LMWH for Treatment of Early Fetal Growth Restriction (HepaGrowth) (HepaGrowth)

Low Molecular Weight Heparin for the Treatment of Early Fetal Growth Restriction

Early fetal growth restriction (FGR) is associated with considerable fetal and neonatal morbimortality (Miller et al. 2008, Nardozza et al. 2017). 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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Pre-Eclampsia; Fetal Growth Retardation; Prematurity
• Intervention / Treatment: Drug: subcutaneous Enoxaparin; Other: standard of care

Detailed Description

FGR is the second leading cause of perinatal mortality, being associated with approximately 30% of stillbirths (Nardozza et al. 2017). 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 (Arbeille et al. 1995, Nardozza et al. 2017a). 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 (Elder et al. 1976, Bellart et al. 1998, Fuke at al. 1994). 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 (Seravalli et al. 2015). 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 (Tyrell et al. 1995, Yu et al. 2004, Yu et al. 2010). We 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
• Enrollment (Estimated): 120
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Catarina Palma-dos-Reis, MD, MSc; Phone Number: +351 965591030; Email: catarina.reis@chlc.min-saude.pt
• Study Contact Backup: Name: Ana-Teresa Martins, MD; Phone Number: +351 969 828 232; Email: ana.t.martins@chlc.min-saude.pt

Study Locations

• Portugal
  • Lisboa, Portugal, 1050-170
    • Centro de Diagnóstico Pré-Natal, Maternidade Dr. Alfredo da Costa, Centro Hospitalar Universitário de Lisboa Central
    • Contact: Catarina Palma-dos-Reis, MD, MSc; Phone Number: +351 965591030; Email: catarina.reis@chlc.minsaude.pt
    • Contact: Fátima Serrano, MD, PhD; Phone Number: +351 919 538 642; Email: maria.serrano@chlc.min-saude.pt
    • Sub-Investigator: Ana-Teresa Martins, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• viable singleton pregnancy
• early FGR diagnosed according to the 2016 consensus criteria
• early FGR confirmed by the research centre

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 l) presence of placental hematoma;

m) maternal diabetic retinopathy; n) bacterial endocarditis; o) 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; p) persistent blood pressure > 160/100 mmHg, despite optimal anti-hypertensive regimen; q) history of severe renal disease (eGFR <30mL/min); r) known or suspected hepatic impairment; s) current participation in another clinical trial; t) patients that are not part of the national health system (SNS); u) delivery already scheduled, or predicted in the next 7 days.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention group, enoxaparin; Enoxaparin subcutaneous injections	Drug: 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.; Other Names: experimental
Placebo Comparator: Placebo, normal saline; Normal saline subcutaneous injections	Other: standard of care; Obsteric standard of care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
live-birth	a live birth occurs when a fetus, whatever its gestational age, is delivered and subsequently shows any sign of life	day of delivery

Collaborators and Investigators

• Sponsor: Centro Hospitalar de Lisboa Central
• Collaborators: NOVA Medical School
• Investigators: Study Chair: Fátima Serrano, MD, PhD, Centro Hospitalar Universitário de Lisboa Central; Principal Investigator: Catarina Palma-dos-Reis, MD, MSc, Centro Hospitalar Universitário de Lisboa Central

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2023
• Primary Completion (Estimated): December 30, 2024
• Study Completion (Estimated): July 30, 2025

Study Registration Dates

• First Submitted: February 17, 2021
• First Submitted That Met QC Criteria: February 17, 2021
• First Posted (Actual): February 21, 2021

Study Record Updates

• Last Update Posted (Actual): July 7, 2023
• Last Update Submitted That Met QC Criteria: July 6, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Prematurity; Pre-Eclampsia; Placenta; Fetal Growth Retardation
• Additional Relevant MeSH Terms: Pathologic Processes; Fetal Diseases; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Hypertension, Pregnancy-Induced; Growth Disorders; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Premature Birth; Eclampsia; Pre-Eclampsia; Fetal Growth Retardation; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Enoxaparin
• Other Study ID Numbers: CHULC.CI.452.2018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No