Preterm Birth, Preeclampsia
Conditions
Keywords
Aspirin, Preeclampsia, Preterm birth, Pregnancy, Pharmacokinetics, Pharmacodynamics, Phase I/II, Randomized clinical trial
Brief summary
Aspirin is recommended in high risk patients to reduce the risk of preeclampsia and preterm birth, which are leading causes of both maternal and neonatal morbidity and mortality, but up to 20% will have these adverse outcomes despite therapy. Gaps in knowledge regarding pregnancy specific aspirin pharmacology and the relationship of aspirin response and pregnancy outcome, along with a lack of consensus on aspirin dosing has limited the effective use of this intervention. The investigators aim to apply principles of clinical pharmacology to determine how to optimally utilize this low cost medication to improve maternal/child health outcomes. This is a Phase I/II randomized controlled trial of high risk pregnancies recommended aspirin; participants will be randomized to take aspirin either 162mg once daily, or 81mg twice a day. Outcomes evaluated will include the difference in aspirin response between these two dosing regimens, the individual factors that impact aspirin pharmacology in pregnancy, and evaluate markers or aspirin response that may be associated with pregnancy outcome.
Detailed description
This is an unblinded randomized controlled Phase I/II trial comparing high risk singleton pregnancies randomized to 162mg daily (daily dose) vs 81mg q12hours (split dose). Participants will be enrolled prior to 16 weeks gestation. The primary outcome is platelet inhibition as assessed by PFA-100 epinephrine closure time, assessed 2-4 weeks after initiation and again at 28-32 weeks gestation. A subset of participants will be enrolled in a pharmacokinetic study to evaluate pharmacokinetics of aspirin in pregnancy at the two dosing intervals. Secondary outcomes include urine thromboxane at each visit, platelet associated microRNAs. Individual factors associated with aspirin pharmacokinetics and pharmacodynamics in pregnancy will be assessed. Finally, the relationship between these pharmacodynamic markers and pregnancy outcome will be evaluated.
Interventions
162mg aspirin taken daily
DRUGSplit dose aspirin (ASA)
81mg aspirin q12hours
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Thomas Jefferson University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Masking description
Biostatistical analysis, all laboratory assessments will be conducted by personnel blinded to study groupl
Eligibility
Sex/Gender
FEMALE
Age
16 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Singleton gestation gestational age \<16 0/7 weeks, dating confirmed with ultrasound * ≥1 high risk factor for preeclampsia or ≥2 moderate risk factors as per United States Preventative Services Task Force (2021) * Recommendation for 162mg aspirin daily in pregnancy * Age 16-55 years old
Exclusion criteria
* Contraindication to aspirin * Current or planned use of any other anticoagulation * Thrombocytopenia, other known platelet or bleeding disorder * Abnormally elevated baseline PFA-100 epinephrine closure time prior to aspirin initiation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Aspirin Response PFA-100 epinephrine closure time (seconds) | 2-4 weeks after aspirin initiation | Difference in PFA-100 epinephrine closure time (seconds) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Urinary thromboxane concentration | 2-4 weeks after aspirin initiation | Difference in Urine thromboxane (AspirinWorks) |
| Urinary Thromboxane concentration | 28-32 weeks gestation | Difference in Urinary thromboxane (AspirinWorks) |
| Inadequate aspirin response | 2-4 weeks after aspirin initiation | Number of participants with PFA-100 epinephrine closure time\<150 seconds |
| Preterm birth | Delivery | Number of participants with Preterm birth\<37 weeks |
| Indicated preterm birth | delivery | Number of participants with Preterm birth\<37 weeks due to preeclampsia or fetal growth restriction |
| Spontaneous preterm birth | delivery | Number of participants with spontaneous preterm birth \<37 weeks |
| MicroRNAs | 2-4 weeks after aspirin initiation | Fold-change from baseline for concentration of circulating microRNAs |
| Placental histopathology | Delivery | Placental pathology per Amsterdam criteria. Number of participants with maternal vascular malperfusion, intervillous thrombosis |
| Birthweight | Delivery | Infant birthweight (grams) |
| Fetal growth restriction | delivery | Number of participants diagnosed with Fetal growth restriction |
| Aspirin response (PFA-100 epinephrine closure time) | 28-32 weeks gestation | Difference in PFA-100 epinephrine closure time (seconds) |
| Gestational age at delivery | Delivery | Gestational age at delivery (weeks) |
| Pregnancy loss<20 weeks | delivery | Number of participants with Pregnancy loss (delivery, demise, miscarriage)\<20 weeks gestation |
| Adherence | 2-4 weeks after aspirin | Number of participants with Adherence\>75% |
| Fetal demise | delivery | Number of participants with Fetal demise diagnosed \>=20 weeks gestation |
| Antepartum bleeding | Delivery | Number of participants with any admission for antepartum bleeding |
| Abruption | delivery | Number of participants with Abruption diagnosed prior to or at delivery |
| Placental hematoma | delivery | Number of participants with Placental hematoma suspected on ultrasound |
| Postpartum hemorrhage | Delivery | Number of participants with Postpartum hemorrhage \>1000ml |
| Neonatal intraventricular hemorrhage Grade II or higher | Neonatal discharge | Number of participants with infants found to have Neonatal IVH grade II or higher diagnosed on ultrasound post natally |
| Cordblood serum thromboxane | Delivery | cordblood serum thromboxane concentration |
| Hypertensive disorder of pregnancy | delivery | Number of participants diagnosed with Preeclampsia or gestational hypertension |
Countries
United States
Contacts
Primary ContactRupsa C Boelig, MD
Outcome results
None listed