Multisensory Early Oral Administration of Human Milk in Preterm Infants (M-MILK)

Multisensory Early Oral Administration of Human Milk in Preterm Infants to Attenuate Early Life Toxic Stress on Epigenetic Modifications and Dysbiosis: Randomized Controlled Trial Pilot Study

More than 60,000 infants are born between 22 to 32 weeks gestation age annually in the US. Approximately 11% of them develop comorbidities. During NICU hospitalization, preterm infants inevitably endure early life toxic stress without adequate protective buffers. Early life toxic stress results in adverse epigenetic modifications of glucocorticoid-related genes and dysbiosis, impairing neurodevelopment. These adversities further exacerbate the risk of comorbidities and inappropriate brain development during sensitive periods of neuroplasticity. Adverse epigenetic modifications and dysbiosis may set a life-long trajectory of risk for chronic health conditions. It is a clinical and scientific priority to test an early NICU intervention to attenuate stress-related adverse epigenetic modifications and dysbiosis. Human milk influences the structure and relative abundance of healthy gut bacteria and neurodevelopment. Maternal nurturing, e.g., licking and grooming (in rodents), and breastfeeding and touch (in humans), promotes neurodevelopment, reduces stress, and reverses stress-related epigenetic modifications. The multisensory early oral administration of human milk (M-MILK) intervention is designed to provide an enjoyable and nurturing experience for infants, through a safe and consistent infant-guided provision of human milk droplets, given orally as early as 22 weeks postmenstrual age. M-MILK is implemented from day 3 of life, after every hands-on care, and during the beginning of a full gavage feeding. We propose the M-MILK pilot randomized controlled trial (RCT): a 2-group (N = 12, 6 per group), parallel, and longitudinal design in preterm infants who are born between 22 to 28 weeks gestational age. The aims of this pilot are to determine the feasibility and acceptability of the M-MILK intervention, recruitment, retention, and obtain data for sample size estimation. This study will advance nursing science and practice because it will inform our R01 RCT to examine the efficacy of M-MILK to attenuate adverse effects of early life toxic stress in preterm infants.

Study Overview

• Status: Recruiting
• Conditions: Stress; Infant Development
• Intervention / Treatment: Procedure: Multisensory Early Oral Administration of Human Milk (M-MILK)

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Thao Griffith, PhD; Phone Number: 708-216-5708; Email: tgriffith1@luc.edu

Study Locations

• United States
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Recruiting
      • Loyola University Chicago
      • Contact: Thao Griffith, PhD; Phone Number: 708-216-5708; Email: tgriffith1@luc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• born between 22 to 28 weeks gestational age and receiving mother's own milk and/or donor milk.

Exclusion Criteria:

• receiving only formula, oral cavity defects, gastrointestinal defects, chromosomal abnormalities, severe cardiac defects that require surgery, or intraventricular hemorrhage grade III or IV

