Aspirin for Miscarriage and Preeclampsia

(APPLE Trial)

Overseen By Enrique Schisterman, PhD

Age: 18 - 65

Sex: Female

Trial Phase: Phase 3

Sponsor: University of Pennsylvania

Must be taking: Aspirin

Must not be taking: Anticoagulants, NSAIDs

Disqualifiers: Aspirin allergy, Anticoagulant need, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: From enrollment to delivery, approximately 38 weeks

1150 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on anticoagulant therapy or need to use NSAIDs regularly during pregnancy, you may not be eligible to participate.

What data supports the effectiveness of the drug aspirin for preventing miscarriage and preeclampsia?

Research shows that aspirin can help prevent preeclampsia (a pregnancy complication characterized by high blood pressure) in high-risk patients, and it has been used safely during pregnancy in low doses. However, its benefits for preventing unexplained recurrent miscarriages have not been clearly demonstrated. ^{1 2 3 4 5}

Is low-dose aspirin safe for pregnant women?

Low-dose aspirin is generally considered safe for pregnant women, especially when used to prevent preeclampsia in those at high risk, as long as the daily dose does not exceed 100mg. ^{1 2 3 6 7}

How does aspirin differ from other drugs for miscarriage and preeclampsia?

Aspirin is unique because it is used in low doses to prevent preeclampsia and miscarriage by reducing platelet activity and improving blood flow to the placenta. Unlike other treatments, aspirin is recommended for women at high risk of preeclampsia, with specific guidelines on dosage and timing to maximize its effectiveness. ^{1 2 3 8 9}

What is the purpose of this trial?

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.

Research Team

Enrique Schisterman, PhD

Principal Investigator

University of Pennsylvania

Kurt Barnhart, MD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

The APPLE trial is for pregnant women who can start treatment no later than 6 weeks and 6 days into their pregnancy. It's designed to see if early aspirin use can prevent complications like pre-eclampsia or pregnancy loss. Women with certain health conditions or on conflicting medications may not be eligible.

Inclusion Criteria

I can take pills and will follow the aspirin plan.

Provision of signed and dated informed consent form

Patients with a gestation less than or equal to 6 weeks, 6 days (as determined by patient record of LMP or ART date)

Exclusion Criteria

I cannot take aspirin due to asthma, nasal polyps, bleeding disorders, or past stomach ulcers.

I have severe pelvic pain or heavy bleeding needing urgent care.

Known allergies to aspirin or non-steroidal anti-inflammatory agents (NSAID)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants begin taking either 162mg of aspirin or placebo until 12 weeks, then 81mg of aspirin through delivery

From enrollment to delivery, approximately 38 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Aspirin

Trial Overview This study tests whether taking a double low-dose of aspirin (162mg) daily from very early in pregnancy, compared to a standard dose (81mg after the first trimester), reduces the risk of developing pre-eclampsia or experiencing pregnancy loss.

Participant Groups

Group I: Double low-dose aspirin Active Control 1 Intervention

Participants will take 2 81mg aspirin tablets daily from entrance into the trial until delivery.

Group II: Standard of Care Placebo Group 1 Intervention

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.

Aspirin is already approved in European Union, United States, Canada, China for the following indications:

Approved in European Union as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in United States as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in Canada as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in China as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Findings from Research

A systematic review of studies indicates that low-dose aspirin (80-150 mg daily) taken in the first trimester (before 16 weeks) may effectively reduce the severity of preeclampsia in at-risk pregnancies.

In contrast, studies administering aspirin later in pregnancy showed mixed results, suggesting that the timing and dosage of aspirin are crucial for its effectiveness in preventing preeclampsia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The Role of Aspirin in Preeclampsia Prevention: State of the Art]. Campos, A.[2018]

A quality improvement project in an academic OB/Gyn practice showed that implementing a standardized approach to aspirin (ASA) prescription significantly increased screening rates for preeclampsia risk from 47% to 99% among new obstetric patients.

Post-intervention, 79% of patients who screened positive received an ASA recommendation, demonstrating that the standardized process is effective and equitable, with no significant differences in recommendations based on race.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leveraging quality improvement to promote health equity: standardization of prenatal aspirin recommendations. Gross, ME., Godecker, A., Hughes, A., et al.[2023]

Aspirin is considered safe for use during pregnancy at daily doses not exceeding 100mg and has been shown to effectively prevent pre-eclampsia and fetal growth restriction in high-risk patients.

