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Epigenetics and Protective Factors in the Preterm Infant (EPIC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04804280
Recruitment Status : Recruiting
First Posted : March 18, 2021
Last Update Posted : August 30, 2021
Sponsor:
Information provided by (Responsible Party):
IRCCS Eugenio Medea

Brief Summary:
Preterm infants (PT) spend their first weeks of life in the Neonatal Intensive Care Unit (NICU) where they are exposed to unfavorable conditions with different effects on child development including long-term alterations in epigenetic regulation (DNA methylation). Recent studies document that these epigenetic changes are associated with behavioral modifications, such as altered stress reactivity at 3 months and 4 years. A growing number of studies suggest that protective Developmental Care (DC) procedures (e.g., breastfeeding, skin-to-skin contact (SSC), maternal holding) positively impact neurophysiological and behavioral adaptation of PT with long-term effects. Additionally, a neuro-imaging study reported that parental support in the NICU is associated with improved brain connectivity. While in term (FT) infants, parental interpersonal touch (breastfeeding, affectionate touch) is associated with reduced methylation and activation of specific brain areas associated with affective interpersonal touch, to date no study has investigated whether DC practices and maternal care in NICU (specifically, SSC) buffer methylation and support the brain response to affectionate physical touch in PT. The present study investigates the association between DC procedures in NICU, DNA methylation, and brain responses to affectionate touch, investigated through the use of MRI, at 2 months of age (corrected for prematurity), controlling for: (1) birth status (PT vs FT); (2) the duration of SSC during the NICU stay; (3) parental affectionate touch in the home environment and during mother-child interaction.

Condition or disease Intervention/treatment
Preterm Birth Parent-Child Relations Epigenetics Genetic: DNA methylation of target genes Diagnostic Test: Functional Magnetic Resonance Imaging (fMRI) acquisition

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Study Type : Observational
Estimated Enrollment : 94 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Epigenetics and Protective Factors in the Preterm Infant: Neural and Methylation Correlates of Developmental Care During Neonatal Intensive Care Unit Hospitalization
Actual Study Start Date : January 1, 2019
Estimated Primary Completion Date : March 31, 2022
Estimated Study Completion Date : June 30, 2022

Group/Cohort Intervention/treatment
Preterm children (PT)
  • gestational age at birth: 26+0 to 31+6 weeks;
  • absence of documented neurological pathology;
  • absence of sensory deficits;
  • absence of malformative syndromes and/or major malformations.
Genetic: DNA methylation of target genes
The methylation status of target genes (BDNF, SLC6A4, OXTR, NR3C1) will be investigated. Cord blood will be collected at birth for PT and FT, only for PT a peripheral blood sample will be collected at hospital discharge, during routine clinical procedures. Genomic DNA will be extracted from aliquots of 0. 2 ml of each blood sample with the GeneElute Blood Genomic DNA kit (Sigma) and stored at -20°C. Aliquots of 250 ng of each DNA will be edited for methylation analysis with the EZ DNA Methylation Lightning kit (Zymo Research). Amplification of samples and their preparation for NGS sequencing will be performed. Samples will be sequenced on NextSeq 500 (Illumina). Individual processed sequences (PE reads) will be independently aligned to reference sequences using a parallel Smith-Waterman algorithm. Only reads that consistently align to the same reference sequence will be retained. At each CpG site in each analyzed sequence, the frequencies of the four bases will be evaluated.

Diagnostic Test: Functional Magnetic Resonance Imaging (fMRI) acquisition
Infants will undergo an MRI exam with a 3 Tesla Philips Achieva scanner and a 32-channel head coil. a trained experimenter will apply tactile stimulation associated with affective touch characteristics to the child with a soft brush on the right anterior tibial region in proximal and distal directions. The length of the stimulated area will be measured to cover approximately 15 cm, and tactile stimulations will be applied at a rate of 5 cm/s for 15s, with randomized intervals between stimuli of 10-15s (resulting in 5 stimulations in a 15s block). A regular audio signal will help the researcher to keep a constant stroke velocity. Audio commands will also be used to direct the experimenter. Infant must be asleep (natural sleep) during the fMRI acquisition.

Full-term children (FT)
  • gestational age at birth ≥ 37 weeks;
  • birth weight ≥ 2,500g;
  • APGAR 5' ≥ 7
  • delivery without any complications for baby and/or mother;
  • no prenatal and/or postnatal clinical conditions;
  • no hospitalizations at the time of birth or postpartum;
  • absence of malformative syndromes and/or major malformations.
Genetic: DNA methylation of target genes
The methylation status of target genes (BDNF, SLC6A4, OXTR, NR3C1) will be investigated. Cord blood will be collected at birth for PT and FT, only for PT a peripheral blood sample will be collected at hospital discharge, during routine clinical procedures. Genomic DNA will be extracted from aliquots of 0. 2 ml of each blood sample with the GeneElute Blood Genomic DNA kit (Sigma) and stored at -20°C. Aliquots of 250 ng of each DNA will be edited for methylation analysis with the EZ DNA Methylation Lightning kit (Zymo Research). Amplification of samples and their preparation for NGS sequencing will be performed. Samples will be sequenced on NextSeq 500 (Illumina). Individual processed sequences (PE reads) will be independently aligned to reference sequences using a parallel Smith-Waterman algorithm. Only reads that consistently align to the same reference sequence will be retained. At each CpG site in each analyzed sequence, the frequencies of the four bases will be evaluated.

