LMWH for Treatment of Early Fetal Growth Restriction (HepaGrowth)

Phase 3

• Conditions: Prematurity; Pre-Eclampsia; Fetal Growth Retardation
• Interventions: Drug: subcutaneous Enoxaparin; Other: standard of care

• Registration Number: NCT04762992
• Lead Sponsor: Centro Hospitalar de Lisboa Central

Brief Summary

Early fetal growth restriction (FGR) is associated with considerable fetal and neonatal morbimortality. Placental thrombosis, infarcts and hypercoagulability are frequently seen in these pregnancies, suggesting a role for the activation of the coagulation cascade in the genesis of FGR. Patients will be randomized for low-molecular weight heparin or standard of care, and the outcomes of both arms (gestational age at delivery, gestational and fetal morbidity) will be compared.

Detailed Description

FGR is the second leading cause of perinatal mortality, being associated with approximately 30% of stillbirths. Early FGR is associated with substantial disturbances of placental implantation and fetal hypoxia, which requires fetal cardiovascular adaptation. Both maternal and fetal Doppler alterations are present, allowing for risk stratification and monitoring. Although the precise etiology for FGR due to placental causes is unknown, placental thrombosis, infarcts and hypercoagulability are frequently seen, suggesting a role for the activation of the coagulation cascade in the genesis of FGR. Currently, the management of early FGR is limited to the monitoring of fetal Doppler parameters until the risks for preterm delivery outweight the benefits of ongoing monitoring. As such, there is a special need for effective preventive and therapeutic interventions that improve the outcomes. Low molecular weight heparin (LMWH), for its anticoagulant and anti-inflammatory properties has been suggested as a possible therapeutic agent in this setting. The investigators will randomize the participants to two intervention arms in a one-to-one ratio, using a computer generated randomization program. The randomization will be stratified for gestational age at diagnosis of FGR (22 to 26 weeks and \>26 to 32 weeks). The experimental group will be administered enoxaparin subcutaneous injections (40 mg, 4000 IU daily) and the control group will be provided standard of care. Both groups will start intervention immediately after the diagnosis of FGR, and will continue it until 36 weeks of gestation or 12 hours before delivery, whichever comes first.

Study Timeline

• Study First Submitted: 2021-02-17
• Study First Submitted QC: 2021-02-17
• Study First Posted: 2021-02-21
• Study Start: 2022-07-18
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-24
• Last Update Posted: 2025-03-26
• Primary Completion: 2026-07-30
• Study Completion: 2026-12-30

Recruitment & Eligibility

• Status: ENROLLING_BY_INVITATION
• Sex: Female
• Target Recruitment: 12

Inclusion Criteria

1. being 18 years old or older
2. being able to provide consent
3. having a viable singleton pregnancy with diagnosed early FGR confirmed in our unit according to the 2020 International Society of Ultrasound in Obstetrics & Gynecology (ISUOG) criteria (one solitary parameter: estimated fetal weight/ abdominal circumference lower than the 3rd centile or absent end-diastolic flow in umbilical artery; or estimated fetal weight/abdominal circumference below the 10th centile combined with either umbilical artery pulsatility index > 95th centile or uterine artery mean pulsatility index > 95th centile)

Exclusion Criteria

1. multiple gestation;
2. diagnosed fetal chromosomal abnormalities;
3. associated fetal morphological malformations;
4. evidence of fetal infection (serological or after invasive testing);
5. use of LMWH or NFH in the index pregnancy before randomization or start of any of these medications for another indication if the patient is in the control group
6. present use of systemic salicylates in anti-inflammatory dosage (> 150mg/day) or NSAIDs (including ketorolac)
7. maternal history of allergy to LMWH or non-fractionated heparin (NFH);
8. hypersensitivity to pork products;
9. maternal history of heparin-induced thrombocytopenia;
10. maternal thrombocytopenia (platelets < 100 000);
11. history of maternal hemophilia or Von Willebrand disease
12. presence of placental hematoma;
13. maternal diabetic retinopathy;
14. bacterial endocarditis;
15. active clinically significant bleeding and conditions with a high risk of hemorrhage, including recent hemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm at high risk of bleeding, recent brain, spinal or ophthalmic surgery, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities;
16. persistent blood pressure > 160/100 mmHg, despite optimal anti-hypertensive regimen;
17. history of severe renal disease (eGFR <30mL/min);
18. known or suspected hepatic impairment;
19. current participation in another clinical trial;
20. patients that are not part of the national health system (SNS);
21. delivery already scheduled, or predicted in the next 7 days.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Intervention group, enoxaparin	subcutaneous Enoxaparin	Enoxaparin subcutaneous injections
Standard of care	standard of care	Obsteric standard of care

Primary Outcome Measures

Name	Time	Method
Gestational age at delivery	day of delivery	Best assessment of the time of gestation, either by first trimester sonography, last menstrual day or day of implantation of in vitro conception product

Secondary Outcome Measures

Name	Time	Method
Time from diagnosis of FGR until delivery	from randomization to delivery	Time from FGR diagnosis to delivery, inweeks
Neonatal birthweight	day of delivery	Neonatal weight at birth, in grams
Maternal and fetal Doppler parameters	from randomization to delivery	Pulsatility index (PI) of the uterine arteries, PI anddiastolic flow in the umbilical artery, PI in the middle cerebral artery, cerebro-placental ratio, ductusvenosus PI and a wave
Fetal and neonatal morbimortality	from randomization up to 1 year after delivery	Complications arising during pregnancy (e.g.,hypoxia, fetal demise) or in the neonatal period (preterm birth, respiratory distress syndrome,sepsis, or other health complications). Neonatal death is defined as death occurring within the first28 days of life
Placental pathology	day of delivery	Percentage of placenta occupied by fibrosis or infarcts
Sflt1-PLGF ratio	from randomization to delivery	Evolution of Sflt1-PLGF ratio from diagnosis of FGR to delivery
Syncytiotrophoblast membrane extracellular vesicles (STB-EV)	from randomization up to 1 week after delivery	Protein and genetic composition
Hypertensive complications of pregnancy	from randomization up to 1 week after delivery	Pregnancy induced hypertension, preeclamspia,HELLP syndrome
Adverse effects of enoxaparin during pregnancy, labor and postpartum	from randomization up to 1 week after delivery	Hemorrhage, bruising,pain
Clinical response to enoxaparin based on gestational age at diagnosis of FGR	from randomization to delivery	Evaluation of whether clinical response to enoxaparin varies by gestational age at FGR diagnosis
Clinical response to enoxaparin based on severity of FGR at randomization	from randomization to delivery	Assessment of clinical response to enoxaparin relative to the severity of FGR at randomization
Clinical response to enoxaparin based on maternal body mass index at randomization	from randomization to delivery	Analysis of whether maternal BMI at randomization influences clinical response to enoxaparin

Trial Locations

Locations (1)

Centro de Diagnóstico Pré-Natal, Maternidade Dr. Alfredo da Costa, Centro Hospitalar Universitário de Lisboa Central; 🇵🇹 Lisboa, Portugal