrea Morley; Email: andrea.morley@pennmedicine.upenn.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

1. Provision of signed and dated informed consent form.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Ability to take oral medication and be willing to adhere to the prescribed aspirin regimen.
4. Patients with a gestation less than or equal to 6 weeks, 6 days (as determined by patient record of LMP or ART date).

5. Patients between 18-45-year old who have one or more risk factors for preeclampsia and/or pregnancy loss, including:

   1. preeclampsia in a previous pregnancy,
   2. gestational diabetes in a previous pregnancy,
   3. any documentation of fetal growth restriction or low birth weight in a prior pregnancy,
   4. preterm birth in a previous pregnancy,
   5. known multifetal gestation at enrollment,
   6. chronic hypertension,
   7. pregestational diabetes,
   8. kidney disease,
   9. systemic lupus erythematosus,
   10. nulliparity,
   11. pre-pregnancy body mass index >30,
   12. family history of preeclampsia (i.e., mother or sister),
   13. Black persons (due to social, not biological reasons),
   14. Maternal age 35 years or older,
   15. lower income (will be determined by qualification of public health insurance),
   16. conceived with fertility treatment (including in vitro fertilization, ovulation induction, or intrauterine insemination),
   17. history of one or more prior pregnancy losses <20 weeks gestation,
   18. history of stillbirth in a prior pregnancy,
   19. An interval of greater than 10 years since the last pregnancy.

Exclusion Criteria

1. Known allergies to aspirin or non-steroidal anti-inflammatory agents (NSAID);
2. Clinical indication for anticoagulant therapy, including prior or current thrombosis, antiphospholipid syndrome, or known major thrombophilia;
3. Clinical indication for chronic use of NSAIDS during pregnancy;
4. Medical contraindication to aspirin therapy, including untreated uncontrolled asthma, untreated symptomatic nasal polyps, bleeding disorders, or history of gastrointestinal ulcer.
5. Patients with pelvic pain or bleeding who require urgent care (i.e., active vaginal bleeding greater than or equal to expected menses, open cervical os suggesting active miscarriage or severe pain requiring evaluation for ectopic pregnancy)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Double low-dose aspirin; Participants will take 2 81mg aspirin tablets daily from entrance into the trial until delivery.	Drug: Aspirin 162 mg; Aspirin is a nonsteroidal anti-inflammatory drug.; Other Names: ASA; acetylsalicylic acid
Placebo Comparator: Standard of Care; Participants will take 2 placebo pills from entrance into the study until 12 weeks gestational age, they will then take 1 placebo pill and 1 81mg aspirin until delivery.	Drug: Aspirin 81mg; Aspirin is a nonsteroidal anti-inflammatory drug.; Other Names: ASA; acetylsalicylic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preeclampsia with or without severe features	defined as two blood pressures (BPs) ≥ 140/90 mmHg at least 4 hours apart with proteinuria	from 20 weeks pregnancy to delivery, approximately 20 weeks
Pregnancy Loss	Pregnancy loss prior to 24 weeks gestation	from enrollment to time of pregnancy loss, up to 24 weeks gestation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite outcome of hypertensive disorders of pregnancy or pregnancy loss	This composite outcome will include the diagnosis of any of the following: preterm preeclampsia, term preeclampsia, gestational hypertension, preeclampsia with severe features, preeclampsia without severe features, biochemical pregnancy loss, clinical pregnancy loss	From enrollment to end of pregnancy, up to 38 weeks
Preterm preeclampsia	Diagnosis of preterm preeclampsia, occurring prior to 37 weeks in pregnancy	From enrollment up to 37 weeks of pregnancy, up to 37 weeks of pregnancy
Term preeclampsia	Diagnosis of term preeclampsia, occurring at 37 weeks or later in pregnancy	From 37 weeks until delivery, up to 3 weeks
Gestational Hypertension	Defined as two BPs ≥ 140/90 mmHg at least 4 hours apart without proteinuria	From 20 weeks of pregnancy to delivery, approximately 20 weeks
Preeclampsia with severe features	Diagnosis of preeclampsia with severe hypertension and/or specific signs or symptoms of significant end-organ dysfunction	From 20 weeks of pregnancy to delivery, up to 20 weeks
Preeclampsia without severe features	defined as two BPs ≥160/110 mmHg at least 4 hours apart or any of the following lab abnormalities or symptoms: platelets <100,000/microliter, liver enzymes at least twice the normal concentration, and/or severe right upper quadrant/epigastric pain, serum creatinine > 1.1 mg/dL or a doubling of baseline serum creatinine, pulmonary edema, or new-onset cerebral or visual disturbances (headache, blurry vision). Preeclampsia super-imposed on chronic hypertension will also be considered as part of this outcome.	From 20 weeks of pregnancy to delivery, up to 20 weeks
Biochemical pregnancy loss	Defined as losses that occur prior to identification of a gestational sac via ultrasound	From enrollment to time of pregnancy loss, up to approximately 20 weeks
Clinical pregnancy loss	Defined as any pregnancy loss occurring following ultrasound confirmation of pregnancy	From time of first ultrasound to 20 weeks pregnancy
Preterm birth	Defined as delivery at less than 37 weeks gestation	From enrollment to 36 weeks 6 days of pregnancy, up to delivery
Small for gestational age	Defined as a birth weight less than 10th percentile for gestational age	At time of delivery

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Enrique Schisterman, PhD, University of Pennsylvania; Principal Investigator: Kurt Barnhart, MD, University of Pennsylvania

Study record dates

Study Major Dates

• Study Start (Actual): June 12, 2024
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: May 1, 2024
• First Submitted That Met QC Criteria: May 7, 2024
• First Posted (Actual): May 10, 2024

Study Record Updates

• Last Update Posted (Actual): January 20, 2026
• Last Update Submitted That Met QC Criteria: January 16, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Pregnancy Complications; Hypertension, Pregnancy-Induced; Pre-Eclampsia; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Phenols; Benzene Derivatives; Salicylates; Hydroxybenzoates; Aspirin
• Other Study ID Numbers: 854886; 1R01HD112308-01 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No