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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
SINGLE
Enrollment
400
162mg aspirin taken daily
81mg aspirin q12hours
Thomas Jefferson University
Philadelphia, Pennsylvania, United States
RECRUITINGAspirin Response PFA-100 epinephrine closure time (seconds)
Difference in PFA-100 epinephrine closure time (seconds)
Time frame: 2-4 weeks after aspirin initiation
Aspirin response (PFA-100 epinephrine closure time)
Difference in PFA-100 epinephrine closure time (seconds)
Time frame: 28-32 weeks gestation
Urinary thromboxane concentration
Difference in Urine thromboxane (AspirinWorks)
Time frame: 2-4 weeks after aspirin initiation
Urinary Thromboxane concentration
Difference in Urinary thromboxane (AspirinWorks)
Time frame: 28-32 weeks gestation
Inadequate aspirin response
Number of participants with PFA-100 epinephrine closure time\<150 seconds
Time frame: 2-4 weeks after aspirin initiation
Inadequate aspirin response
Number of participants with PFA-100 epinephrine closure time\<150seconds
Time frame: 28-32 weeks gestation
Preterm birth
Number of participants with Preterm birth\<37 weeks
Time frame: Delivery
Indicated preterm birth
Number of participants with Preterm birth\<37 weeks due to preeclampsia or fetal growth restriction
Time frame: delivery
Spontaneous preterm birth
Number of participants with spontaneous preterm birth \<37 weeks
Time frame: delivery
MicroRNAs
Fold-change from baseline for concentration of circulating microRNAs
Time frame: 2-4 weeks after aspirin initiation
MicroRNAs
Fold-change from baseline for concentration of circulating microRNAs
Time frame: 28-32 weeks gestation
Placental histopathology
Placental pathology per Amsterdam criteria. Number of participants with maternal vascular malperfusion, intervillous thrombosis
Time frame: Delivery
Birthweight
Infant birthweight (grams)
Time frame: Delivery
Fetal growth restriction
Number of participants diagnosed with Fetal growth restriction
Time frame: delivery
Hypertensive disorder of pregnancy
Number of participants diagnosed with Preeclampsia or gestational hypertension
Time frame: delivery
Gestational age at delivery
Gestational age at delivery (weeks)
Time frame: Delivery
Pregnancy loss<20 weeks
Number of participants with Pregnancy loss (delivery, demise, miscarriage)\<20 weeks gestation
Time frame: delivery
Fetal demise
Number of participants with Fetal demise diagnosed \>=20 weeks gestation
Time frame: delivery
Antepartum bleeding
Number of participants with any admission for antepartum bleeding
Time frame: Delivery
Abruption
Number of participants with Abruption diagnosed prior to or at delivery
Time frame: delivery
Placental hematoma
Number of participants with Placental hematoma suspected on ultrasound
Time frame: delivery
Postpartum hemorrhage
Number of participants with Postpartum hemorrhage \>1000ml
Time frame: Delivery
Adherence
Number of participants with Adherence\>75%
Time frame: 2-4 weeks after aspirin
Adherence
Number of participants with Adherence\>75%
Time frame: 28-32 weeks
Neonatal intraventricular hemorrhage Grade II or higher
Number of participants with infants found to have Neonatal IVH grade II or higher diagnosed on ultrasound post natally
Time frame: Neonatal discharge
Cordblood serum thromboxane
cordblood serum thromboxane concentration
Time frame: Delivery
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