Extremely preterm infants (EPIs) (< 28 weeks' gestation) have increased susceptibility for multiple significant short- and long-term medical complications that significantly delay the development of essential milestones, such as oral feeding, required for discharge. Further, infants who develop bronchopulmonary dysplasia (BPD) are at even greater risk for oral feeding difficulties compared to gestationally aged matched controls. Despite the frequency of oral feeding difficulties in this at-risk population, there currently exists no objective assessment tool to predict when an infant may safely feed by mouth and only limited intervention strategies to improve feeding behavior. The overall goal of this research proposal is to pair the expertise of Co-PIs Drs. Steven Barlow and Jill Maron to develop an innovative, novel, personalized and integrative approach that directly addresses the important need for oral feeding treatment strategies for the EPI population. In this multicenter trial, 180 EPIs will be enrolled from three neonatal intensive care units (CHI Health St. Elizabeth, Lincoln, NE; Tufts Medical Center, Boston, MA; and Santa Clara Valley Medical Center, Santa Jose, CA). Infants will be randomized to receive either PULSED orocutaneous somatosensory stimulation (PULSED NTrainer(r)) previously developed in the Barlow Laboratory, or SHAM (blind pacifier) starting at 30 weeks' post- conceptional age (PCA) up to the achievement of full oral feeds or discharge home. Serial salivary samples (n=2/week) will be obtained concomitantly to examine the gene expression profiles of six biomarkers (AMPK, NPY2R, NPHP4, WNT3, PLXNA1, PLXNA3) previously shown by the Maron Laboratory to be associated with oral feeding success in the premature newborn.
In Aim #1, we will test the hypothesis that infants who received PULSED NTrainer(r) intervention will have a shortened duration of time to achieve full oral feeds and that their salivary gene expression profiles will correlate with feeding success. Infants will be stratified based upon their gestational age, sex, and BPD status.
In Aim #2, computational analyses of both clinical and gene expression data from Aim #1 will be performed to identify responders and non-responders to the PULSED NTrainer(r) intervention and to identify critical times in neurodevelopment when infants may most benefit from the intervention. Finally in Aim #3, infants will undergo Bayley III Developmental Screen at 18-24 months' PCA to assess both the long-term effect of the PULSED NTrainer(r) on feeding behavior and neurodevelopment and the accuracy of neonatal salivary gene expression profiles to predict impairments later in childhood. Infants will also be assessed with the NICHD NRN 18-month Feeding-Growth-Nutrition Questionnaire to further our understanding of the PULSED NTrainer(r) on long-term growth and feeding behavior.

Public Health Relevance

Two innovative approaches, pulsatile orocutaneous entrainment of non-nutritive suck via NTrainer(r) device technology and serial salivary gene expression analyses, will be merged to examine the relation between gene expression, oral somatosensory stimulation, feeding behavior, and neurodevelopmental outcomes at 18 months corrected age (CA) on 180 extremely preterm infants [EPIs] (< 28 weeks GA) enrolled at three neonatal intensive care units: CHI Health St. Elizabeth (Lincoln, NE), Tufts Medical Center (Boston, MA), and Santa Clara Valley Medical Center (San Jose, CA). EPIs will be randomized to SHAM (blind pacifier) or PULSED NTrainer treatment groups, and stratified by GA, sex, and bronchopulmonary dysplasia status (BPD vs non-BPD). We hypothesize that the combination of the NTrainer(r) intervention for improved oral feeding skills, along with objective salivary gene expression data to monitor response to treatment and feeding development, will result in a novel, objective, and personalized approach to neonatal oral feeding and reduce the duration of time to attain oral feeds while improving feeding, growth and neurodevelopmental outcomes at 18 months' CA.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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National Institute of Child Health and Human Development Initial Review Group (CHHD)
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Koso-Thomas, Marion
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University of Nebraska Lincoln
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United States
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Hage, Benjamin; Way, Emily; Barlow, Steven M et al. (2018) Real-Time Cerebral Hemodynamic Response to Tactile Somatosensory Stimulation. J Neuroimaging 28:615-620
Barlow, Steven Michael; Maron, Jill Lamanna; Alterovitz, Gil et al. (2017) Somatosensory Modulation of Salivary Gene Expression and Oral Feeding in Preterm Infants: Randomized Controlled Trial. JMIR Res Protoc 6:e113