LDA and LMWH vs LDA Alone in High-risk Patients for Preeclampsia Prevention

Phase 4RecruitingNCT07361679

Alexandra Hospital, Athens, Greece100 enrolled

Overview

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.

This is a prospective, randomized, single-center, open-label trial conducted at the First Obstetrics and Gynecology Clinic of Alexandra Hospital, Athens, Greece. One hundred pregnant women at high risk of preeclampsia (risk \>1:150) will be randomly allocated 1:1 to receive either 160mg aspirin daily (n=50) or 160mg aspirin plus weight-adjusted therapeutic doses of LMWH (tinzaparin 4,500-8,000 IU daily based on weight) (n=50) initiated before 16 weeks gestation until 36 weeks. Risk assessment will be performed using the internationally recognized FMF (Fetal Medicine Foundation) model, combining first trimester ultrasound examination, biochemical markers, and individual medical history. The primary outcome is the incidence of preeclampsia. Secondary outcomes include development of early preeclampsia (\<34 weeks), gestational hypertension, HELLP syndrome, spontaneous preterm labor, intrauterine growth restriction, placental abruption, and various neonatal outcomes. Blood samples will be collected at 20-24, 32-34, and 36 weeks to measure biomarkers including PlGF, sFlt-1, E-Selectin, IL-1β, IL-6, IL-10, TNF-α, sFlt-1/PlGF ratio, and systemic immune-inflammation index (SII). Regular telephone follow-up will be conducted to monitor adherence and adverse events.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Interventions

AspirinDRUG

Aspirin 160 mg orally once daily before bedtime. Duration: From enrollment (\<16 weeks gestation) until 36 weeks gestation.

TinzaparinDRUG

Weight-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.

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * 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 * Willing and able to provide written informed consent * Adequate ability for follow-up (direct telephone communication, accessible residence) Exclusion Criteria: * 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 * Pre-existing severe renal failure (creatinine clearance \<30 mL/min) * Unable to provide informed consent * Low probability of adequate follow-up (residence in remote areas without telephone access, accommodation in temporary structures)

Outcomes

Primary Outcomes

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.

Time frame: From enrollment until delivery (up to 40 weeks gestation)

Secondary Outcomes

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)

Time frame: At 20-24 weeks, 32-34 weeks, and 36 weeks gestation

Incidence of Preterm Preeclampsia

Development of preeclampsia before 37 weeks gestation

Time frame: From enrollment until 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

Time frame: At delivery

Soluble fms-like Tyrosine Kinase-1 (sFlt-1) Levels

Serum levels of soluble fms-like tyrosine kinase-1 (sFlt-1) measured by immunoassay

Time frame: At 20-24 weeks, 32-34 weeks, and 36 weeks gestation

Placental Growth Factor (PlGF) Levels

Serum levels of placental growth factor (PlGF) measured by immunoassay

Time frame: At 20-24 weeks, 32-34 weeks, and 36 weeks gestation

sFlt-1/PlGF Ratio

Ratio of soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1/PlGF ratio) measured by immunoassay

Time frame: At 20-24 weeks, 32-34 weeks, and 36 weeks gestation

Interleukin-6 (IL-6) Levels

Serum levels of interleukin-6 (IL-6) measured by immunoassay

Time frame: At 20-24 weeks, 32-34 weeks, and 36 weeks gestation

Incidence of Early-Onset Preeclampsia

Development of preeclampsia before 34 weeks gestation (early-onset preeclampsia)

Time frame: From enrollment until 34 weeks gestation

Incidence of Gestational Hypertension

New-onset hypertension (blood pressure ≥140/90 mmHg on two occasions at least 4 hours apart) after 20 weeks gestation without proteinuria or evidence of end-organ dysfunction

Time frame: From 20 weeks gestation until delivery (up to 40 weeks)

Rate of Spontaneous Preterm Birth

Spontaneous preterm labor resulting in delivery before 34 weeks gestation and before 37 weeks gestation

Time frame: From enrollment until delivery, assessed up to 40 weeks gestation

Incidence of Small for Gestational Age

Birth weight below the 3rd, 5th, and 10th percentile for gestational age based on standardized fetal growth charts (small for gestational age)

Time frame: At delivery

Perinatal Death

Miscarriage, intrauterine fetal death, or neonatal death within 28 days after birth attributed to preeclampsia or fetal growth restriction

Time frame: From enrollment until 28 days after delivery

Neonatal Complications and Therapy

Composite of neonatal adverse outcomes including sepsis, intraventricular hemorrhage grade III-IV, necrotizing enterocolitis, respiratory distress syndrome (RDS), need for surfactant therapy, mechanical ventilation, blood transfusion, and admission to neonatal intensive care unit (NICU) with duration of stay

Time frame: From delivery until hospital discharge (up to 3 months)

Placental Abruption

Premature separation of the placenta from the uterine wall before delivery

Time frame: From enrollment until delivery (up to 40 weeks gestation)

LDA and LMWH vs LDA Alone in High-risk Patients for Preeclampsia Prevention

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts