LMWH for Treatment of Early Fetal Growth Restriction (HepaGrowth)

Phase 3Enrolling By InvitationNCT04762992

Centro Hospitalar de Lisboa Central12 enrolled

Overview

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.

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Gestational age at 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

Time frame: day of delivery

Secondary Outcomes

Neonatal birtweight and birthweight centile

Weight at birth of the newborn (in grams) and respective percentile

Time frame: day of delivery

Newborn Apgar Score in the 5th minute

Newborn Apgar score in the 5th minute, assessed by a nurse or pediatrician

Time frame: day of delivery

Newborn Umbilical Artery pH

pH of the umbilical artery, assessed immediately after delivery

Time frame: day of delivery

Stillbirth, neonatal intensive care admission and duration of admission

A composite outcome of severe neonatal morbidity (evidence of one or more of: intraventricular hemorrhage grade 3 or 4; cystic periventricular leukomalacia; chronic lung disease; retinopathy of prematurity requiring treatment; necrotizingenterocolitis requiring surgery

Time frame: from randomization up to 1 year after delivery

Maternal and fetal Doppler parameters

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

Time frame: from randomization to delivery

Placental pathology

Percentage of placenta occupied by fibrosis or infarcts

Time frame: day of delivery

Sflt1-PLGF ratio

Evolution of Sflt1-PLGF ratio from diagnosis of FGR to delivery

Time frame: from randomization to delivery

Syncytiotrophoblast membrane extracellular vesicles (STB-EV)

Protein and genetic composition

Time frame: from randomization up to 1 week after delivery

Gestational hypertension or preeclampsia; placental abruption

Pregnancy induced hypertension, preeclamspia,HELLP syndrome

Time frame: from randomization up to 1 week after delivery

Antepartum hemorrhage; maternal thrombocytopenia (platelets < 100 000 x 10 9/L); postpartum hemorrhage

Hemorrhage, bruising,pain

Time frame: from randomization up to 1 week after delivery

Mode and indication for delivery

As spontaneous vaginal birth, operative vaginal birth (forceps orvacuum/ventouse), or cesarean section. For induced labor or planned cesarean section, theindication for scheduling the delivery will be documented (e.g., gestational age, maternal or fetalindications). In cases of operative vaginal or cesarean delivery, the indication for intervention willbe specified (e.g., non-reassuring fetal status, labor dystocia).

Time frame: from randomization up to 48h after delivery

LMWH for Treatment of Early Fetal Growth Restriction (HepaGrowth)

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes