Early Intervention in Preterm Infants: Short and Long Term Developmental Outcome After a Parental Training Program

Early Intervention in Preterm Infants: Effects of a Parental Training Program on Neonatal Brain Development, Visual Functions and Neurobehavioral Outcome

Preterm infants, during their stay in the Neonatal Intensive Care Unit (NICU), face a period of stressful environment, which may negatively impact early brain development and subsequent neurobehavioral outcomes. This study aims to assess the effectiveness of training parents in reducing stressful experiences early in life and in enhancing brain development and long term developmental outcomes.

Study Overview

• Status: Completed
• Conditions: Premature Birth
• Intervention / Treatment: Behavioral: Early Intervention

Detailed Description

Very preterm birth is associated with motor, cognitive and behavioral problems.

Micro-structural brain abnormalities, even in the absence of focal lesions, have been documented by neuroimaging studies in preterm infants at term corrected age and later in childhood. These alterations in brain maturation occurring during the neonatal period may be implicated in long-term neurobehavioral disorders later experienced by preterm babies.

However, there is increasing evidence that also negative environmental factors (intensive care, excessive sensory stimulation, paucity of parental contact etc.) can affect later outcomes.

Potential benefits of early dyadic interaction and preterm baby massage in reducing the effects of the NICU stressor environment have been demonstrated. More recently, few studies have investigated visual function in preterm infants focusing on the potential role of early visual interaction to enhance attention and improve later neurodevelopment.

The role of early intervention strategies to improve neurodevelopment has been recently emphasized.

Early intervention programs based on the concept of "individualized care" have proved to be effective in promoting brain maturation and neurodevelopmental outcome. In this context, early interventions as the Mother Infant Transaction Program (MITP) and the Premie Start, both targeting parenting, have the greatest potential to have sustained effects on child development.

In addition, recent studies have shown that exposure to stressful events in the neonatal period can cause epigenetic modifications in children born preterm; in particular alteration of serotonergic tone was observed, associated with methylation of the serotonin transporter gene, which could be implicated in the etiology of behavioral disorders observed in these children. In animal models these epigenetic effects appear to be influenced by maternal care that can epigenetically modulate the offsprings' stress response.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20122
    • NICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 6 months (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Gestational age between 25+0 and 29+6 weeks

Exclusion Criteria:

• major brain lesions as documented by cranial ultrasound (intraventricular hemorrhage > 2 grade, cystic periventricular leukomalacia)
• neurosensorial deficits (retinopathy of prematurity > stage 2)
• genetic syndromes and/or major congenital malformations
• major neonatal comorbidities

Mothers are selected according to the following inclusion criteria: age over 18 years, good comprehension of Italian language, no obvious cognitive impairments or psychiatric disorders, no drug addiction and no single-parent families.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SUPPORTIVE_CARE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Early Intervention; The early intervention program is delivered during the NICU stay, according to the MITP and Premie Start Protocol, in order to train parents to: recognize signs of infant stress and alert-available behavior to promote mother-infant interaction; adopt principles of graded stimulation; optimize interactions and avoid overwhelming infants through facilitation strategies (for example, engage and support the visual attention of the newborn). The program is held in eight main sessions and one additional post-discharge session. In addition parents are trained and invited to daily promote preterm baby massage therapy and visual attention according to a detailed protocol.	Behavioral: Early Intervention
NO_INTERVENTION: Standard Care; Standard Care according to NICU protocols including Kangaroo Mother Care, nesting and minimal handling

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neonatal Visual Assessment Battery to evaluate visual function	Neonatal Visual Function is assessed using the Visual Assessment Battery developed by Ricci et al. The assessment evaluates the following items: Ocular spontaneous motility, ability to fix and follow a target, reaction to colour, visual acuity and visual attention at distance. Each item is scored as normal (score 0) or abnormal (score 1). The global score is then calculated as the sum of all the individual items, as designed by the authors.	40 weeks postmenstrual age
Neonatal Behavior	Neonatal behavior is assessed using the Neonatal Behavior Assessment Scale that evaluates: habituation, social-interactive, motor system, state organization and regulation, autonomic system, reflexes.	2 months corrected age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain development	Conventional and advanced MRI	40 weeks postmenstrual age
Developmental outcome	Children development is assessed using the Bayley Scales of Infant and Toddlers (Third edition) - including: cognitive, motor, language, social-emotional and adaptive behavior)	24 months corrected age
Epigenetic changes	epigenetic analysis is performed at birth on a cord blood sample (0.5 ml) and at hospital discharge on a peripheral blood sample (0.5 ml) collected according routine clinical procedures	up to 48 weeks gestational age
overall duration of hospitalisation	number of days from admission to home discharge from NICU	up to 48 weeks gestational age
Weight (in grams) at 40 weeks postmenstrual age		40 week gestational age
Length(in centimeters) at 40 weeks postmenstrual age		40 week gestational age
Head circumference (in centimeters) at 40 weeks postmenstrual age		40 week gestational age
Acquisition of full oral feeding	Postmenstrual age at the acquisition of full oral feeding	up to 48 weeks gestational age
Feeding with Human milk	Feeding with human milk at 40 weeks postmenstrual age (yes or no)	up to 40 weeks gestational age
Neurodevelopmental outcome	Children neurodevelopment is assessed using the Griffiths Development Scales (GMDS). Scores range from 50 to 150 General quotient mean 100 SD 12, sub scales mean 100 SD 16 Higher scores mean a better outcome	5-6 years of age
Behavioral outcome	Children behavior is assessed using the Child Behavior Checklist. A T score above 70 is considered to be in the clinical range, a T score between 65 an 70 is considered borderline while a T score below 65 is considered normal	5-6 years of age
Neuromotor outcome	Children neuromotor is assessed using the Movement Assessment Battery for Children (Movement ABC). A score above 67 is considered to be in the normal range, a score between 57 an 67 is considered borderline while a score below 56 is considered pathological	5-6 years of age
Attention outcome	Child attention abilities is assessed using the Early Childhood Attention Battery (ECAB). Scaled scores range from 1 to 19. Lower scores indicate worst outcome	5-6 years of age
L1 promoter methylation levels on buccal swab	epigenetic analysis - L1 promoter methylation (Percent) assessment is performed on a buccal swab collected at follow-up assessment at 5-6 years.	5-6 years of age

Collaborators and Investigators

• Sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
• Investigators: Principal Investigator: Monica Fumagalli, MD, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Publications and helpful links

General Publications

• 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.
• Provenzi L, Fumagalli M, Sirgiovanni I, Giorda R, Pozzoli U, Morandi F, Beri S, Menozzi G, Mosca F, Borgatti R, Montirosso R. Pain-related stress during the Neonatal Intensive Care Unit stay and SLC6A4 methylation in very preterm infants. Front Behav Neurosci. 2015 Apr 21;9:99. doi: 10.3389/fnbeh.2015.00099. eCollection 2015.
• Guzzetta A, D'Acunto MG, Carotenuto M, Berardi N, Bancale A, Biagioni E, Boldrini A, Ghirri P, Maffei L, Cioni G. The effects of preterm infant massage on brain electrical activity. Dev Med Child Neurol. 2011 Sep;53 Suppl 4:46-51. doi: 10.1111/j.1469-8749.2011.04065.x.
• Ricci D, Cesarini L, Romeo DM, Gallini F, Serrao F, Groppo M, De Carli A, Cota F, Lepore D, Molle F, Ratiglia R, De Carolis MP, Mosca F, Romagnoli C, Guzzetta F, Cowan F, Ramenghi LA, Mercuri E. Visual function at 35 and 40 weeks' postmenstrual age in low-risk preterm infants. Pediatrics. 2008 Dec;122(6):e1193-8. doi: 10.1542/peds.2008-1888.
• 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.
• Fontana C, Marasca F, Provitera L, Mancinelli S, Pesenti N, Sinha S, Passera S, Abrignani S, Mosca F, Lodato S, Bodega B, Fumagalli M. Early maternal care restores LINE-1 methylation and enhances neurodevelopment in preterm infants. BMC Med. 2021 Feb 5;19(1):42. doi: 10.1186/s12916-020-01896-0.
• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (ACTUAL): April 1, 2017
• Study Completion (ACTUAL): January 1, 2023

Study Registration Dates

• First Submitted: November 16, 2016
• First Submitted That Met QC Criteria: December 2, 2016
• First Posted (ESTIMATE): December 6, 2016

Study Record Updates

• Last Update Posted (ACTUAL): February 10, 2023
• Last Update Submitted That Met QC Criteria: February 9, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Early intervention; Neurodevelopment; Brain Development
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth
• Other Study ID Numbers: MITP Preterm

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: individual patient consent would be required according to the EU GDPR and Italian regulations