Preeclampsia is a major cause of maternal and perinatal morbidity and mortality worldwide. Low-dose aspirin started in the first trimester reduces the risk of preeclampsia in high-risk women. Low molecular weight heparin (LMWH) has shown potential benefits in addition to aspirin for preventing preeclampsia through its anticoagulant, anti-inflammatory, and endothelial protective effects. However, current evidence is limited and conflicting regarding the added value of LMWH to aspirin. This randomized controlled trial aims to evaluate the efficacy of combined aspirin and LMWH, compared to aspirin alone, for reducing the incidence of preeclampsia in high-risk gravidas.
Singleton pregnancy
High risk for preeclampsia (risk >1:150) based on FMF screening algorithm combining first-trimester ultrasound, biochemical markers, and medical history
Gestational age <16 weeks at enrollment
Maternal age ≥18 years
Multiple pregnancy
Current permanent aspirin use for other medical indications
Serious congenital fetal abnormality detected on ultrasound
Contraindication to aspirin or low molecular weight heparin including: known hypersensitivity, active peptic ulcer disease, bleeding disorders or coagulopathy, severe thrombocytopenia (platelet count <100,000/μL), active or recent significant bleeding, history of heparin-induced thrombocytopenia
Parallel
Aspirin
DrugAspirin 160 mg orally once daily before bedtime. Duration: From enrollment (\<16 weeks gestation) until 36 weeks gestation.
Tinzaparin
DrugWeight-adjusted tinzaparin administered subcutaneously once daily in the morning: 4,500 Anti-Xa IU/day for weight ≤60 kg, 6,000 Anti-Xa IU/day for weight 60-90 kg, and 8,000 Anti-Xa IU/day for weight \>90 kg. Duration: From enrollment (\<16 weeks gestation) until 36 weeks gestation.
Incidence of Preeclampsia
Preeclampsia defined as gestational hypertension (BP ≥140/90 mmHg on at least two measurements ≥4 hours apart) after 20 weeks' gestation accompanied by one or more of: (1) Proteinuria (≥30 mg/mmol protein:creatinine ratio, ≥8 mg/mmol albumin:creatinine ratio, ≥0.3 g/24h, or ≥2+ dipstick); (2) Maternal end-organ dysfunction including neurological complications (severe headaches, visual scotomata, eclampsia, stroke, clonus), pulmonary oedema, haematological complications (platelet count \<150,000/μL, disseminated intravascular coagulation, haemolysis), acute kidney injury (creatinine ≥90 μmol/L or 1 mg/dL), or liver involvement (elevated ALT or AST \>40 IU/L); or (3) Uteroplacental dysfunction (fetal growth restriction, abnormal umbilical artery Doppler waveform analysis, placental abruption, angiogenic imbalance, or intrauterine fetal death), per ISSHP 2021 classification.
Systemic Immune-Inflammation Index (SII)
Systemic immune-inflammation index calculated as SII = P × N/L, where P, N, and L are the peripheral blood platelet count, neutrophil count, and lymphocyte count respectively (cells per liter)
Incidence of Preterm Preeclampsia
Development of preeclampsia before 37 weeks gestation
Prevalence of placental histopathological lesions
Histopathological examination of placental tissue including assessment of maternal vascular malperfusion, fetal vascular malperfusion, villous lesions, inflammatory lesions, and other pathological findings according to standardized criteria
Soluble fms-like Tyrosine Kinase-1 (sFlt-1) Levels
Serum levels of soluble fms-like tyrosine kinase-1 (sFlt-1) measured by immunoassay
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