However, aspirin has not demonstrated benefits for preventing vascular placental disease in low-risk patients or for unexplained recurrent miscarriages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Aspirin: Indications and use during pregnancy]. Belhomme, N., Doudnikoff, C., Polard, E., et al.[2018]

First-trimester uterine artery Doppler studies can identify 50-65% of women at high risk for severe preeclampsia, which is crucial for early intervention, especially in cases requiring delivery before 35 weeks.

Combining uterine artery Doppler with the serum marker placental protein 13 may enhance detection rates of severe preeclampsia to up to 90%, suggesting a promising approach for screening high-risk pregnancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First trimester screening for preeclampsia. Papageorghiou, AT., Campbell, S.[2016]

In a study of 41 first-time pregnant women at risk for pregnancy-induced hypertension, those treated with 80 mg of aspirin daily had significantly lower rates of hypertension and preeclampsia compared to the placebo group, with no hypertensive complications in the aspirin group.

The aspirin treatment did not lead to any significant differences in pregnancy duration, birth weight, or fetal health indicators, and there was no increased risk of bleeding for mothers or babies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose aspirin in primigravidae with positive roll-over test. Schröcksnadel, H., Sitte, B., Alge, A., et al.[2018]

Low-dose aspirin has been shown to be beneficial in preventing pre-eclampsia in high-risk pregnant women, based on results from four large clinical trials involving over 13,000 participants.

The use of low-dose aspirin is considered safe for mothers and their babies, although its effect on preventing fetal growth retardation is minimal and no significant therapeutic benefits were found.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose aspirin therapy in obstetrics. Wallenburg, HC.[2019]

Low-dose aspirin has been shown to effectively reduce the risk of preeclampsia and fetal growth restriction in at-risk pregnant populations, but its benefits in low-risk groups remain unclear.

There is ongoing debate among medical organizations regarding the guidelines for aspirin use in pregnancy, with some recommending it only for at-risk women while others suggest it may be more effective and cost-efficient to prescribe it universally from the first trimester.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Should we recommend universal aspirin for all pregnant women? Mone, F., Mulcahy, C., McParland, P., et al.[2022]

Aspirin therapy significantly reduces the risk of perinatal death and preeclampsia in women with historical risk factors, based on a meta-analysis of 14 trials involving 12,416 women.

The use of aspirin is associated with a decrease in spontaneous preterm birth rates and an increase in mean birth weight, without increasing the risk of placental abruption, highlighting its safety and efficacy as a preventive treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aspirin for prevention of preeclampsia in women with historical risk factors: a systematic review. Coomarasamy, A., Honest, H., Papaioannou, S., et al.[2019]

Aspirin is recommended for women at risk of preeclampsia, with guidelines suggesting initiation between 11 to 28 weeks of gestation, and dosages varying from 75 mg to 150 mg depending on the level of risk.

Evidence indicates that higher doses of aspirin (greater than 100 mg daily) started before 16 weeks of gestation may be more effective in reducing the risk of preeclampsia, highlighting the need for further randomized control trials to determine optimal dosages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose aspirin therapy for the prevention of preeclampsia: time to reconsider our recommendations? Horgan, R., Hage Diab, Y., Waller, J., et al.[2023]

References

1. Portugal pubmed.ncbi.nlm.nih.gov

[The Role of Aspirin in Preeclampsia Prevention: State of the Art]. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Leveraging quality improvement to promote health equity: standardization of prenatal aspirin recommendations. [2023]

3. France pubmed.ncbi.nlm.nih.gov

[Aspirin: Indications and use during pregnancy]. [2018]

4. England pubmed.ncbi.nlm.nih.gov

First trimester screening for preeclampsia. [2016]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Low-dose aspirin in primigravidae with positive roll-over test. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Low-dose aspirin therapy in obstetrics. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Should we recommend universal aspirin for all pregnant women? [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Aspirin for prevention of preeclampsia in women with historical risk factors: a systematic review. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Low-dose aspirin therapy for the prevention of preeclampsia: time to reconsider our recommendations? [2023]