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

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ClinicalTrials.gov Identifier: NCT04762992

Recruitment Status : Not yet recruiting

First Posted : February 21, 2021

Last Update Posted : July 16, 2021

See Contacts and Locations

Sponsor:

Collaborator:

NOVA CRU, NOVA Medical School

Information provided by (Responsible Party):

Centro Hospitalar de Lisboa Central

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Fetal Growth Retardation Prematurity Pre-Eclampsia	Drug: subcutaneous Enoxaparin Other: standard of care	Phase 3

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	120 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Intervention Model Description:	pharmacological intervention and standard of care arms
Masking:	Triple (Care Provider, Investigator, Outcomes Assessor)
Masking Description:	Both the pharmacological intervention and the standard of care group will be identified by randomized code ID.
Primary Purpose:	Treatment
Official Title:	Low Molecular Weight Heparin for the Treatment of Early Fetal Growth Restriction
Estimated Study Start Date :	October 1, 2021
Estimated Primary Completion Date :	December 30, 2024
Estimated Study Completion Date :	July 30, 2025

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Preeclampsia

Drug Information available for: Enoxaparin sodium

Genetic and Rare Diseases Information Center resources: Eclampsia

U.S. FDA Resources

Arms and Interventions

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 Name: experimental
Placebo Comparator: Placebo, normal saline Normal saline subcutaneous injections	Other: standard of care Obsteric standard of care.

Outcome Measures

Primary Outcome Measures :

Gestational age at delivery [ Time Frame: day of 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
live-birth [ Time Frame: day of delivery ]
a live birth occurs when a fetus, whatever its gestational age, is delivered and subsequently shows any sign of life

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	Female
Gender Based Eligibility:	Yes
Gender Eligibility Description:	biologic (genotipic and fenotipic) female sex
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

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

Exclusion Criteria:

diagnosed fetal chromosomal abnormalities;
associated fetal morphological malformations;
evidence of fetal infection (serological or after invasive testing);
use of aspirin, LMWH or non-fractionated heparin (NFH) in the index pregnancy before randomization;
known allergy to LMWH or NFH;
hypersensitivity to porcine products;
antecedents of heparin-induced thrombocytopenia;
maternal thrombocytopenia (platelets < 100 000);
antecedents of anticoagulant hemostatic disorder;
diagnosed placental hematoma;
diagnosed maternal diabetic retinopathy;
bacterial endocarditis;
high risk of bleeding (recent ophthalmological, spinal or brain surgery);
previous hemorrhagic stroke;
persistent high blood pressure (> 160/100 mmHg), despite optimal anti-hypertensive regimen;
active ulcerative or angiodysplastic diseases;
severe renal disease (eGFR <30mL/min)

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04762992

Contacts

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Contact: Catarina Palma-dos-Reis, MD, MSc	+351 965591030	catarina.reis@chlc.min-saude.pt
Contact: Ana-Teresa Martins, MD	+351 969 828 232	ana.t.martins@chlc.min-saude.pt

Locations

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

Sponsors and Collaborators

Centro Hospitalar de Lisboa Central

NOVA CRU, NOVA Medical School

Investigators

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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

More Information

Publications of Results:

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.

Other Publications:

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. Review.

Nardozza LMM, Zamarian ACP, Araujo Júnior 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.

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.

Nardozza LM, Caetano AC, Zamarian AC, Mazzola JB, Silva CP, Marçal VM, Lobo TF, Peixoto AB, Araujo Júnior 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. Review.

Elder MG, Myatt L. Coagulation and fibrinolysis in pregnancies complicated by fetal growth retardation. Br J Obstet Gynaecol. 1976 May;83(5):355-60.

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.

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.

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. Review.

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. Review.

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

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Responsible Party:	Centro Hospitalar de Lisboa Central
ClinicalTrials.gov Identifier:	NCT04762992
Other Study ID Numbers:	CHULC.CI.452.2018
First Posted:	February 21, 2021 Key Record Dates
Last Update Posted:	July 16, 2021
Last Verified:	July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:	No
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by Centro Hospitalar de Lisboa Central:


Fetal Growth Retardation Prematurity Pre-Eclampsia Placenta

Additional relevant MeSH terms:

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Premature Birth Eclampsia Pre-Eclampsia Fetal Growth Retardation Obstetric Labor, Premature Obstetric Labor Complications Pregnancy Complications Hypertension, Pregnancy-Induced	Fetal Diseases Growth Disorders Pathologic Processes Enoxaparin Anticoagulants Fibrinolytic Agents Fibrin Modulating Agents Molecular Mechanisms of Pharmacological Action

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