Somatosensory Modulation of Salivary Gene Expression and Oral Feeding in Preterm Infants: Randomized Controlled Trial

Steven Michael Barlow, Jill Lamanna Maron, Gil Alterovitz, Dongli Song, Bernard Joseph Wilson, Priya Jegatheesan, Balaji Govindaswami, Jaehoon Lee, Austin Oder Rosner, Steven Michael Barlow, Jill Lamanna Maron, Gil Alterovitz, Dongli Song, Bernard Joseph Wilson, Priya Jegatheesan, Balaji Govindaswami, Jaehoon Lee, Austin Oder Rosner

Abstract

Background: Despite numerous medical advances in the care of at-risk preterm neonates, oral feeding still represents one of the first and most advanced neurological challenges facing this delicate population. Objective, quantitative, and noninvasive assessment tools, as well as neurotherapeutic strategies, are greatly needed in order to improve feeding and developmental outcomes. Pulsed pneumatic orocutaneous stimulation has been shown to improve nonnutritive sucking (NNS) skills in preterm infants who exhibit delayed or disordered nipple feeding behaviors. Separately, the study of the salivary transcriptome in neonates has helped identify biomarkers directly linked to successful neonatal oral feeding behavior. The combination of noninvasive treatment strategies and transcriptomic analysis represents an integrative approach to oral feeding in which rapid technological advances and personalized transcriptomics can safely and noninvasively be brought to the bedside to inform medical care decisions and improve care and outcomes.

Objective: The study aimed to conduct a multicenter randomized control trial (RCT) to combine molecular and behavioral methods in an experimental conceptualization approach to map the effects of PULSED somatosensory stimulation on salivary gene expression in the context of the acquisition of oral feeding habits in high-risk human neonates. The aims of this study represent the first attempt to combine noninvasive treatment strategies and transcriptomic assessments of high-risk extremely preterm infants (EPI) to (1) improve oral feeding behavior and skills, (2) further our understanding of the gene ontology of biologically diverse pathways related to oral feeding, (3) use gene expression data to personalize neonatal care and individualize treatment strategies and timing interventions, and (4) improve long-term developmental outcomes.

Methods: A total of 180 extremely preterm infants from three neonatal intensive care units (NICUs) will be randomized to receive either PULSED or SHAM (non-pulsing) orocutaneous intervention simultaneous with tube feedings 3 times per day for 4 weeks, beginning at 30 weeks postconceptional age. Infants will also be assessed 3 times per week for NNS performance, and multiple saliva samples will be obtained each week for transcriptomic analysis, until infants have achieved full oral feeding status. At 18 months corrected age (CA), infants will undergo neurodevelopmental follow-up testing, the results of which will be correlated with feeding outcomes in the neo-and post-natal period and with gene expression data and intervention status.

Results: The ongoing National Institutes of Health funded randomized controlled trial R01HD086088 is actively recruiting participants. The expected completion date of the study is 2021.

Conclusions: Differential salivary gene expression profiles in response to orosensory entrainment intervention are expected to lead to the development of individualized interventions for the diagnosis and management of oral feeding in preterm infants.

Trial registration: ClinicalTrials.gov NCT02696343; https://ichgcp.net/clinical-trials-registry/NCT02696343 (Archived by WebCite at http://www.webcitation.org/6r5NbJ9Ym).

Keywords: brain; gene expression; mechanoreceptors; mouth; preterm infants.

Conflict of interest statement

Conflicts of Interest: None declared.

©Steven Michael Barlow, Jill Lamanna Maron, Gil Alterovitz, Dongli Song, Bernard Joseph Wilson, Priya Jegatheesan, Balaji Govindaswami, Jaehoon Lee, Austin Oder Rosner. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 14.06.2017.

Figures

Figure 1
Figure 1
Somatosensory intervention plan for stratified populations of Extremely Premature Infants along with the salivary sampling protocol and digitized measurements of nonnutritive suck progression is shown below, with primary (salivary gene expression, time to attain oral feeds, and nonnutritive suck pattern formation) and secondary (National Institute of Child Human Development Neonatal Research Network feeding-growth questionnaire and Bayley III screener at the neonatal intensive care unit follow-up) outcome variables listed as well.
Figure 2
Figure 2
Preterm infant receiving PULSED NTrainer stimulation during gavage feeding in the neonatal intensive care unit, with a nasogastric tube placed through the left nares (not visible); pneumatic stimulus control signals and output through the pacifier nipple are shown in the left panel: (a) voltage-controller gate signal, (b) intraluminal pressure (inside) the nipple, and (c) mechanical displacement at the nipple cylinder wall (Photo courtesy of Innara Health, Inc., Olathe, Kansas USA).

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