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

Official title

Combined Administration of Low Molecular Weight Heparin and Aspirin Versus Aspirin Alone in Gravidas at High Risk for Preeclampsia: A Randomized Controlled Trial

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.

Detailed description

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.

Interventions

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

Primary outcome measures

• Incidence of Preeclampsia [Time frame: From enrollment until delivery (up to 40 weeks gestation)]

Secondary outcome measures (12)

• Systemic Immune-Inflammation Index (SII) [Time frame: At 20-24 weeks, 32-34 weeks, and 36 weeks gestation]
• Incidence of Preterm Preeclampsia [Time frame: From enrollment until 37 weeks gestation]
• Prevalence of placental histopathological lesions [Time frame: At delivery]
• Soluble fms-like Tyrosine Kinase-1 (sFlt-1) Levels [Time frame: At 20-24 weeks, 32-34 weeks, and 36 weeks gestation]
• Placental Growth Factor (PlGF) Levels [Time frame: At 20-24 weeks, 32-34 weeks, and 36 weeks gestation]
• sFlt-1/PlGF Ratio [Time frame: At 20-24 weeks, 32-34 weeks, and 36 weeks gestation]
• Interleukin-6 (IL-6) Levels [Time frame: At 20-24 weeks, 32-34 weeks, and 36 weeks gestation]
• Incidence of Early-Onset Preeclampsia [Time frame: From enrollment until 34 weeks gestation]
• Incidence of Gestational Hypertension [Time frame: From 20 weeks gestation until delivery (up to 40 weeks)]
• Rate of Spontaneous Preterm Birth [Time frame: From enrollment until delivery, assessed up to 40 weeks gestation]
• Incidence of Small for Gestational Age [Time frame: At delivery]
• Perinatal Death [Time frame: From enrollment until 28 days after delivery]

Eligibility criteria

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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Prevention

Study locations

Greece · 1 center

• First Department of Obstetrics and Gynecology, Alexandra Hospital — Athens

Publications

• McLaughlin K, Baczyk D, Potts A, Hladunewich M, Parker JD, Kingdom JC. Low Molecular Weight Heparin Improves Endothelial Function in Pregnant Women at High Risk of Preeclampsia. Hypertension. 2017 Jan;69(1):180-188. doi: 10.1161/HYPERTENSIONAHA.116.08298. Epub 2016 Nov 13. PMID 27840330
• Cruz-Lemini M, Vazquez JC, Ullmo J, Llurba E. Low-molecular-weight heparin for prevention of preeclampsia and other placenta-mediated complications: a systematic review and meta-analysis. Am J Obstet Gynecol. 2022 Feb;226(2S):S1126-S1144.e17. doi: 10.1016/j.ajog.2020.11.006. Epub 2021 Apr 20. PMID 34301348
• Wright D, Wright A, Nicolaides KH. The competing risk approach for prediction of preeclampsia. Am J Obstet Gynecol. 2020 Jul;223(1):12-23.e7. doi: 10.1016/j.ajog.2019.11.1247. Epub 2019 Nov 13. PMID 31733203
• Magee LA, Brown MA, Hall DR, Gupte S, Hennessy A, Karumanchi SA, Kenny LC, McCarthy F, Myers J, Poon LC, Rana S, Saito S, Staff AC, Tsigas E, von Dadelszen P. The 2021 International Society for the Study of Hypertension in Pregnancy classification, diagnosis & management recommendations for international practice. Pregnancy Hypertens. 2022 Mar;27:148-169. doi: 10.1016/j.preghy.2021.09.008. Epub 20 PMID 35066406
• Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco Matallana C, Akolekar R, Cicero S, Janga D, Singh M, Molina FS, Persico N, Jani JC, Plasencia W, Papaioannou G, Tenenbaum-Gavish K, Meiri H, Gizurarson S, Maclagan K, Nicolaides KH. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med. 2017 Aug 17;377(7):613-622. doi: 10.1056/NEJMoa1704559. Epub 201 PMID 28657417
• Magee LA, Nicolaides KH, von Dadelszen P. Preeclampsia. N Engl J Med. 2022 May 12;386(19):1817-1832. doi: 10.1056/NEJMra2109523. No abstract available. PMID 35544388

Identifiers

NCT: NCT07361679 · 724/23-11-2022

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