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

Phase 3

Completed

• Conditions: Fetal Growth Retardation
• Interventions: Drug: Enoxaparin; Other: Usual care

• Registration Number: NCT02672566
• Lead Sponsor: Centre Hospitalier Universitaire de Saint Etienne

Brief 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2016-01-28
• Study First Submitted QC: 2016-02-01
• Study First Posted: 2016-02-03
• Study Start: 2016-07-22
• Status Verified: 2019-04
• Primary Completion: 2019-09-05
• Study Completion: 2020-01-22
• Last Update Submitted: 2020-03-19
• Last Update Posted: 2020-03-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 82

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Experimental group : enoxaparin	Enoxaparin	Experimental group will take enoxaparin (4000 Ui / Day) and will benefit from the usual care.
Experimental group : enoxaparin	Usual care	Experimental group will take enoxaparin (4000 Ui / Day) and will benefit from the usual care.
Control group	Usual care	The control group will only benefit from the usual care.

Primary Outcome Measures

Name	Time	Method
Number of new born with a weight inferior at the 10th percentile	Week 36	With the AUDIPOG formula, the number of new born with a weight inferior at the 10th percentile will be calculated.

Secondary Outcome Measures

Name	Time	Method
birth weight	delivery	birth weight (grams)
Change in doppler parameters of uterine arterie	baseline from delivery	Doppler parameters is a composite outcome : pulsatility index and presence of notch
Change in doppler fetal weight	baseline from delivery	doppler fetal weight (grams)
number of major neonatal parameters	1 month after delivery	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
number of minor neonatal parameters	1 month after delivery	Minor neonatal parameters is a composite outcome : Caesarean section for fetal distress, Cord arterial pH \< 7.1, Apgar score \<7 at 5 minutes
Change in doppler parameters of ombilical arterie	baseline from delivery	Doppler parameters is a composite outcome : resistance index, presence of a zero diastole or reverse flow
Number of new born with a weight inferior at the 3rd percentile	delivery	With the AUDIPOG formula, the number of new born with a weight inferior at the 3rd percentile will be calculated.
Number of fetal extraction	before 36 weeks of gestation	fetal extraction
Number of Major bleeding events (MB) and clinically relevant non-major bleeding events (CRNMB)	from randomisation to 1 month postpartum	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.
Number of thrombocytopenia	From randomisation to 36 weeks	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

Trial Locations

Locations (8)

Hopital Croix Rousse Lyon; 🇫🇷 Lyon, France

Ch Lyon Sud Pierre Benite; 🇫🇷 Lyon, France

Chu Grenoble; 🇫🇷 Grenoble, France

HFME - Lyon Est; 🇫🇷 Lyon, France

Chru Brest; 🇫🇷 Brest, France

Chu Saint Etienne; 🇫🇷 St Etienne, France

Ch Roanne; 🇫🇷 Roanne, France

Chu Clermont-Ferrand; 🇫🇷 Clermont Ferrand, France