Study Protocol for a Randomized Controlled Trial of Multisensory Early Oral Administration of Human Milk (M-MILK) for Very Preterm Infants: Enhancing Stress Regulation, Neurodevelopment, and Oral Feeding Skills

Background. Early life stress results in disrupted stress regulation, and less optimal neurodevelopment and oral feeding skills in very preterm infants. Despite these associations, there are few evidence-based interventions to help these fragile infants during critical stages of development. Purpose. This article describes an ongoing research protocol of a randomized controlled trial (RCT) to evaluate the multisensory early oral administration of human milk (M-MILK) as an early NICU intervention to improve stress regulation, support optimal neurodevelopment, and promote competent oral feeding skills in very preterm infants. Method. M-MILK is an infant-led early NICU intervention beginning on day 3 of life to provide very preterm infants with small droplets of milk orally while engaging their innate senses. Infants (N = 124) born <32 weeks gestational age are randomized to either the M-MILK or control group (standard of care). M-MILK begins on day 3 of life. We assess stress regulation, neurodevelopment, and oral feeding skills over time via salivary cortisol, buccal cell DNA methylation, NeoNatal Neurobehavioral Scale, Ages and Stages Questionnaire, Early Feeding Skills Assessment, and Neonatal Feeding Assessment Tool. Endpoints will be compared by treatment arm using linear regression and mixed-effects models for cross-sectional and longitudinal analyses, respectively. Discussion. Findings from this study will advance knowledge as to the efficacy of M-MILK as an epigenetically-informed intervention to enhance stress regulation, neurodevelopment, and oral feeding skills in very preterm infants during critical periods of neuroplasticity. The study has been registered at https://ClinicalTrials.gov (NCT07216664).