Neurodevelopmental Outcomes of Extremely Preterm Infants Fed Donor Milk or Preterm Infant Formula: A Randomized Clinical Trial.

Importance: Maternal milk feeding of extremely preterm infants during the birth hospitalization has been associated with better neurodevelopmental outcomes compared with preterm formula. For infants receiving no or minimal maternal milk, it is unknown whether donor human milk conveys similar neurodevelopmental advantages vs preterm formula. Objective: To determine if nutrient-fortified, pasteurized donor human milk improves neurodevelopmental outcomes at 22 to 26 months' corrected age compared with preterm infant formula among extremely preterm infants who received minimal maternal milk. Design, Setting, and Participants: Double-blind, randomized clinical trial conducted at 15 US academic medical centers within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants younger than 29 weeks 0 days' gestation or with a birth weight of less than 1000 g were enrolled between September 2012 and March 2019. Intervention: Preterm formula or donor human milk feeding from randomization to 120 days of age, death, or hospital discharge. Main Outcomes and Measures: The primary outcome was the Bayley Scales of Infant and Toddler Development (BSID) cognitive score measured at 22 to 26 months' corrected age; a score of 54 (score range, 54-155; a score of ≥85 indicates no neurodevelopmental delay) was assigned to infants who died between randomization and 22 to 26 months' corrected age. The 24 secondary outcomes included BSID language and motor scores, in-hospital growth, necrotizing enterocolitis, and death. Results: Of 1965 eligible infants, 483 were randomized (239 in the donor milk group and 244 in the preterm formula group); the median gestational age was 26 weeks (IQR, 25-27 weeks), the median birth weight was 840 g (IQR, 676-986 g), and 52% were female. The birthing parent's race was self-reported as Black for 52% (247/478), White for 43% (206/478), and other for 5% (25/478). There were 54 infants who died prior to follow-up; 88% (376/429) of survivors were assessed at 22 to 26 months' corrected age. The adjusted mean BSID cognitive score was 80.7 (SD, 17.4) for the donor milk group vs 81.1 (SD, 16.7) for the preterm formula group (adjusted mean difference, -0.77 [95% CI, -3.93 to 2.39], which was not significant); the adjusted mean BSID language and motor scores also did not differ. Mortality (death prior to follow-up) was 13% (29/231) in the donor milk group vs 11% (25/233) in the preterm formula group (adjusted risk difference, -1% [95% CI, -4% to 2%]). Necrotizing enterocolitis occurred in 4.2% of infants (10/239) in the donor milk group vs 9.0% of infants (22/244) in the preterm formula group (adjusted risk difference, -5% [95% CI, -9% to -2%]). Weight gain was slower in the donor milk group (22.3 g/kg/d [95% CI, 21.3 to 23.3 g/kg/d]) compared with the preterm formula group (24.6 g/kg/d [95% CI, 23.6 to 25.6 g/kg/d]). Conclusions and Relevance: Among extremely preterm neonates fed minimal maternal milk, neurodevelopmental outcomes at 22 to 26 months' corrected age did not differ between infants fed donor milk or preterm formula. Trial Registration: ClinicalTrials.gov Identifier: NCT01534481.

Global State of the Art and Science of Childhood Dysphagia: Similarities and Disparities in Burden.

Feeding/swallowing and airway protection are complex functions, essential for survival, and continue to evolve throughout the lifetime. Medical and surgical advances across the globe have improved the long-term survival of medically complex children at the cost of increasing comorbidities, including dysfunctional swallowing (dysphagia). Dysphagia is prominent in children with histories of preterm birth, neurologic and neuromuscular diagnoses, developmental delays, and aerodigestive disorders; and is associated with medical, health, and neurodevelopmental problems; and long-term socioeconomic, caregiver, health system, and social burdens. Despite these survival and population trends, data on global prevalence of childhood dysphagia and associated burdens are limited, and practice variations are common. This article reviews current global population and resource-dependent influences on current trends for children with dysphagia, disparities in the availability and access to specialized multidisciplinary care, and potential impacts on burdens. A patient example will illustrate some questions to be considered and decision-making options in relation to age and development, availability and accessibility to resources, as well as diverse cultures and family values. Precise recognition of feeding/swallowing disorders and follow-up intervention are enhanced by awareness and knowledge of global disparities in resources. Initiatives are needed, which address geographic and economic barriers to providing optimal care to children with dysphagia.