Diagnostic Test: Functional Magnetic Resonance Imaging (fMRI) acquisition
Infants will undergo an MRI exam with a 3 Tesla Philips Achieva scanner and a 32-channel head coil. a trained experimenter will apply tactile stimulation associated with affective touch characteristics to the child with a soft brush on the right anterior tibial region in proximal and distal directions. The length of the stimulated area will be measured to cover approximately 15 cm, and tactile stimulations will be applied at a rate of 5 cm/s for 15s, with randomized intervals between stimuli of 10-15s (resulting in 5 stimulations in a 15s block). A regular audio signal will help the researcher to keep a constant stroke velocity. Audio commands will also be used to direct the experimenter. Infant must be asleep (natural sleep) during the fMRI acquisition.




Primary Outcome Measures :
  1. DNA methylation changes in PT [ Time Frame: first 6 months (Corrected Age for PT) of infant's life ]
    Correlation between DNA methylation changes of target genes (BDNF, SLC6A4, OXTR, NR3C1) and the duration of Developmental Care practice that involved proximity and pyisical contact during the NICU stay measured by a specific APP.


Secondary Outcome Measures :
  1. Insular cortex and somatosensory cortex activation in PT and FT infants [ Time Frame: when the infants is 2 months-old (Corrected Age for PT) ]
    Significant differences in mean BOLD signal magnitude in the insular cortex and in somatosensory cortex between PT and FT in the slow skin stroking experimental task during the fMRI session.

  2. Developmental Care procedures in NICU and insular cortex/somatosensory cortex activation in preterm infants [ Time Frame: first 2 months (Corrected Age for PT) of infant's life ]
    Correlation between the duration of Developmental Care practice taht involved proximity and physical contact during the NICU stay measured by a specific APP and mean BOLD signal magnitude in the insular cortex and in somatosensory cortex (in the slow skin stroking experimental task during the fMRI session) in PT.


Biospecimen Retention:   Samples With DNA
The study will investigate the methylation status of target genes (such as BDNF, SLC6A4, OXTR, NR3C1) in preterm children (PT), compared with a sample of full term children (FT). Cord blood will be collected at birth for both PT and FT groups and, only for PT infants, a peripheral blood sample will be collected at hospital discharge, following routine clinical procedures. Blood samples will be obtained by trained nurses.


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Ages Eligible for Study:   up to 30 Minutes   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Preterm infants. Preterm infants infants will be pre-screened for medical status variables by the NICU neonatologists of different hospital in Lombardy. Following a letter outlining the general research, parents will be meet per person in NICU or contacted by telephone and asked to voluntarily participate.

Full-term infants. Mothers and their infants will be enrolled during the prenatal/ postnatal parenting coursein different hospital in Lombardy. Following a letter outlining the general research, parents will be contacted by telephone and asked to voluntarily participate.

Criteria

Inclusion criteria for PT children are:

  • gestational age: 26+0 to 31+6 weeks;
  • absence of documented neurological pathology;
  • absence of sensory deficits;
  • absence of malformative syndromes and/or major malformations.

Inclusion criteria for FT infants are:

  • gestational age ≥ 37weeks;
  • birth weight ≥ 2,500g;
  • APGAR 5' ≥ 7 - delivery without any complications for the child and/or mother;
  • no pre/postnatal/postnatal clinical conditions;
  • no hospitalizations at the time of birth or postpartum;
  • absence of malformative syndromes and/or major malformations.

Inclusion criteria for mothers are:

  • mothers of Italian nationality;
  • mother over 18 years of age;
  • mother with absence of manifest psychiatric and/or cognitive pathologies (must be previously diagnosed major psychiatric pathologies);
  • non-addicted/no habitual use of psychotropic medications, drugs, alcohol no smoking;
  • non-single-parent families.

Exclusion criteria: refer to inclusion criteria.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04804280


Contacts
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Contact: Rosario Montirosso +39031877494 rosario.montirosso@lanostrafamiglia.it

Locations
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Italy
Associalzione La Nostra Famiglia - IRCCS Eugenio Medea Recruiting
Bosisio Parini, Lecco, Italy, 23842
Contact: Rosario Montirosso    +39031877494    rosario.montirosso@lanostrafamiglia.it   
Sponsors and Collaborators
IRCCS Eugenio Medea
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Responsible Party: IRCCS Eugenio Medea
ClinicalTrials.gov Identifier: NCT04804280    
Other Study ID Numbers: RC2020_751
First Posted: March 18, 2021    Key Record Dates
Last Update Posted: August 30, 2021
Last Verified: August 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by IRCCS Eugenio Medea:
At-risk Infants
Developmental Care
DNA methylation
affectionate touch
Insular cortex
Additional relevant MeSH terms:
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Premature Birth
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications