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Fetal Growth RetardationPhase 3HepaGrowthNCT04762992

LMWH for Treatment of Early Fetal Growth Restriction (HepaGrowth)

A Phase 3 study testing subcutaneous Enoxaparin in people with Fetal Growth Retardation and Prematurity, run by Centro Hospitalar de Lisboa Central at 1 site in Portugal.

Enrolling by invitation

Enrolling by invitation. The study team selects and invites participants, usually from an existing group of patients.

Sites and contacts
Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older, women only
What is being tested?
subcutaneous Enoxaparin
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
12 participants
Where
1 sitePortugal
Study dates
18 Jul 2022to 30 Dec 2026
Phase
Phase 3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)

Who cannot join

  • 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)
Show all 21Show fewer
  • 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;
  • persistent blood pressure > 160/100 mmHg, despite optimal anti-hypertensive regimen;
  • history of severe renal disease (eGFR <30mL/min);
  • known or suspected hepatic impairment;
  • current participation in another clinical trial;
  • patients that are not part of the national health system (SNS);
  • delivery already scheduled, or predicted in the next 7 days.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Portugal1 site

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

    Lisbon, 1050-170

Other trials in Portugal

About this study

Official title: 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. 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.

Read the 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.

Being tested
subcutaneous Enoxaparin, standard of care
Keywords
Fetal Growth Retardation, Prematurity, Pre-Eclampsia, Placenta
Medical subject headings
Fetal Growth Retardation, Premature Birth, Pre-Eclampsia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • subcutaneous EnoxaparinDrug

    Also called experimental

    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 careOther

    Obsteric standard of care.

Study groups in NCT04762992
Study groupRoleWhat they receive
Intervention group, enoxaparinExperimentalEnoxaparin subcutaneous injections
Receives: Drug: subcutaneous Enoxaparin
Standard of careOtherObsteric standard of care
Receives: Other: standard of care

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    Measured: day of delivery

Secondary outcomes (11)

  1. Neonatal birtweight and birthweight centile

    Weight at birth of the newborn (in grams) and respective percentile

    Measured: day of delivery

  2. Newborn Apgar Score in the 5th minute

    Newborn Apgar score in the 5th minute, assessed by a nurse or pediatrician

    Measured: day of delivery

  3. Newborn Umbilical Artery pH

    pH of the umbilical artery, assessed immediately after delivery

    Measured: day of delivery

  4. Stillbirth, neonatal intensive care admission and duration of admission

    A composite outcome of severe neonatal morbidity (evidence of one or more of: intraventricular hemorrhage grade 3 or 4; cystic periventricular leukomalacia; chronic lung disease; retinopathy of prematurity requiring treatment; necrotizingenterocolitis requiring surgery

    Measured: from randomization up to 1 year after delivery

  5. Maternal and fetal Doppler parameters

    Pulsatility index (PI) of the uterine arteries, PI anddiastolic flow in the umbilical artery, PI in the middle cerebral artery, cerebro-placental ratio, ductusvenosus PI and a wave

    Measured: from randomization to delivery

  6. Placental pathology

    Percentage of placenta occupied by fibrosis or infarcts

    Measured: day of delivery

  7. Sflt1-PLGF ratio

    Evolution of Sflt1-PLGF ratio from diagnosis of FGR to delivery

    Measured: from randomization to delivery

  8. Syncytiotrophoblast membrane extracellular vesicles (STB-EV)

    Protein and genetic composition

    Measured: from randomization up to 1 week after delivery

  9. Gestational hypertension or preeclampsia; placental abruption

    Pregnancy induced hypertension, preeclamspia,HELLP syndrome

    Measured: from randomization up to 1 week after delivery

  10. Antepartum hemorrhage; maternal thrombocytopenia (platelets < 100 000 x 10 9/L); postpartum hemorrhage

    Hemorrhage, bruising,pain

    Measured: from randomization up to 1 week after delivery

  11. Mode and indication for delivery

    As spontaneous vaginal birth, operative vaginal birth (forceps orvacuum/ventouse), or cesarean section. For induced labor or planned cesarean section, theindication for scheduling the delivery will be documented (e.g., gestational age, maternal or fetalindications). In cases of operative vaginal or cesarean delivery, the indication for intervention willbe specified (e.g., non-reassuring fetal status, labor dystocia).

    Measured: from randomization up to 48h after delivery

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Feb 2021
  2. Study start18 Jul 2022
  3. Primary completion30 Jul 2026 (estimated)
  4. Study completion30 Dec 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
pharmacological intervention and standard of care arms
Masking
Double blind
Who is masked
Care provider, Outcomes assessor
Enrolment
12 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04762992
Sponsor's protocol ID
CHULC.CI.452.2018
Acronym
HepaGrowth
Status last verified
Mar 2025
First submitted
17 Feb 2021
Last updated
13 Aug 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

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.

    PubMed 18652928

  • 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.

    PubMed 28605820

  • 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.

    PubMed 7491742

  • 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.

    PubMed 28285426

  • 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.

    PubMed 1268144

  • 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.

    PubMed 9514130

  • 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.

    PubMed 7959327

  • 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.

    PubMed 26002166

  • 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.

    PubMed 7652929

  • 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.

    PubMed 7366291

  • 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.

    PubMed 24864018

  • 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.

    PubMed 17980196

  • 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.

    PubMed 19951008

  • 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.

    PubMed 15733401

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing subcutaneous Enoxaparin in people with Fetal Growth Retardation and Prematurity, run by Centro Hospitalar de Lisboa Central at 1 site in Portugal.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: enrolling by invitation, as of the sponsor's last update on 13 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Portugal. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Gestational age at delivery (time frame: day of delivery). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04762992, which also lists 14 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Aug 2025.

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