Clinical trial NCT02676063: Long Term Prognostic of Neonatal Hypoxic Ischemic Encephalopathy With Hypothermia Treatment
Official title: Long Term Prognostic of Neonatal Hypoxic Ischemic Encephalopathy in the Era of Neuroprotective Treatment With Hypothermia
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Ischemic-Hypoxic Encephalopathy
Keywords: predictive factors
neurodevelopmental disabilities
Lead sponsor: University Hospital, Grenoble
Sponsor class: OTHER
First posted: 2016-02-08
Enrollment: 800
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: This study will be performed on all moderate or severe cases of hypoxic ischemic encephalopathyhie, 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.

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).

Eligibility criteria: 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

Primary outcomes:
measure: The primary outcome measure is a combined criterion : death, neurodevelopmental disabilities in survivors
timeFrame: between birth and 3 years of age
Secondary outcomes:
measure: 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.
timeFrame: before H6 and at 3 days
measure: Second secondary objective: the predictive value of clinical investigations during the first weeks of life and treatments.
timeFrame: first week, At 18 months and 3 years of age
measure: Third secondary objective : Number and percentage of participants with cooling.
timeFrame: birth
measure: Fourth secondary objective : Number and percentage of various obstetrical conditions leading to the worse outcomes
timeFrame: birth
Other outcomes:
Locations:
city: Amiens
country: France
facility: Chu Amiens
city: Besançon
country: France
facility: Chu Besancon
city: Bordeaux
country: France
facility: Chu Bordeaux
city: Brest
country: France
facility: Chu Brest
city: Caen
country: France
facility: CHU CAEN
city: Clermont-Ferrand
country: France
facility: CHU Clermond-Ferrand
city: Creteil
country: France
facility: Chi Creteil
city: Dijon
country: France
facility: Chu Dijon
city: Fort De France
country: France
facility: CHU FORT de France
city: Grenoble
country: France
facility: Chu Grenoble
city: Lille
country: France
facility: Chru Lille
city: Limoges
country: France
facility: Chu Limoges
city: Marseille
country: France
facility: Chu Marseille
city: Montpellier
country: France
facility: CHU Montpellier
city: Poitiers
country: France
facility: Chu La Miletrie
city: Reims
country: France
facility: Chu Reims
city: Rouen
country: France
facility: Chu Rouen
city: Saint-Denis De La Réunion
country: France
facility: CHU St Denis
city: Saint-Pierre
country: France
facility: CHU St Pierre
city: Strasbourg
country: France
facility: Chu Strasbourg
city: Toulouse
country: France
facility: Chu Toulouse
city: Tours
country: France
facility: Chu Tours
Study officials:
affiliation: University Hospital, Grenoble
name: Thierry DEBILLON, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Volpe JJ. Neonatal encephalopathy: an inadequate term for hypoxic-ischemic encephalopathy. Ann Neurol. 2012 Aug;72(2):156-66. doi: 10.1002/ana.23647.
citation: Use and abuse of the Apgar score. Committee on Fetus and Newborn, American Academy of Pediatrics, and Committee on Obstetric Practice, American College of Obstetricians and Gynecologists. Pediatrics. 1996 Jul;98(1):141-2.
citation: Fenichel GM. Hypoxic-ischemic encephalopathy in the newborn. Arch Neurol. 1983 May;40(5):261-6. doi: 10.1001/archneur.1983.04050050029002.
citation: Levene ML, Kornberg J, Williams TH. The incidence and severity of post-asphyxial encephalopathy in full-term infants. Early Hum Dev. 1985 May;11(1):21-6. doi: 10.1016/0378-3782(85)90115-x.
citation: Debillon T, Sentilhes L, Kayem G, Chevallier M, Zeitlin J, Baud O, Vilotitch A, Pierrat V, Guellec I, Ancel PY, Bednarek N, Ego A. Risk factors for unfavorable outcome at discharge of newborns with hypoxic-ischemic encephalopathy in the era of hypothermia. Pediatr Res. 2023 Jun;93(7):1975-1982. doi: 10.1038/s41390-022-02352-w. Epub 2022 Oct 22.
citation: Beck J, Debillon T, Guellec I, Vilotitch A, Loron G, Bednarek N, Ancel PY, Pierrat V, Ego A. Healthcare organizational factors associated with delayed therapeutic hypothermia in neonatal hypoxic-ischemic encephalopathy: the LyTONEPAL cohort. Eur J Pediatr. 2023 Jan;182(1):181-190. doi: 10.1007/s00431-022-04666-7. Epub 2022 Oct 21.
citation: Beck J, Bednarek N, Pierrat V, Vilotitch A, Loron G, Alison M, Guellec I, Hertz-Pannier L, de Launay C, Ego A, Vo-Van P, Ancel PY, Debillon T. Cerebral injuries in neonatal encephalopathy treated with hypothermia: French LyTONEPAL cohort. Pediatr Res. 2022 Sep;92(3):880-887. doi: 10.1038/s41390-021-01846-3. Epub 2021 Nov 20.
citation: Debillon T, Bednarek N, Ego A; LyTONEPAL Writing Group. LyTONEPAL: long term outcome of neonatal hypoxic encephalopathy in the era of neuroprotective treatment with hypothermia: a French population-based cohort. BMC Pediatr. 2018 Aug 1;18(1):255. doi: 10.1186/s12887-018-1232-6.