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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Aspirin Alone | Active Comparator | Participants receive aspirin 160 mg orally once daily before bedtime from enrollment (<16 weeks gestation) until 36 weeks gestation. |
|
| Aspirin plus LMWH | Experimental | Participants receive aspirin 160 mg orally once daily before bedtime PLUS weight-adjusted tinzaparin subcutaneously once daily in the morning (4,500 Anti-Xa IU for weight ≤60 kg, 6,000 Anti-Xa IU for weight 60-90 kg, 8,000 Anti-Xa IU for weight >90 kg) from enrollment (<16 weeks gestation) until 36 weeks gestation. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Aspirin | Drug | Aspirin 160 mg orally once daily before bedtime. Duration: From enrollment (<16 weeks gestation) until 36 weeks gestation. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | From enrollment until delivery (up to 40 weeks gestation) |
| Measure | Description | Time Frame |
|---|---|---|
| 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) | At 20-24 weeks, 32-34 weeks, and 36 weeks gestation |
| Incidence of Preterm Preeclampsia |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Dimitrios Baroutis, MD, MSc, PhD(c) | Contact | +306978275745 | dbaroutis@gmail.com |
| Name | Affiliation | Role |
|---|---|---|
| Georgios Daskalakis, PhD | First Department of Obstetrics and Gynecology, Alexandra Hospital | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| First Department of Obstetrics and Gynecology, Alexandra Hospital | Recruiting | Athens | Attica | 11528 | Greece |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27840330 | Background | 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. | |
| 34301348 | Background | 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. |
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The decision on individual participant data sharing will be made in accordance with institutional policies and ethical requirements. The data sharing plan will be finalized prior to study completion and publication of results.
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| ID | Term |
|---|---|
| D011225 | Pre-Eclampsia |
| D011248 | Pregnancy Complications |
| D046110 | Hypertension, Pregnancy-Induced |
| D014115 | Toxemia |
| ID | Term |
|---|---|
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D006973 | Hypertension |
| D014652 | Vascular Diseases |
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| ID | Term |
|---|---|
| D001241 | Aspirin |
| D000078222 | Tinzaparin |
| D006495 | Heparin, Low-Molecular-Weight |
| ID | Term |
|---|---|
| D012459 | Salicylates |
| D062385 | Hydroxybenzoates |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
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Two parallel groups: Arm 1 receives aspirin alone, Arm 2 receives aspirin plus weight-adjusted LMWH
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|
| Tinzaparin | Drug | 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. |
|
|
Development of preeclampsia before 37 weeks gestation |
| 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 | 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 | 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 | 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 | 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 | 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) | 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 | 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 | 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) | At delivery |
| Perinatal Death | Miscarriage, intrauterine fetal death, or neonatal death within 28 days after birth attributed to preeclampsia or fetal growth restriction | 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 | From delivery until hospital discharge (up to 3 months) |
| Placental Abruption | Premature separation of the placenta from the uterine wall before delivery | From enrollment until delivery (up to 40 weeks gestation) |
| 31733203 | Background | 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. |
| 35066406 | Background | 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 2021 Oct 9. |
| 28657417 | Background | 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 2017 Jun 28. |
| 35544388 | Background | 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. |
| D002318 | Cardiovascular Diseases |
| D007239 | Infections |
| D006841 |
| Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D006493 | Heparin |
| D006025 | Glycosaminoglycans |
| D011134 | Polysaccharides |
| D002241 | Carbohydrates |