Comparison of direct effects of rice-thickened formula vs routine feeds on symptoms and gastroesophageal reflux indices: A crossover cohort study.

BACKGROUND: We compared the direct effects of routine vs rice-thickened formula on 24-h pH-impedance and symptom characteristics and then examined if dietary effects were modified by acid reflux index severity in infants. METHODS: Forty infants under consideration for gastroesophageal reflux disease and therapies were evaluated at 43 ± 1 weeks postmenstrual age. Each infant was equally fed routine diet and thickened formula during evaluations. Postprandial sessions were analyzed for acid reflux index, reflux events, clearance times, distal baseline impedance, and symptoms. RESULTS: Thickened formula has no effect (P ≥ 0.05) on acid reflux events' characteristics or overall symptom frequency. However, refluxate height and frequency of weakly acidic events and cough were decreased (P < 0.05). Prolonged bolus clearance and a decrease in distal baseline impedance were noted with thickened feeds (vs routine feeds) when acid reflux index was >7 (P < 0.05). CONCLUSION: Our pH-impedance testing protocol identifies direct effects of potential therapies at the point of care. Acutely, thickened formula does not impact acid-specific reflux indices but decreases full-column reflux and cough reflexes. In those with an acid reflux index of >7, thickened formula prolongs the distal esophageal bolus clearance (the mechanisms of which are uncertain). Clinical trials are needed to clarify objective indications and therapeutic use of thickened formulas for infants with gastroesophageal reflux disease, along with short- and long-term side effects.

Characteristics of esophageal refluxate and symptoms in infants compared between pre-treatment and on treatment with proton pump inhibitors.

OBJECTIVE: To examine longitudinal pH-impedance characteristics from those infants who remained on proton pump inhibitors therapy for gastroesophageal reflux disease (GERD) as parents/providers refused to discontinue therapy after 4 weeks. STUDY DESIGN: Eighteen infants with acid reflux index >3% underwent treatment, and pH-impedance data were compared prior to and on proton pump inhibitors at 42 ± 1 and 46 ± 1 weeks' postmenstrual age, respectively. Esophageal acid and bolus exposure, symptoms and swallowing characteristics were examined. RESULTS: Proton pump inhibitors reduces the acid-mediated effects of reflux but modifies impedance and clearance mechanisms (P < 0.05). Prolonged therapy did not reduce symptoms (P > 0.05). Infants evaluated while on proton pump inhibitors were 1.8 times more likely to have swallows before and after reflux. CONCLUSIONS: Prescription of proton pump inhibitors for objectively determined GERD should have time limits, as prolonged treatment can result in prolonged esophageal bolus clearance time without relieving symptoms.

The Irritable Infant in the Neonatal Intensive Care Unit: Risk Factors and Biomarkers of Gastroesophageal Reflux Disease.

OBJECTIVES: To determine risk factors for arching/irritability in high-risk infants and examine the significance of comorbidity and gastroesophageal reflux (GER) characteristics. STUDY DESIGN: Retrospective analysis of 24-hour pH-impedance studies of symptomatic infants in a neonatal intensive care unit (ICU) (n = 516, 30.1 ± 4.5 weeks of gestation, evaluated at 41.7 ± 3.2 weeks postmenstrual age) was conducted. Comparisons were made between infants with >72 vs ≤72 arching/irritability events per day. We characterized risk factors for arching/irritability along with clinical, pH-impedance, and outcome correlates. RESULTS: Of 39 973 arching/irritability events and 42 155 GER events, the averages per day were 77.6 ± 41.0 and 81.7 ± 48.2, respectively. Acid reflux and impedance bolus characteristics were not significantly different between infants with >72 and ≤72 arching/irritability events (P ≥ .05). The odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for postmenstrual age and weight at evaluation were significant for risk factors of preterm birth (2.3 [1.2-4.4]), moderate or severe neuropathology (2.0 [1.1-3.6]), and presence of oral feeding at testing (1.57 [1.07-2.30]). CONCLUSIONS: Acid GER disease is unlikely the primary cause of arching/irritability and empiric treatment should not be used when arching/irritability is present. Prematurity and neurologic impairment may be more likely the cause of the arching/irritability. Arching/irritability may not be a concern in orally fed infants.