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Attention Control; Infants in the attention control group will receive standard of care.
Experimental: M-MILK; Infants in the M-MILK group will receive the M-MILK intervention in addition to standard of care.	Procedure: Multisensory Early Oral Administration of Human Milk (M-MILK); M-MILK is implemented as droplets, at day 3 of life, after every hands-on care, and during the beginning of a full gavage feeding. The infant may be supportively positioned in bed, held skin-to-skin by caregiver, or held/cradled by nurse or caregiver. The nurse draws up 1 mL of milk into the 1-mL syringe from a prepared bottle or enteral feeding syringe. The nurse then proceeds to implement M-MILK while observing the infant's responses closely. The nurse talks to the infant with a soft calm voice while providing gentle touch throughout the intervention. The nurse begins M-MILK by first placing 1-2 drops of milk onto the infant's upper lip, allowing the infant to feel and smell the milk. The nurse gently strokes the infant's lips with a pacifier/swab or infant's fingers. M-MILK will be provided based on infants' responses and cues. M-MILK is concluded if the infant is no longer engaged or has finished the 1 mL of milk.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of intervention	Determine the feasibility of intervention. M-MILK will be considered feasible if M-MILK is implemented by nurses or parents after every hands-on care and during the beginning of a full gavage feeding at least 50% of the time.	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.
Acceptability of intervention	The percentage of parents who rate the intervention as very positive, slightly positive, or acceptable on a 5-point Likert scale.	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.
Retention	Retention will be described by the percentage of post-discharge follow-up surveys completed.	2 months corrected age
Variability in the Scarf Sign cluster of the Neurobehavioral Assessment of the Preterm Infants score	The Neurobehavioral Assessment of the Preterm Infants (NAPI, 73 items, 32-37 weeks PMA): cluster score for scarf sign ranges from 0-100, where higher scores indicate better neurodevelopmental performance.	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.
Variability in the motor development & vigor cluster of the Neurobehavioral Assessment of the Preterm Infants score	The Neurobehavioral Assessment of the Preterm Infants (NAPI, 73 items, 32-37 weeks PMA): cluster score for motor development & vigor ranges from 0-100, where higher scores indicate better neurodevelopmental performance.	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.
Variability in the popliteal angle cluster of the Neurobehavioral Assessment of the Preterm Infants score	The Neurobehavioral Assessment of the Preterm Infants (NAPI, 73 items, 32-37 weeks PMA): cluster score for popliteal angle ranges from 0-100, where higher scores indicate better neurodevelopmental performance.	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.
Variability in the alertness and orientation cluster of the Neurobehavioral Assessment of the Preterm Infants score	The Neurobehavioral Assessment of the Preterm Infants (NAPI, 73 items, 32-37 weeks PMA): cluster score for alertness and orientation ranges from 0-100, where higher scores indicate better neurodevelopmental performance.	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.
Variability in the irritability cluster of the Neurobehavioral Assessment of the Preterm Infants score	The Neurobehavioral Assessment of the Preterm Infants (NAPI, 73 items, 32-37 weeks PMA): cluster score for irritability ranges from 0-100, where higher scores indicate better neurodevelopmental performance.	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.
Variability in the quality of cry cluster of the Neurobehavioral Assessment of the Preterm Infants score	The Neurobehavioral Assessment of the Preterm Infants (NAPI, 73 items, 32-37 weeks PMA): cluster score for quality of cry ranges from 0-100, where higher scores indicate better neurodevelopmental performance.	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.
Variability in the percent sleep cluster of the Neurobehavioral Assessment of the Preterm Infants score	The Neurobehavioral Assessment of the Preterm Infants (NAPI, 73 items, 32-37 weeks PMA): cluster score for percent sleep ranges from 0-100, where higher scores indicate better neurodevelopmental performance.	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.
Variability in Early Feeding Skill Assessment score	EFS has 22 items (32-50 weeks PMA), summary scores, 5 subscales: respiratory regulation (range 5 - 15), oral-motor functioning (range 4 - 12), swallowing coordination (range 4 - 12), engagement (range 2 - 6), & physiologic stability (range 4 - 12), where higher scores indicate better oral feeding skill development.	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.
Variability in the Nursing Child Assessment Satellite Training-Feeding Scale score	The Nursing Child Assessment Satellite Training-Feeding Scale (76 items) consists of six subscales: (a) maternal-sensitivity to cues (range 0 - 16); (b) maternal response to distress (range 0 - 11); (c) maternal social-emotional growth-fostering (range 0 - 14); (d) maternal cognitive growth fostering (range 0 -9); (e) infant clarity of cues (range 0 - 15); and (f) infant responsiveness to caregiver (range 0 - 11), where higher scores indicate better interactions and responses. .	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Variability in Parent Stressor Scale: NICU score	Scores range from 26 to 130, where higher scores indicate greater parental stress..	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.
Variability in Parent Discharge Readiness score	Scores range from 44 to 308, where higher scores indicate more parental readiness for discharge.	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.
Breastmilk pumping rate	The percentage of mothers who report breastmilk pumping at discharge.	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.
Breastfeeding rate	The percentage of mothers who report breastfeeding at discharge.	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.
Variability in maternal Edinburgh Postnatal Depression Scale score	Scores range from 0 to 30, where higher scores indicate greater depressive symptoms	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Variability in gut microbial community structure and relative abundance of SCFA- and lactate- producing bacteria	Alpha diversity indices will be obtained. Differential abundance individual taxa will be obtained.	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.
Variability in DNA methylation of NR3C1 promoter	The percent DNAm at the NR3C1 promoters and at each CpG site will be quantified.	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.
Variability in DNA methylation of HSD11B2 promoter	The percent DNAm at the HSD11B2 promoters and at each CpG site will be quantified.	At the time of discharge from NICU, which is typically 10 to 16 weeks from birth.

Collaborators and Investigators

• Sponsor: Loyola University

Study record dates

Study Major Dates

• Study Start (Actual): October 23, 2023
• Primary Completion (Estimated): October 23, 2024
• Study Completion (Estimated): October 23, 2024

Study Registration Dates

• First Submitted: January 5, 2024
• First Submitted That Met QC Criteria: January 25, 2024
• First Posted (Actual): January 30, 2024

Study Record Updates

• Last Update Posted (Actual): January 30, 2024
• Last Update Submitted That Met QC Criteria: January 25, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: stress; preterm infants; gut microbiome; epigenetics; parent-infant relationship
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Premature Birth
• Other Study ID Numbers: 217411

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No