Long Term Prognostic of Neonatal Hypoxic Ischemic Encephalopathy With Hypothermia Treatment

• Conditions: Ischemic-Hypoxic Encephalopathy

• Registration Number: NCT02676063
• Lead Sponsor: University Hospital, Grenoble

Brief Summary

The primary objective is to evaluate neonatal characteristics, and biological and clinical investigations as predictive factors of death, or of severe and moderate neurodevelopmental disability at 3 years, in a large population-based cohort of full-term and late preterm neonates with moderate or severe HIE.

Contrary to most previous studies which have often analyzed the accuracy of one factor among all other clinical investigations, the investigators objective's is to seek a relevant combination of several factors among the following list:

* Neonatal characteristics: gestational age and birthweight, maternal disease, acute intrapartum event, delivery mode, acidosis, neurological examination, place of birth and neonatal transfer

* Laboratory investigations: pH, lactates and new biological markers as detailed below

* Clinical investigations: aEEG, EEG, MRI, diffusion-weighted MRI

Detailed Description

Hypoxic-ischemic encephalopathy (HIE) is a rare neonatal condition affecting about 1‰ births and with a high rate of death and severe neurological disability despite significant improvement of the management of this illness in the last ten years. During the first hours and days of life, different examinations are made by neonatologists to guide decisions about the management of HIE and to provide information to families. Nevertheless, better knowledge about the early and late predictive factors of long-term severe and moderate neurodevelopmental outcomes is badly needed.

This study is a prospective national observational population-based study involving all level III intensive care units in France.

This population-based cohort study will be performed including all moderate or severe cases of HIE, occurring between 34 and 42 completed weeks gestation in newborns admitted to a neonatal intensive care unit of the participating French regions. Children will be followed-up until the age of 3 years.

Participating centers will be invited to adhere to current HIE management guidelines and/or clinical investigations considered optimal to date, to ensure standardize clinical practice. The study will ensure high quality data collection.

About indications, timing and characteristics of treatments and investigations will be elaborated by the scientific committee during the preparation stage of the cohort study. This professional advice will have the double advantage of enabling us to record more homogeneous and high-quality data, and to standardize and improve clinical management and investigations among newborns with HIE.

Within this main study, an ancillary study will be performed by 21 centers to address the first secondary objective (predictive value of very early - first 6 hours of life - neurological examination and biological investigations, including specific new biomarkers such as Interleukin-6, Metalloproteinase-9, TIMP-1, Albumin modified by hypoxia, troponin I, acylcarnitins and amino acids).

Study Timeline

• Study Start: 2015-09
• Study First Submitted: 2015-09-28
• Study First Submitted QC: 2016-02-02
• Study First Posted: 2016-02-08
• Status Verified: 2018-06
• Last Update Submitted: 2018-06-04
• Last Update Posted: 2018-06-06
• Primary Completion: 2019-03
• Study Completion: 2021-03

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 800

Inclusion Criteria

• Infants born at a gestational age of 34 weeks or more;

• Presenting early neurological distress with clinical signs of moderate to severe HIE at a standardized neurologic examination performed by a senior examiner:

  • Moderate HIE: lethargy, hyper-reflexia, miosis, bradycardia, seizures, hypotonia with weak suck and Moro reflex
  • Severe HIE: stupor, flaccidity, small to mid-position pupils that react poorly to light, reduced stretch reflexes, hypothermia or no Moro reflex

• With criteria for asphyxia:

  • pH of 7.0 or less or a base deficit of 16 mmol per liter or more in a sample of umbilical-cord blood or any blood sampled in the first hour after birth.
  • If, during this interval, the pH is between 7.01 and 7.15, base deficit is between 10 and 15.9 mmol per liter, or blood gas is not available, additional criteria will be required. These include:
  • an acute perinatal event (e.g., late or variable decelerations, cord prolapse, cord rupture, uterine rupture, maternal trauma, hemorrhage, or cardiorespiratory arrest)
  • or an abrupt change in fetal heart rate (FHR), defined as a persistent abnormal FHE after a period of normal tracing: bradycardia or prolonged deceleration, persistent variable decelerations, persistent late decelerations, and reduced heart variability
  • or either a 10-minute Apgar score of 5 or less or assisted ventilation initiated at birth and continued for at least 10 minutes.

