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 - PROJECT SUMMARY Up to 60% of the 60,000 very preterm infants (<32 weeks gestational age) born annually in the US exhibit neurodevelopmental impairments and 80% experience oral feeding difficulties. These critical comorbidities lead to oral aversion, failure to thrive, developmental delays, and extended NICU stay. Admission to the NICU exposes infants to substantial early life stress. Early life stress is linked to disrupted stress regulation, evidenced by elevated salivary cortisol and altered buccal cell DNA methylation (DNAm) at specific CpG sites of glucocorticoid regulating genes, NR3C1 exon 1F and HSD11B2 promoter. These stress-related biomarkers are further associated with less optimal neurodevelopment and oral feeding skills. We propose the multisensory early oral administration of human milk (M-MILK), an infant-led early NICU intervention beginning on day 3 of life. M-MILK provides very preterm infants with the oral administration of small droplets of milk while engaging their innate senses. Our M-MILK pilot data showed a trend that the M-MILK group demonstrated lower overall mean DNAm of NR3C1 exon 1F, along with higher oral feeding skill competency and shorter transition from first to full oral feeding compared to the standard of care group. Others showed that early human milk administration provided immune protection, supported oral feeding transition, and reduced ventilator-associated pneumonia, oxygen needs, NICU stay, and cost of care. The purpose of this randomized controlled trial is to evaluate M- MILK as an effective intervention to improve stress regulation, support optimal neurodevelopment, and promote competent oral feeding skills in very preterm infants. We will randomly assign infants (n = 125) born <32 weeks gestational age to either the M-MILK or control group (standard of care). M-MILK will begin on day 3 of life and continue until oral feeding initiation. We will assess stress regulation (salivary cortisol and buccal cell DNAm of NR3C1 exon 1F and HSD11B2 promoter), neurodevelopment (NeoNatal Neurobehavioral Scale, NNNS-II and Ages and Stages Questionaire-3, ASQ-3), and oral feeding skills (Early Feeding Skills Assessment, EFS and Neonatal Eating Assessment Tool, NeoEAT). Outcomes will be measured at baseline, oral feeding initiation, 36 weeks postmenstrual age, and 2 months corrected age. The study aims 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. Further, insights into the benefits of M-MILK in the NICU will lay the groundwork for future research exploring its broader applications e.g., acute pain management and palliative care. Expanded applications have potential to enhance the healthy development of very preterm infants beyond the NICU stay, while accounting for risk and protective factors associated with the home and neighborhood environment. This work will inform future studies of the long-term efficacy of early NICU interventions, like M-MILK, on modifiable epigenetic processes, that have potential to reduce lifelong health risks for very preterm infants.