Proton pump inhibitor therapy may alter the sensory motor characteristics of pharyngoesophageal motility in infants with suspected GERD.

BACKGROUND: Acid reflux index (ARI) is a biomarker for gastroesophageal reflux disease (GERD). The effects of short-term proton pump inhibitor (PPI) therapy on pharyngoesophageal motility and clearance mechanisms in infants remain unknown. We hypothesized that pharyngoesophageal reflexes and response to PPI are distinct between infants with 3%-7% and >7% ARI. METHODS: Secondary analysis was performed from a subset of infants who participated in a randomized controlled trial (NCT: 02486263). Infants (N = 36, 29.9 ± 4.3 weeks gestation) underwent 4 weeks of PPI therapy, 1 week of washout, and longitudinal testing to assess: (a) clinical outcomes; (b) pH-impedance and symptom metrics including ARI, distal baseline impedance, clearance time, refluxate height, symptoms, I-GERQ-R scores, symptom association probability; (c) pharyngoesophageal motility reflexes and sensory motor characteristics. Comparisons were performed between infants with 3%-7% versus >7% ARI. KEY RESULTS: From the 36 hospitalized infants treated: Pharyngoesophageal reflex latencies were prolonged (p > 0.05) and duration in ARI 3%-7% group only (p = 0.01); GER frequency, proximal ascent and clearance increased (ARI 3%-7%); weight gain velocity, oral feeding success, and fine motor score decreased while length of hospital stays increased in the ARI >7% group despite the decrease in symptoms and I-GERQ-R scores. CONCLUSIONS & INFERENCES: Distinct changes in pharyngoesophageal sensory motor aspects of motility and reflex mechanisms exist after using PPI therapy in infants. Contributory factors may include the effects of maturation and aerodigestive comorbidities (GERD and BPD). Controlled studies incorporating placebo are needed to delineate the effects of PPI on causal and adaptive GERD mechanisms in infants with aerodigestive and feeding-related comorbidities.

A decade of evidence: standardized feeding initiative targeting feeding milestones and predicting NICU stays in premature infants in an all-referral level IV NICU.

OBJECTIVE: Ten-year data from the simplified, individualized, milestone-targeted, pragmatic, longitudinal and educational (SIMPLE) feeding initiative were examined by gestational age (GA) category to characterize the feeding milestones, length of hospital stays (LOHS), annual variability and predictive models for LOHS. STUDY DESIGN: Preterm infants (≤32 weeks GA, N = 434) in level-IV NICU had milestone-targeted feeding plans. Continuous data were analyzed for outcomes. RESULTS: Over 93% successfully attained full oral feedings. Earlier acquisition of feeding milestones correlated with earlier discharge (P < 0.05). Year-wise analysis showed sustained maintenance of milestones (P < 0.05). Milestones and outcomes (P < 0.001) were significantly correlated with different GA categories. Prediction models for LOHS were derived using GA, BPD, age at full enteral, postmenstrual age (PMA) at 1st and full oral feeds. CONCLUSIONS: The SIMPLE feeding program minimized variability and promoted acquisition of feeding milestones consistently. LOHS is predictable using feeding milestones, co-morbidities, GA, and PMA at feeding milestones.

Pharyngeal biorhythms during oral milk challenge in high-risk infants: Do they predict chronic tube feeding?

