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Principal Investigator: Cande V. Ananth
Organization: GEORGE WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $2,555,013
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
PROJECT SUMMARY/ABSTRACT
Preterm birth is well established as the leading cause of perinatal mortality and a significant contributor to both
chronic medical conditions and learning/societal challenges amongst those born too soon. Though complex in
its origins, preterm birth is predominantly the result of spontaneous preterm birth and ischemic placental diseases
(preeclampsia, fetal growth restriction and abruption). Beginning in the 1980's low dose aspirin (LDA) was trialed
as a therapy for the prevention of preeclampsia. Subsequent meta-analyses of randomized controlled trials of
LDA have demonstrated its efficacy in preventing both preterm birth and other components of ischemic placental
diseases. Limited data suggest that the effect of LDA in preventing both preterm birth and preeclampsia may be
greater if therapy is begun before 16 weeks and utilizing doses >100 mg. Recently the ASPIRIN trial randomized
11,976 nulliparous women with a singleton gestation in low-middle income countries to either aspirin 81 mg orally
or an identical appearing placebo between 60/7 weeks and 136/7 weeks. This trial demonstrated a 11% decrease
in preterm birth, 25% decrease in early preterm birth <34 weeks, 11% decrease in hypertensive disorders of
pregnancy and 62% decrease in preterm delivery at <34 weeks with hypertension. Though promising, Aspirin
has yet to be fully accepted as a preventive strategy for preterm birth, whether aspirin portends efficacy in a
dose-response fashion remains unexplored, and mechanistic studies of the pathways by which LDA prevents
both preterm birth and ischemic placental disease are lacking. The proposed project is designed to overcome
these limitations.
The goal is to enroll 1,300 women with a prior preterm birth due to either spontaneous birth or indicated preterm
birth and a current singleton pregnancy between 100/7 weeks to 166/7 to a randomized clinical trial of Aspirin 81
mg orally daily and a sham (n = 650) or 162 mg orally daily (n = 650). We will test three overarching
hypotheses: (i) Women with a prior preterm birth randomized to 162 mg of Aspirin daily compared to 81 mg of
Aspirin daily will have lower rates of preterm birth; (ii) Women with a prior preterm birth randomized to 162 mg
of aspirin daily compared to 81 mg of Aspirin daily will have lower rates of ischemic placental diseases; and (iii)
Biochemical markers (Thromboxane B2, Specialized pro-resolving mediators, etc.) will correlate with clinical
outcomes. Our research group will draw upon the collective experience and leadership of the Perinatal Research
Consortium (10 academic centers), an experienced data management and statistical analysis core and a strong
biospecimen analytic core. This innovative project by combining a rigorously conducted RCT with appropriate
biospecimen analysis will both address a pressing question about one of the few therapies shown to improve
the obstetrical outcomes of preterm birth and ischemic placental diseases and provide insight to the mechanisms
of how aspirin improves outcomes.
Terms: <Abruptio Placentae><Acetylsalicylic Acid><Address><Adrenal Cortex Hormones><Affect><Animal Model><Animal Models and Related Studies><Aspirin><Assay><Basic Research><Basic Science><Bioassay><Biochemical Markers><Biological Assay><Birth><COX-1><COX-1 protein><COX-2><COX2><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cells Placenta-Tissue><Cervical><Childhood><Chronic><Clinical><Clinical Research><Clinical Study><Complex><Corpus Luteum Hormone><Corticoids><Corticosteroids><Cyclo-Oxygenase-1><Cyclooxygenase 3><Data><Delta4-pregnene-3,20-dione><Diagnosis><Discipline of obstetrics><Disease><Disorder><Dose><Double-Blind Method><Double-Blind Study><Double-Blinded><Double-Masked Method><Double-Masked Study><EPH Gestosis><Enrollment><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Failure><Fatty Acid Cyclooxygenase><Fetal Growth Restriction><Fetal Growth Retardation><Gestation><Goals><Heart Vascular><High Risk Woman><Hypertension><IUGR><Iatrogenesis><Inflammation><Inflammation Mediators><Intervention><Intervention Strategies><Intrauterine Growth Retardation><Invaded><Ischemia><Knowledge><LMIC><Laboratories><Leadership><Learning><Length><Literature><Measures><Mediator><Medical><Meta-Analysis><Morbidity><Morbidity - disease rate><Normal Placentoma><Nulliparas><Nulliparity><Nulliparous><Obstetrics><Oral><Outcome><PGH Synthase 1><PGHS-2><PHS-2><PTGS2><PTGS2 gene><Parturition><Pathway interactions><Perinatal><Perinatal Mortalities><Perinatal lethality><Perinatal mortality demographics><Peripartum><Placebos><Placenta><Placenta Diseases><Placenta Disorders><Placenta Embryonic Tissue><Placental Diseases><Placentome><Pre-Eclampsia><Preeclampsia><Pregn-4-ene-3,20-dione><Pregnancy><Pregnancy Toxemias><Pregnant Women><Pregnenedione><Premature Birth><Premature Separation of Placenta><Prematurely delivering><Preterm Birth><Preventative strategy><Prevention><Prevention strategy><Prevention therapy><Preventive strategy><Production><Progesterone><Prostaglandin G/H Synthase 1><Prostaglandin H2 Synthase><Prostaglandin H2 Synthase 1><Prostaglandin-Endoperoxide Synthase 1><Proteinuria-Edema-Hypertension Gestosis><Publications><Randomization trial><Randomized><Randomized, Controlled Trials><Recommendation><Recurrence><Recurrent><Reporting><Research><Resistance><Risk><Scientific Publication><Sham Treatment><Statistical Data Analyses><Statistical Data Analysis><Statistical Data Interpretation><Supplementation><Testing><Therapeutic Progesterone><Thrombosis><Thromboxane B2><Tocolytic Agents><Tocolytics><United States><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Woman><antenatal><antepartum><at-risk females><at-risk women><circulatory system><cyclo-oxygenase I><cyclooxygenase 1><data management><design><designing><enroll><epidemiologic investigation><epidemiology study><expectant mother><expecting mother><experience><females at high risk><hCOX-2><high blood pressure><high risk females><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><iatrogenic><iatrogenically><iatrogenicity><impaired fetal growth><improved><improved outcome><inflammation marker><inflammatory marker><inflammatory mediator><innovate><innovation><innovative><insight><interventional strategy><intra-uterine growth restriction><intra-uterine growth retardation><intrauterine growth restriction><low and middle-income countries><model of animal><mortality><neonatal care><neonatal period><obstetric outcomes><obstetrical complication><obstetrical syndromes><pathway><pediatric><perinatal deaths><pill><placental abruption><placental disorders><pre-eclamptic><pregnancy disorder><pregnancy toxemia/hypertension><pregnant mothers><premature childbirth><premature delivery><prenatal growth disorder><preterm delivery><prevent><preventing><prostaglandin H synthase-1><public health intervention><randomisation><randomization><randomized control trial><randomized trial><randomized, clinical trials><randomly assigned><recurrence prevention><resistant><response><screening><screenings><sham therapy><socio-economic><socio-economically><socioeconomically><socioeconomics><statistical analysis><thrombotic disease><thrombotic disorder><women at high risk>