Early-onset preeclampsia (PE), defined as preeclampsia presenting before 34 weeks of gestation, is a severe placental disorder associated with significant maternal and perinatal morbidity. There is currently no disease-modifying treatment; management relies on close surveillance and delivery, frequently resulting in extreme prematurity.
Recent laboratory research identified ferroptosis, a form of iron-dependent regulated cell death driven by lipid peroxidation, as a key mechanism of placental injury in early-onset preeclampsia. A high-throughput drug screen identified dipyridamole, an approved oral antiplatelet and vasodilatory agent, as a potent ferroptosis inhibitor in primary human trophoblast cultures (EC50 = 0.146 µM), acting through mechanisms independent of its known phosphodiesterase-inhibitory pharmacology. In preeclamptic placental explants, dipyridamole markedly reduced release of sFlt-1, a central mediator of the maternal syndrome. Dipyridamole carries an established pregnancy safety record supported by randomized trials and a Cochrane meta-analysis of antiplatelet agents in pregnancy.
This is a prospective, single-center, open-label pilot study using a sequential, fixed dose-escalation design. The study will enroll 15 hospitalized pregnant women with early-onset preeclampsia (gestational age 26+0 to 33+6 weeks) and an elevated sFlt-1/PlGF ratio (≥85), for whom expectant management is clinically appropriate. Enrollment proceeds through a staged sentinel design with safety gates reviewed by an independent Safety Monitoring Committee. Participants receive oral dipyridamole added to standard clinical care, using a fixed dose-escalation protocol (75 mg twice daily on Day 1, escalating over 2-3 days to a target dose of 75 mg four times daily, 300 mg/day total). Standard obstetric care continues unchanged, determined entirely on clinical grounds, independent of study participation.
The primary objective is to evaluate the feasibility and clinical implementability of the dipyridamole treatment protocol within routine inpatient obstetric care. Secondary objectives include characterizing the pharmacokinetics of dipyridamole during pregnancy, assessing tolerability, and evaluating longitudinal circulating angiogenic biomarkers (sFlt-1 and PlGF). Exploratory objectives include assessment of placental markers of oxidative stress and ferroptosis-related pathways in tissue obtained at delivery.
Study drug is administered during the antepartum period only and discontinued before delivery. This pilot study is not designed to establish clinical efficacy, but to provide the pharmacokinetic, tolerability, and biological data required to design a subsequent randomized trial.
Age ≥ 18 years
Singleton pregnancy
Established early-onset preeclampsia, with or without severe features, with gestational age from 26+0 to 33+6 weeks at enrollment, confirmed by best obstetric estimate
Hospitalization for maternal and/or fetal surveillance
Immediate indication for delivery at time of screening, including uncontrolled severe hypertension, eclampsia, HELLP syndrome, or severe fetal compromise
Active maternal bleeding or clinically significant bleeding disorder
Therapeutic-dose anticoagulation (e.g., enoxaparin >1 mg/kg/day)
Known hypersensitivity or contraindication to dipyridamole
Sequential
Dipyridamole 75 MG
DrugOral dipyridamole 75 mg tablets, administered via a fixed structured dose escalation across the sequential arms described above (75 mg twice daily → three times daily → four times daily). The escalation schedule is identical for all participants; dosing is not individualized and accelerated escalation is not permitted.
Protocol Feasibility
Composite feasibility endpoint defined as: (1) successful enrollment of ≥10 of 15 planned participants within the recruitment period; (2) completion of the full dose-escalation ramp-up to the target dose of 300 mg/day in ≥70% of enrolled participants; and (3) successful collection of at least the sparse pharmacokinetic sampling set (Day 1 pre-dose + 2 post-dose samples) in ≥70% of participants, within the routine inpatient care setting.
Peak Plasma Concentration (Cmax) of Dipyridamole
Maximum observed plasma concentration of dipyridamole, estimated from sparse sampling during dose escalation and intensive PK profiling
Incidence of Dipyridamole-Related Adverse Events
Number and proportion of participants experiencing adverse events attributed to dipyridamole during the ramp-up and maintenance dosing period (per your protocol's documented AE categories: dizziness, headache, rash, abdominal distress, bleeding). Unit: Number of participants
Change in Serum Soluble fms-Like Tyrosine Kinase-1 (sFlt-1)
Longitudinal change in maternal circulating sFlt-1 concentration following dipyridamole treatment initiation. Unit: pg/mL
Change in Maternal Blood Pressure
Systolic and diastolic blood pressure trends from treatment initiation to delivery
Concentration of Placental Oxidative Stress and Ferroptosis-Related Markers
Assessment of placental tissue obtained at delivery for markers of lipid peroxidation, oxidative stress, and ferroptosis-related pathways, including hydroperoxy-phosphatidylethanolamine species and ferroptosis-associated proteins, compared to historical preeclamptic and normotensive controls.
Maternal and Fetal Dipyridamole Exposure at Delivery
Maternal and cord blood dipyridamole concentrations measured at delivery to assess transplacental drug transfer and fetal exposure.
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