• Written parental informed consent

• Covered by the French social security

Exclusion Criteria

• Congenital malformations
• Chromosomal disorders
• Congenital neuromuscular disorders

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
The primary outcome measure is a combined criterion : death, neurodevelopmental disabilities in survivors	between birth and 3 years of age	A combined criterion which includes: * Death between birth and 3 years of age; * Neurodevelopmental disabilities in survivors, defined as : o Severe disabilities; * Intellectual impairment with a mental score \>2SD below the mean or \<70 (ASQ); * Or Cerebral palsy with a Gross Motor Function level of 3-5 according to the GMFCS; * Or bilateral blindness (vision \<20/200 acuity); * Or deafness requiring amplification (\>60dB)and/; * Or a persistent disorder defined as recurrent seizures after discharge from neonatal intensive care requiring anti-convulsion therapy at the examination time point; o Moderate disabilities; * Intellectual impairment with a mental score \>1SD below the mean or 70 to 84 (ASQ); * Cerebral palsy with a Gross Motor Function level of 1 or 2 according to the GMFCS; * Or hearing impairment requiring no amplification

Secondary Outcome Measures

Name	Time	Method
Second secondary objective: the predictive value of clinical investigations during the first weeks of life and treatments.	first week, At 18 months and 3 years of age	To analyze the predictive value of clinical investigations during the first weeks of life and treatments, including cooling: * for normal outcomes (absence of death, any disability, any epilepsy or any need for physiotherapy, orthophonist or psychologist or other measures of reeducation), moderate or severe neurodevelopmental disabilities, and death; * At 18 months and 3 years of age; * In this part, we will assess the ability of a normal developmental assessment at 18 months to predict survival free of disability or retardation at 3 years. This information will be useful in the future to define different strategies of follow up according to the assessment at 18 months of age.
Fourth secondary objective : Number and percentage of various obstetrical conditions leading to the worse outcomes	birth	Number and percentage of : * Maternal pyrexia,; * a persistent occipito-posterior position,; * an acute intrapartum event (hemorrhage, maternal convulsions, rupture of uterus, snapped cord, and birth of baby before arrival at obstetric facility),; * an instrumental vaginal delivery; * an emergency caesarean section
First secondary objective : The relevance of specific new biomarkers : Protein levels (IL-6, MMP-9, TIMP-1, Albumine modified by hypoxia, troponine I), acylcarnitins and amino acids.	before H6 and at 3 days	The biologist will evaluate the relevance of specific new biomarkers : * Protein levels (IL-6, MMP-9, TIMP-1, Albumine modified by hypoxia, troponine I) unites will be determined using an ELISA; * the measurement of acylcarnitins and amino acids by tandem liquid phase chromatography coupled with mass spectroscopy.; The analyses will be blinded and centralized to Reims University laboratory
Third secondary objective : Number and percentage of participants with cooling.	birth	The third secondary objective is analyzed thanks to : * number of patients with method of cooling : Criticool, tecotherm, craft, other; * duration of cooling in hours; * number of severe or modere HIE according to the Sarnat classification; * time to initiate cooling in minutes

Trial Locations

Locations (22)

Chu Bordeaux; 🇫🇷 Bordeaux, France

Chu Besancon; 🇫🇷 Besançon, France

Chu Amiens; 🇫🇷 Amiens, France

CHU CAEN; 🇫🇷 Caen, France

Chi Creteil; 🇫🇷 Creteil, France

Chu Brest; 🇫🇷 Brest, France

Chu Dijon; 🇫🇷 Dijon, France

CHU Clermond-Ferrand; 🇫🇷 Clermont-Ferrand, France

CHU FORT de France; 🇫🇷 Fort De France, France

Chu Grenoble; 🇫🇷 Grenoble, France

CHU Montpellier; 🇫🇷 Montpellier, France

Chu La Miletrie; 🇫🇷 Poitiers, France

Chru Lille; 🇫🇷 Lille, France

Chu Limoges; 🇫🇷 Limoges, France

Chu Marseille; 🇫🇷 Marseille, France

Chu Reims; 🇫🇷 Reims, France

CHU St Denis; 🇫🇷 Saint-Denis De La Réunion, France

Chu Rouen; 🇫🇷 Rouen, France

CHU St Pierre; 🇫🇷 Saint-Pierre, France

Chu Strasbourg; 🇫🇷 Strasbourg, France

Chu Tours; 🇫🇷 Tours, France

Chu Toulouse; 🇫🇷 Toulouse, France