Clinical trial NCT04762992: LMWH for Treatment of Early Fetal Growth Restriction (HepaGrowth)
Official title: Low Molecular Weight Heparin for the Treatment of Early Fetal Growth Restriction
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE3
Conditions: Fetal Growth Retardation
Prematurity
Pre-Eclampsia
Keywords: Fetal Growth Retardation
Prematurity
Pre-Eclampsia
Placenta
Lead sponsor: Centro Hospitalar de Lisboa Central
Sponsor class: OTHER
Collaborators: name: NOVA Medical School
First posted: 2021-02-21
Enrollment: 12
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: pharmacological intervention and standard of care arms
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Gestational age at delivery
timeFrame: day of delivery
Secondary outcomes:
measure: Time from diagnosis of FGR until delivery
timeFrame: from randomization to delivery
measure: Neonatal birthweight
timeFrame: day of delivery
measure: Fetal and neonatal morbimortality
timeFrame: from randomization up to 1 year after delivery
measure: Maternal and fetal Doppler parameters
timeFrame: from randomization to delivery
measure: Placental pathology
timeFrame: day of delivery
measure: Sflt1-PLGF ratio
timeFrame: from randomization to delivery
measure: Syncytiotrophoblast membrane extracellular vesicles (STB-EV)
timeFrame: from randomization up to 1 week after delivery
measure: Hypertensive complications of pregnancy
timeFrame: from randomization up to 1 week after delivery
measure: Adverse effects of enoxaparin during pregnancy, labor and postpartum
timeFrame: from randomization up to 1 week after delivery
measure: Clinical response to enoxaparin based on gestational age at diagnosis of FGR
timeFrame: from randomization to delivery
measure: Clinical response to enoxaparin based on severity of FGR at randomization
timeFrame: from randomization to delivery
measure: Clinical response to enoxaparin based on maternal body mass index at randomization
timeFrame: from randomization to delivery
Other outcomes:
Locations:
city: Lisboa
country: Portugal
facility: Centro de Diagnóstico Pré-Natal, Maternidade Dr. Alfredo da Costa, Centro Hospitalar Universitário de Lisboa Central
Study officials:
affiliation: Centro Hospitalar Universitário de Lisboa Central
name: Fátima Serrano, MD, PhD
role: STUDY_CHAIR
affiliation: Centro Hospitalar Universitário de Lisboa Central
name: Catarina Palma-dos-Reis, MD, MSc
role: PRINCIPAL_INVESTIGATOR
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