Low-molecular-weight Heparin in Constituted Vascular Intrauterine Growth Restriction

Fetal Growth Retardation Clinical Trial

— GROWTH  

Official title:

Low-molecular-weight Heparin in Constituted Vascular Intrauterine Growth Restriction. Randomized Multicenter Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02672566
• Other study ID #: 1508175
• Secondary ID: 2016-000424-25
• Status: Completed
• Phase: Phase 3
• Start date: July 22, 2016
• Est. completion date: January 22, 2020

Study information

• Verified date: April 2019
• Source: Centre Hospitalier Universitaire de Saint Etienne
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Intrauterine growth restriction (IUGR) is correlated to an abnormal placenta development, with an alteration of the maternal-fetal circulation, coagulation troubles, and apparition of placental infarcts. IUGR represents the third cause of perinatal mortality in France, and is associated to an important morbidity. For birth-weights < 10th percentile of the gestational age, the neonatal death risk is doubled, compared to abnormal weights. In 35% of cases, IUGR is of vascular origin and is included in the broader framework of placental vascular pathology (PVP).

Up to now, studies have focused on the primary or secondary prevention of PVP. Few studies have evaluated the treatment of constituted vascular IUGR. Currently, the management of vascular IUGR is mainly based on active surveillance, or termination of pregnancy. Pathological findings suggest that placental pro-thrombotic phenomena play a role in the constitution of vascular IUGR. Since aspirin is not effective in reducing this type of event, a randomized, open-label study conducted in China compared 14-day treatment with low-molecular-weight heparin (LMWH) versus Dan-Shen (a product not used in France) after diagnosis of IUGR. This trial, including 73 patients, showed a significant improvement in average growth kinetics in the LMWH group. The mean birth weight was 2877 g in the heparin group and 2492 g in the Dan-Shen group (p <0.0001). However, no data were provided concerning the number of newborns with a birth weight <10th percentile, i.e. the risk of morbidity and mortality, or complications occurring. Due to the lack of reliable data, LMWH are not included in the currently recommended therapeutic strategy for vascular IUGR.

The studies in IUGR reported to date mainly focused on primary or secondary prevention in women at risk of PVP, assessing the value of aspirin, which showed only a modest effect. No effective therapeutic strategy is available to treat patients with constituted vascular IUGR, a situation where LMWH should be more effective than antiplatelets given the vascular context.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 82
• Est. completion date: January 22, 2020
• Est. primary completion date: September 5, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patient over 18 years being at a gestational age = 22 and <34 weeks of gestation with vascular fetal growth retardation defined according CNGOF

• Ultrasound Estimated fetal weight below the 10th percentile

• Clinical and ultrasound findings suggesting pathologically impaired growth or diminished foetal well-being

• Clinical and ultrasound findings suggesting placental insufficiency

• Precise dating of pregnancy with an ultrasound between 11 + 0 and 13 + 6 weeks of gestation

• Written informed consent

Exclusion Criteria:

• multiple pregnancy or identified cause of IUGR (intra-uterine growth retardation)

• Patient with an immediate indication of fetal extraction

• Women with a history of venous thromboembolism or already treated with anti-coagulant

• Women with a contraindication to enoxaparin treatment at prophylactic doses

• Patient refusing to participate or unable to consent

• Patient with less than 80,000 platelets / mm 3 with the initial assessment

Related Conditions & MeSH terms

• Fetal Growth Retardation

Intervention

Drug:
• Enoxaparin
Enoxaparin will be delivered to the patients every day at the dose of 4 000 Ui.

Other:
• Usual care
Patients will all benefit from the usual care

Locations

Country	Name	City	State
France	Chru Brest	Brest
France	Chu Clermont-Ferrand	Clermont Ferrand
France	Chu Grenoble	Grenoble
France	Ch Lyon Sud Pierre Benite	Lyon
France	HFME - Lyon Est	Lyon
France	Hopital Croix Rousse Lyon	Lyon
France	Ch Roanne	Roanne
France	Chu Saint Etienne	St Etienne

Sponsors (1)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire de Saint Etienne

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of new born with a weight inferior at the 10th percentile	With the AUDIPOG formula, the number of new born with a weight inferior at the 10th percentile will be calculated.	Week 36
Secondary	Change in doppler parameters of uterine arterie	Doppler parameters is a composite outcome : pulsatility index and presence of notch	baseline from delivery
Secondary	Change in doppler parameters of ombilical arterie	Doppler parameters is a composite outcome : resistance index, presence of a zero diastole or reverse flow	baseline from delivery
Secondary	Change in doppler fetal weight	doppler fetal weight (grams)	baseline from delivery
Secondary	birth weight	birth weight (grams)	delivery
Secondary	Number of new born with a weight inferior at the 3rd percentile	With the AUDIPOG formula, the number of new born with a weight inferior at the 3rd percentile will be calculated.	delivery
Secondary	Number of fetal extraction	fetal extraction	before 36 weeks of gestation
Secondary	number of major neonatal parameters	Major neonatal parameters is at least one or more : Perinatal death, Ischemic encephalopathy Major intra- or periventricular bleeding (grade 3 or 4), Periventricular leukomalacia, Necrotizing enterocolitis, Bronchopulmonary dysplasia or Sepsis	1 month after delivery
Secondary	number of minor neonatal parameters	Minor neonatal parameters is a composite outcome : Caesarean section for fetal distress, Cord arterial pH < 7.1, Apgar score <7 at 5 minutes	1 month after delivery
Secondary	Number of Major bleeding events (MB) and clinically relevant non-major bleeding events (CRNMB)	The definitions of major bleeding events and clinically major bleeding events are adapted from the ISTH definition for which were added a specific Obstetrics and Gynaecology definition Bleeding events (MB) is a composite outcome.	from randomisation to 1 month postpartum
Secondary	Number of thrombocytopenia	thrombocytopenia is a composite outcome : Thrombopenia defined by platelet count < 100 G/L Significant thrombocytopenia with HIT suspicion defined as follows:= 40% decline of the platelet count (compared with baseline value) occurring during the first 8 weeks following the start of HBPM Or platelet count < 80 Giga/l to terme	From randomisation to 36 weeks