Clinical trial NCT04617587: Novel Epigenetic Biomarker for Prematurity Related Neurodevelopmental Disorders in Childhood
Official title: Structural Variations of the Neural Genome as Prognostic Biomarkers for Prematurity Related Neurodevelopmental Disorders in Childhood
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Premature Birth
Keywords: Premature Birth
DNA Methylation
L1 Elements
Epigenometics
Early Intervention
Brain Development
Neurodevelopment
Parent-infant interaction
Massage therapy
Visual interaction
Lead sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Sponsor class: OTHER
Collaborators: name: Ministero della Salute, Italy
name: Istituto Nazionale di Genetica Molecolare, Milan Italy
name: IRCCS Humanitas Milan Italy
First posted: 2020-11-05
Enrollment: 104
Sex: ALL
Minimum age (years): 24
Maximum age (years): 32
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Preterms are early exposed to a stressful environment (i.e. excessive sensory stimulation and paucity of parental contact) with subsequent detrimental effects on brain maturation and neurodevelopmental outcomes. In contrast, early interventions seem to reduce stress exposure and promote neurodevelopment. The brain functional plasticity in response to environmental experiences can be partly attributed to changes in DNA methylation. In this context, LINE-1 (L1) promoter (18% of human genome) methylation/demethylation has been associated with L1 somatic mobilization in the brain genomes, contributing to experience-driven brain plasticity; this mechanism being deregulated in important neurological disease. This study aims at identifying and characterizing the role of L1 DNA repeats as a novel biomarker to predict long-term neurodevelopmental outcome in preterm infants. In addition, the study's secondary goal will be to define a preventive approach, based on early intervention strategies, for improving long-term neurodevelopmental outcomes.

Detailed description: Around 25-50% of very preterm infants suffer from neurodevelopmental delays (motor, cognitive and behavioral problems), which are most likely related to brain micro-structural defects and impaired neuronal maturation and connectivity. These alterations in brain maturation occurring during the neonatal period may be implicated in long-term neurobehavioral disorders later experienced by preterm babies.

There is increasing evidence that also stressful events (excessive sensory stimulation, paucity of parental contact and painful procedures) experienced in the Neonatal Intensive Care Unit (NICU) by preterm neonates can affect neurodevelopment through epigenetic mechanisms.

The brain is a genomic mosaic, owing to somatic mutations that arise throughout development. It is already established that mobile genetic elements, including LINE-1 (L1), are one source of somatic mosaicism, inducing copy number variations in neural genome. Environmental experiences can drive brain plasticity at a molecular level, with changes in DNA methylation. In particular, L1 promoter methylation/demethylation is already associated with L1 mobilization in the brain genomes and its deregulation is linked with important neurological diseases. A preliminary study has shown the correlation between L1 promoter methylation levels and preterm birth. In addition, maternal care during early life has been reported to drive variability in L1 mobilization and methylation of the neural hippocampal genome in mice models.

Several studies have reported how individualized developmental care in the NICU can ameliorate preterm infants' medical outcome and subsequent neurodevelopment. More recently, early intervention (EI) strategies based on parental training and multisensory stimulation, such as infant massage and visual stimulation, have been demonstrated to enhance child's neurodevelopment. These programs have the greatest potential to reduce environmental stress in preterms, promoting brain plasticity, optimizing dyadic interaction and ameliorating neurodevelopmental outcomes.

Eligibility criteria: Inclusion Criteria:

* Gestational age at birth between 24+0 and 32+6 weeks
* Mothers age over 18 years
* Good comprehension of the Italian language
* Written informed consent signed by both parents

Exclusion Criteria:

* Infants with major genetic disorders and malformations
* Parents declined study participation
* Single-parent family
* Parents with obvious cognitive or psychiatric disorders and drug addiction

Primary outcomes:
measure: L1 Promoter Methylation Levels on Biological Materials
timeFrame: Up to 24 months corrected age
Secondary outcomes:
measure: Conventional and advanced brain Magnetic Resonance Imaging (MRI)
timeFrame: Term equivalent age, approximately 40 weeks postmenstrual age
measure: Neurological Examination
timeFrame: Term equivalent age, approximately 40 weeks postmenstrual age
measure: General Movements Examination
timeFrame: Term equivalent age, approximately 40 weeks postmenstrual age
measure: Visual Assessment
timeFrame: Term equivalent age, approximately 40 weeks postmenstrual age
measure: Neurodevelopmental Outcome
timeFrame: Up to 24 months corrected age
measure: Behavioral Outcome
timeFrame: 24 months corrected age
Other outcomes:
Locations:
city: Milan
country: Italy
facility: NICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
Study officials:
affiliation: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
name: Monica Fumagalli, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
name: Beatrice Bodega, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fontana C, De Carli A, Ricci D, Dessimone F, Passera S, Pesenti N, Bonzini M, Bassi L, Squarcina L, Cinnante C, Mosca F, Fumagalli M. Effects of Early Intervention on Visual Function in Preterm Infants: A Randomized Controlled Trial. Front Pediatr. 2020 Jun 4;8:291. doi: 10.3389/fped.2020.00291. eCollection 2020.
citation: Newnham CA, Milgrom J, Skouteris H. Effectiveness of a modified Mother-Infant Transaction Program on outcomes for preterm infants from 3 to 24 months of age. Infant Behav Dev. 2009 Jan;32(1):17-26. doi: 10.1016/j.infbeh.2008.09.004. Epub 2008 Nov 20.
citation: Bedrosian TA, Quayle C, Novaresi N, Gage FH. Early life experience drives structural variation of neural genomes in mice. Science. 2018 Mar 23;359(6382):1395-1399. doi: 10.1126/science.aah3378.
citation: Ricci D, Romeo DM, Serrao F, Cesarini L, Gallini F, Cota F, Leone D, Zuppa AA, Romagnoli C, Cowan F, Mercuri E. Application of a neonatal assessment of visual function in a population of low risk full-term newborn. Early Hum Dev. 2008 Apr;84(4):277-80. doi: 10.1016/j.earlhumdev.2007.10.002. Epub 2007 Nov 8.
citation: Guzzetta A, Baldini S, Bancale A, Baroncelli L, Ciucci F, Ghirri P, Putignano E, Sale A, Viegi A, Berardi N, Boldrini A, Cioni G, Maffei L. Massage accelerates brain development and the maturation of visual function. J Neurosci. 2009 May 6;29(18):6042-51. doi: 10.1523/JNEUROSCI.5548-08.2009.