LMWH for Treatment of Early Fetal Growth Restriction (HepaGrowth)

NCT04762992 | Enrolling By Invitation Phase 3 DMC

• 1 other identifier: CHULC.CI.452.2018
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Fetal Growth Retardation; Prematurity; Pre-Eclampsia

Keywords

Fetal Growth Retardation; Prematurity; Pre-Eclampsia; Placenta

Outcome Measures

Primary Outcomes (1)

• 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

  day of delivery

Secondary Outcomes (11)

• Neonatal birtweight and birthweight centile

  day of delivery

• Newborn Apgar Score in the 5th minute

  day of delivery

• Newborn Umbilical Artery pH

  day of delivery

• Stillbirth, neonatal intensive care admission and duration of admission

  from randomization up to 1 year after delivery

• Maternal and fetal Doppler parameters

  from randomization to delivery

Study Arms (2)

Intervention group, enoxaparin

EXPERIMENTAL

Enoxaparin subcutaneous injections

Drug: subcutaneous Enoxaparin

Standard of care

OTHER

Obsteric standard of care

Other: standard of care

Interventions

subcutaneous Enoxaparin 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.

Also known as: experimental

Intervention group, enoxaparin

standard of care OTHER

Obsteric standard of care.

Standard of care

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: biologic (genotipic and fenotipic) female sex
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• being 18 years old or older
• being able to provide consent
• 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)

You may not qualify if:

• multiple gestation;
• diagnosed fetal chromosomal abnormalities;
• associated fetal morphological malformations;
• evidence of fetal infection (serological or after invasive testing);
• 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
• present use of systemic salicylates in anti-inflammatory dosage (\> 150mg/day) or NSAIDs (including ketorolac)
• maternal history of allergy to LMWH or non-fractionated heparin (NFH);
• hypersensitivity to pork products;
• maternal history of heparin-induced thrombocytopenia;
• maternal thrombocytopenia (platelets \< 100 000);
• history of maternal hemophilia or Von Willebrand disease
• presence of placental hematoma;
• maternal diabetic retinopathy;
• bacterial endocarditis;
• 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;

Sponsors & Collaborators

• Centro Hospitalar de Lisboa Central: lead
• NOVA Medical School: collaborator

Study Sites (1)

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

Lisbon, 1050-170, Portugal

Location

Related Publications (14)

• 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.

  PMID: 18652928 BACKGROUND

• 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.

  PMID: 28605820 BACKGROUND

• 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.

  PMID: 7491742 BACKGROUND

• 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.

  PMID: 28285426 BACKGROUND

• 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.

  PMID: 1268144 BACKGROUND

• 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.

  PMID: 9514130 BACKGROUND

• 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.

  PMID: 7959327 BACKGROUND

• 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.

  PMID: 26002166 BACKGROUND

• 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.

  PMID: 7652929 BACKGROUND

• 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.

  PMID: 7366291 BACKGROUND

• 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.

  PMID: 24864018 BACKGROUND

• 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.

  PMID: 17980196 BACKGROUND

• 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.

  PMID: 19951008 RESULT

• 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.

  PMID: 15733401 RESULT

MeSH Terms

Conditions

Fetal Growth Retardation; Premature Birth; Pre-Eclampsia

Interventions

Standard of Care

Condition Hierarchy (Ancestors)

Fetal Diseases; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Growth Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Obstetric Labor, Premature; Obstetric Labor Complications; Hypertension, Pregnancy-Induced

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Fátima Serrano, MD, PhD

  Centro Hospitalar Universitário de Lisboa Central

  STUDY CHAIR

• Catarina Palma-dos-Reis, MD, MSc

  Centro Hospitalar Universitário de Lisboa Central

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: Blinded to clinicians performing the ultrasound and outcomes assessor
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: pharmacological intervention and standard of care arms

Study Record Dates

• First Submitted: February 17, 2021
• First Posted: February 21, 2021
• Study Start: July 18, 2022
• Primary Completion (Estimated): July 30, 2026
• Study Completion (Estimated): December 30, 2026
• Last Updated: August 13, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

PT (1)