LMWH for Treatment of Early Fetal Growth Restriction (HepaGrowth)

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.

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.