Obstetrical Complications, Preterm Delivery
Conditions
Keywords
Preterm Delivery, Stillbirth, Maternal Morbidity, Neonatal Morbidity, Prevention
Brief summary
This is a phase-III multi-center double-blind randomized clinical trial of 1,800 individuals with a history of prior preterm birth at less than 35 weeks gestation who are randomized to either 162 mg aspirin or 81 mg aspirin daily. The study drug will be initiated between 10 and 15 weeks gestation and continued through 36 weeks, 6 days gestation. The primary endpoint is recurrent preterm delivery or fetal death prior to 35 weeks, 0 days gestation.
Detailed description
This is a phase-III multi-center double-blind randomized clinical trial of 1,800 individuals with a history of prior preterm birth at less than 35 weeks gestation who are randomized to either 162 mg aspirin or 81 mg aspirin daily. The primary objective is to assess the efficacy of daily 162 mg of aspirin compared to 81 mg aspirin in reducing recurrent preterm delivery or fetal death before 35 weeks, 0 days gestation in individuals with a proximal birth between 20 weeks, 0 days and 34 weeks, 6 days gestation with spontaneous preterm delivery (sPTB), ischemic placental disease (IPD), or stillbirth. Ischemic placental disease includes small for gestational age, preeclampsia, or placental abruption. The secondary objective is to assess the efficacy of daily 162 mg of aspirin compared to 81 mg aspirin in reducing ischemic placental disease in individuals with a proximal birth between 20 weeks, 0 days and 34 weeks, 6 days gestation with sPTB, IPD, or stillbirth. Tertiary /Exploratory objectives are 1) to assess the efficacy of daily 162 mg of aspirin compared to 81 mg aspirin in reducing adverse maternal and neonatal outcomes, and 2) to assess maternal and neonatal safety in individuals with a proximal birth between 20 weeks, 0 days and 34 weeks, 6 days gestation with sPTB, IPD, or stillbirth. Individuals will be randomized between 10 and 15 weeks gestation to either 162mg or 81mg of aspirin daily and continue the study intervention through 36 weeks, 6 days gestation. Participants will have monthly virtual or in-person visits through 37 weeks gestation to assess study intervention compliance, side effects, medication use, and unscheduled hospitalization. Maternal blood will be collected in a subset of the population. Research staff will abstract maternal and neonatal outcomes following delivery and discharge from the hospital.
Interventions
DRUG162mg Aspirin
Two 81mg aspirin tablets in an over-encapsulated capsule filled with microcrystalline cellulose. Study intervention will be packaged into bottles (35 capsules per bottle).
DRUG81mg Aspirin
One 81mg aspirin tablet in an over-encapsulated capsule filled with microcrystalline cellulose. Study intervention will be packaged into bottles (35 capsules per bottle).
Sponsors
The George Washington University Biostatistics Center
Columbia University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The study intervention is packaged and shipped from the central distribution center to the clinical sites. Participants, clinical staff, and clinical site investigators and research staff are masked to the study intervention.
Intervention model description
Individuals will be randomized between 10 weeks, 0 days gestation and 15 weeks, 6 days gestation to either aspirin 162 mg or aspirin 81 mg daily and continue the study intervention through 36 weeks, 6 days gestation. Randomization will be stratified by clinical site.
Eligibility
Sex/Gender
FEMALE
Age
14 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* 14 years or older * Singleton gestation. Twin gestation reduced to a singleton, either spontaneously or therapeutically, is not eligible unless the reduction occurred before 13 weeks 6 days project gestational age. Higher-order multifetal gestations reduced to singletons are not eligible. * Gestational age at randomization between 10 weeks 0 days and 15 weeks 6 days based on clinical information and evaluation of the earliest ultrasound. * Prior preterm birth between 20 weeks 0 days and 34 weeks 6 days with one of the following in the proximal birth reaching 20 weeks or greater: * Spontaneous preterm birth is defined as spontaneous preterm labor or premature rupture of membranes * Ischemic placental disease is defined as preeclampsia, small for gestational age, fetal growth restriction, or placental abruption, as defined clinically. * Stillbirth excluding those with known genetic disorders or major congenital anomalies.
Exclusion criteria
* Known allergy or hypersensitivity to aspirin or any medical condition where aspirin is contraindicated (e.g., history of peptic ulcer disease, nasal polyps, NSAID-induced asthma, history of gastrointestinal bleeding, known G6PD deficiency, severe hepatic dysfunction, bleeding disorders, and consumption of 3 or more alcoholic drinks per day) * Taking other anticoagulants such as Heparin or Low-Molecular weight Heparin * Thrombocytopenia defined as a platelet count defined as a platelet count \<100,000 microliters * Gastric bypass surgery, regardless of type * Aspirin use \>81 mg daily during the current pregnancy who are not willing or able to go through a 2-week washout before randomization. * Known major Mullerian anomaly of the uterus (specifically bicornuate, unicornuate, or uterine septum not resected) due to increased risk of preterm delivery. * Known fetal genetic disease or major malformations * Fetal demise or planned termination of pregnancy. Selective reduction by 13 weeks 6 days gestation, from twins to singleton, is not an exclusion. * Any fetal/maternal condition requiring invasive in-utero assessment or treatment, for example, significant red cell antigen sensitization or neonatal alloimmune thrombocytopenia. * Patients with any of the following medical conditions because of increased risk for adverse pregnancy outcome or indicated preterm birth: * Treated hypertension requiring more than one agent * Chronic renal disease with baseline serum creatinine ≥1.5 mg/dL * Conditions treated with chronic oral glucocorticoid therapy (e.g., systemic lupus erythematosus) * Uncontrolled hyper- and hypothyroid disease * New York Heart Association (NYHA) stage II or greater cardiac disease * Planned indicated delivery prior to 37 weeks. * Participation in another interventional study that influences the primary outcome in this study (gestational age at delivery). * Participation in this trial in a previous pregnancy. * Delivery planned at a non-participating site
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of recurrent preterm delivery or fetal death prior to 35 weeks 0 days gestation | Between randomization and 35 weeks, 0 days gestation (a period of up to 25 weeks) | Number and rate of participants who experience a recurrent preterm delivery or fetal death before 35 weeks, 0 days gestation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of ischemic placental disease | Between randomization and delivery (a period of up to 32 weeks) | Number and rate of participants who experience ischemic placental disease (preeclampsia, small for gestational age \<10th percentile, or placental abruption). Small for gestational age is defined by "A 2017 US reference for singleton birth weight percentiles using obstetric estimates of gestation" by Aris et. al (2019). |
Countries
United States
Contacts
CONTACTRebecca G Clifton, PhD
CONTACTTrisha Boekhoudt, MPH
PRINCIPAL_INVESTIGATORRebecca G Clifton, PhD
The George Washington University Biostatistics Center
PRINCIPAL_INVESTIGATORMatthew K Hoffman, MD, MPH
ChristianaCare Center for Women & Children's Health Research
PRINCIPAL_INVESTIGATORUma M Reddy, MD, MPH
Columbia University
PRINCIPAL_INVESTIGATORCande Ananth, PhD, MPH
Robert Wood Johnson Medical School - Rutgers Health
Outcome results
None listed