LMWH for Treatment of Early Fetal Growth Restriction (HepaGrowth)

NCT ID: NCT04762992

Last Updated: 2025-08-13

Basic Information

• Recruitment Status: ENROLLING_BY_INVITATION
• Clinical Phase: PHASE3
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-07-18
• Study Completion Date: 2026-12-30

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.

Conditions

Fetal Growth Retardation; Prematurity; Pre-Eclampsia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Intervention group, enoxaparin

Enoxaparin subcutaneous injections

Group Type: EXPERIMENTAL

subcutaneous Enoxaparin

Intervention Type: DRUG

Enoxaparin subcutaneous injections (40 mg, 4000 IU daily) starting immediately after the diagnosis of FGR, and until 36 weeks of gestation or 12 hours before delivery, whichever comes first.

Standard of care

Obsteric standard of care

Group Type: OTHER

standard of care

Intervention Type: OTHER

Obsteric standard of care.

Interventions

subcutaneous Enoxaparin

Enoxaparin subcutaneous injections (40 mg, 4000 IU daily) starting immediately after the diagnosis of FGR, and until 36 weeks of gestation or 12 hours before delivery, whichever comes first.

Intervention Type: DRUG

standard of care

Obsteric standard of care.

Intervention Type: OTHER

Other Intervention Names

experimental

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

NOVA Medical School

OTHER

Sponsor Role: collaborator

Centro Hospitalar de Lisboa Central

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Fátima Serrano, MD, PhD

Role: STUDY_CHAIR

Centro Hospitalar Universitário de Lisboa Central

Catarina Palma-dos-Reis, MD, MSc

Role: PRINCIPAL_INVESTIGATOR

Centro Hospitalar Universitário de Lisboa Central

Locations

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

Lisbon, , Portugal

Countries

Portugal

References

Miller J, Turan S, Baschat AA. Fetal growth restriction. Semin Perinatol. 2008 Aug;32(4):274-80. doi: 10.1053/j.semperi.2008.04.010.

Reference Type: BACKGROUND

PMID: 18652928 (View on PubMed)

Nardozza LMM, Zamarian ACP, Araujo Junior E. New Definition of Fetal Growth Restriction: Consensus Regarding a Major Obstetric Complication. Rev Bras Ginecol Obstet. 2017 Jul;39(7):315-316. doi: 10.1055/s-0037-1603741. Epub 2017 Jun 12. No abstract available.

Reference Type: BACKGROUND

PMID: 28605820 (View on PubMed)

Arbeille P, Maulik D, Fignon A, Stale H, Berson M, Bodard S, Locatelli A. Assessment of the fetal PO2 changes by cerebral and umbilical Doppler on lamb fetuses during acute hypoxia. Ultrasound Med Biol. 1995;21(7):861-70. doi: 10.1016/0301-5629(95)00025-m.

Reference Type: BACKGROUND

PMID: 7491742 (View on PubMed)

Nardozza LM, Caetano AC, Zamarian AC, Mazzola JB, Silva CP, Marcal VM, Lobo TF, Peixoto AB, Araujo Junior E. Fetal growth restriction: current knowledge. Arch Gynecol Obstet. 2017 May;295(5):1061-1077. doi: 10.1007/s00404-017-4341-9. Epub 2017 Mar 11.

Reference Type: BACKGROUND

PMID: 28285426 (View on PubMed)

Elder MG, Myatt L. Coagulation and fibrinolysis in pregnancies complicated by fetal growth retardation. Br J Obstet Gynaecol. 1976 May;83(5):355-60. doi: 10.1111/j.1471-0528.1976.tb00842.x.

Reference Type: BACKGROUND

PMID: 1268144 (View on PubMed)

Bellart J, Gilabert R, Fontcuberta J, Carreras E, Miralles RM, Cabero L. Coagulation and fibrinolytic parameters in normal pregnancy and in pregnancy complicated by intrauterine growth retardation. Am J Perinatol. 1998 Feb;15(2):81-5. doi: 10.1055/s-2007-993903.

Reference Type: BACKGROUND

PMID: 9514130 (View on PubMed)

Fuke Y, Aono T, Imai S, Suehara N, Fujita T, Nakayama M. Clinical significance and treatment of massive intervillous fibrin deposition associated with recurrent fetal growth retardation. Gynecol Obstet Invest. 1994;38(1):5-9. doi: 10.1159/000292434.

Reference Type: BACKGROUND

PMID: 7959327 (View on PubMed)

Seravalli V, Baschat AA. A uniform management approach to optimize outcome in fetal growth restriction. Obstet Gynecol Clin North Am. 2015 Jun;42(2):275-88. doi: 10.1016/j.ogc.2015.01.005.

Reference Type: BACKGROUND

PMID: 26002166 (View on PubMed)

Tyrell DJ, Kilfeather S, Page CP. Therapeutic uses of heparin beyond its traditional role as an anticoagulant. Trends Pharmacol Sci. 1995 Jun;16(6):198-204. doi: 10.1016/s0165-6147(00)89022-7.

Reference Type: BACKGROUND

PMID: 7652929 (View on PubMed)

Lewander R, Lunell NO, Nylund L, Sarby B, Thornstrom S. [Uterine-placental blood flow. Method of measurement and clinical use]. Lakartidningen. 1980 Jan 30;77(5):333-4. No abstract available. Swedish.

Reference Type: BACKGROUND

PMID: 7366291 (View on PubMed)

Seravalli V, Block-Abraham DM, Turan OM, Doyle LE, Blitzer MG, Baschat AA. Second-trimester prediction of delivery of a small-for-gestational-age neonate: integrating sequential Doppler information, fetal biometry, and maternal characteristics. Prenat Diagn. 2014 Nov;34(11):1037-43. doi: 10.1002/pd.4418. Epub 2014 Jun 11.

Reference Type: BACKGROUND

PMID: 24864018 (View on PubMed)

Picklesimer AH, Oepkes D, Moise KJ Jr, Kush ML, Weiner CP, Harman CR, Baschat AA. Determinants of the middle cerebral artery peak systolic velocity in the human fetus. Am J Obstet Gynecol. 2007 Nov;197(5):526.e1-4. doi: 10.1016/j.ajog.2007.04.002.

Reference Type: BACKGROUND

PMID: 17980196 (View on PubMed)

Yu YH, Shen LY, Zou H, Wang ZJ, Gong SP. Heparin for patients with growth restricted fetus: a prospective randomized controlled trial. J Matern Fetal Neonatal Med. 2010 Sep;23(9):980-7. doi: 10.3109/14767050903443459.

Reference Type: RESULT

PMID: 19951008 (View on PubMed)

Yu YH, Shen LY, Zhong M, Zhang Y, Su GD, Gao YF, Quan S, Zeng L. [Effect of heparin on fetal growth restriction]. Zhonghua Fu Chan Ke Za Zhi. 2004 Dec;39(12):793-6. Chinese.

Reference Type: RESULT

PMID: 15733401 (View on PubMed)

Other Identifiers

CHULC.CI.452.2018

Identifier Type: -

Identifier Source: org_study_id