Somatosensory Modulation of Salivary Gene Expression and Oral Feeding in Preterm Infants

The purpose of this study is to combine molecular and behavioral methods in an experimental conceptualization approach to map the effects of trigeminal (PULSED orocutaneous) somatosensory stimulation on salivary gene expression in the context of the acquisition of an exquisitely complex oromotor skill, namely oral feeding, in high-risk human neonates. The aims of this study represent the first attempt to combine non-invasive treatment strategies and transcriptomic assessments of high-risk EPIs 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. This integrative approach to oral feeding is a paradigm shift in neonatal care where rapidly emerging technological advances and personalized transcriptomics can safely and non-invasively be brought to the neonatal bedside to inform medical care decisions and improve care and outcomes.

Methods Participants: Only EPIs born between 24 0/7 and 28 6/7 weeks' gestation, as determined by obstetric ultrasound at < 15 weeks or last menstrual period, are eligible to participate in this study. We will actively enroll EPIs once they have a corrected PCA of ≥ 29 weeks to limit the number of infants who develop serious sequelae of prematurity and would not be eligible for this study based upon the criteria listed below. Parents of enrolled subjects will receive a Babies R Us $50 gift card for their participation. Subjects will be recruited from four neonatal intensive care units including 1) CHI Health St. Elizabeth [Lincoln, NE], 2) Tufts Medical Center NICU [Boston, MA], 3) Santa Clara Valley Medical Center [San Jose, CA], and 4) Childrens Hospital Orange Country [Los Angeles, CA] by a study site PI/Co-Investigator or the neonatal study coordinator. Informed consent will be obtained prior to participants' entry into the study, following consultation with the attending physician and nurse(s). A total of 180 EPIs (approximately equal numbers of males and females, no exclusion based on race/ethnicity) will participate in the study (power >.85, Type I error <.05).

Exclusion criteria: EPIs will not be recruited for this study if they have any of the following: 1) chromosomal and congenital anomalies including craniofacial malformation, nervous system anomalies, cyanotic congenital heart disease, gastroschisis, omphalocele, diaphragmatic hernia and/or other major gastrointestinal anomalies; 2) congenital infection, 3) no documented GA, 4) severe IUGR (3%), 5) abnormal neurological status including head circumference < 10th or > 90th percentile, intracranial hemorrhage grades III and IV, seizures, meningitis, neurological examination showing abnormal tone or movements of all extremities for PCA; 6) history of necrotizing enterocolitis (stage II and III); and, 7) culture-positive sepsis at the time of study enrollment.

Protocol: EPIs will be stratified among two gestational age groups (24 0/7 - 26 6/7 weeks, and 27 0/7 - 28 6/7 weeks). Each infant will be randomized to receive either the PULSED NTrainer or SHAM intervention using a software random integer function in Minitab v.17 (www.minitab.com). Infants assigned to the PULSED NTrainer group will receive a progressive dose of the pulsatile orocutaneous stimulation. Beginning at 30 weeks' PCA, these infants will receive 2 weeks of low-dose PULSED NTrainer stimulation (2 x 3-minute blocks) with a 1-minute stimulus 'off-period' between the stimulation blocks. This form of stimulation will be given simultaneous with tube feedings 3 times/day. The stimulus dose will then be increased over the next 2 weeks (3 x 3-minute blocks of PULSED NTrainer stimulation) with a 1-minute stimulus 'off-period' between the stimulation blocks, also given simultaneously with tube feedings 3 times/day. EPIs randomized to the SHAM condition will be given a regular silicone pacifier during tube feedings over the same time period.

A 1-minute rest period (no stimulation) occurs between stimulation blocks. Criteria for initiation of orocutaneous therapy include the following: 1) stable vital signs and not on continuous vasopressor medications; 2) tolerating enteral feeds in previous 48 hours; and 3) not intubated and mechanically ventilated. If the infant is on nasal intermittent positive pressure ventilation, continuous positive airway pressure or nasal cannula >2 liters per minute, then the FiO2 must be <40%.