BACKGROUND: Eating difficulties are common in high-risk neonatal intensive care unit (NICU) infants; mechanisms remain unclear. Crib-side pharyngo-esophageal motility testing is utilized to assess contiguous swallowing physiology, and cross-system interplay with cardio-respiratory rhythms. Aims were to: (1) identify whether distinct pharyngeal rhythms exist during oral milk challenge (OMC), and (2) develop a chronic tube feeding risk prediction model in high-risk infants. METHODS: Symptomatic NICU infants (N = 56, 29.7 ± 3.7 weeks birth gestation) underwent pharyngo-esophageal manometry with OMC at 40.9 ± 2.5 weeks postmenstrual age (PMA). Exploratory cluster data analysis (partitioning around k-medoids) was performed to identify patient groups using pharyngeal contractile rhythm data (solitary swallows and swallows within bursts). Subsequently, (a) pharyngeal-esophageal, cardio-respiratory, and eating method characteristics were compared among patient groups using linear mixed models, and (b) chronic tube feeding prediction model was created using linear regression. RESULTS: Three distinct patient groups were identified with validity score of 0.6, and termed sparse (high frequency of solitary swallows), intermediate, or robust (high swallow rate within bursts). Robust group infants had: lesser pharyngeal and esophageal variability, greater deglutition apnea, pharyngeal activity, and esophageal activity (all p < 0.05), but less frequent heart rate decreases (p < 0.05) with improved clinical outcomes (milk transfer rate, p < 0.001, and independent oral feeding at discharge, p < 0.03). Chronic tube feeding risk = -11.37 + (0.22 × PMA) + (-0.73 × bronchopulmonary dysplasia) + (1.46 × intermediate group) + (2.57 × sparse group). CONCLUSIONS: Robust pharyngeal rhythm may be an ideal neurosensorimotor biomarker of independent oral feeding. Differential maturation of cranial nerve-mediated excitatory and inhibitory components involving foregut, airway, and cardiac rhythms distinguishes the physiologic and pathophysiologic basis of swallowing and cardio-respiratory adaptation.

Symptom Scores and pH-Impedance: Secondary Analysis of a Randomized Controlled Trial in Infants Treated for Gastroesophageal Reflux.

BACKGROUND AND AIMS: To evaluate and compare gastro-esophageal reflux (GER) symptom scores with pH-impedance and test the effects of acid-suppressive medications with or without feeding modifications on pH-impedance in high-risk infants. METHODS: Infant Gastroesophageal Reflux Questionnaire Revised (I-GERQ-R) and 24-hour pH-impedance data were analyzed from 94 infants evaluated in a tertiary care setting for GER disease. Longitudinal data from 40 infants that received randomized GER therapy (proton pump inhibitor [PPI] with or without feeding modifications) for 4 weeks followed by 1-week washout were analyzed. Relationships between I-GERQ-R and pH-impedance metrics (acid reflux index, acid and bolus GER events, distal baseline impedance, and symptoms) were examined and effects of treatments compared. RESULTS: (A) Correlations between I-GERQ-R and pH-impedance metrics were weak. (B) I-GERQ-R sensitivity, specificity, and positive predictive values were suboptimal when correlated with pH-impedance metrics. I-GERQ-R negative predictive value (NPV) was high for acid symptom-association probability (NPV = 84%) and distal baseline impedence (NPV = 86%) thresholds. (C) PPI with feeding modifications (vs PPI alone) did not alter pH-impedance metrics or symptom scores (P > .05); however, bolus clearance metrics worsened for both treatment groups (P < .05). CONCLUSIONS: In high-risk infants (1) I-GERQ-R may be a helpful clinical screening tool to exclude acid-GER disease diagnosis and minimize unnecessary acid-suppressive treatment, but further testing is needed for diagnosis. (2) Acid-suppressive therapy with feeding modifications has no effect on symptom scores or pH-impedance metrics. Clearance of refluxate worsened despite PPI therapy, which may signal development of pharyngoesophageal dysmotility and persistence of symptoms. (3) Placebo-controlled trials are needed in high-risk infants with objective pH-impedance criteria to determine efficacy, safety, and underlying mechanisms. Clinicaltrials.gov ID: NCT02486263.

Impact of esophageal mucosal permeability markers on provocation-induced esophageal reflexes in high-risk infants.

Esophageal distal baseline impedance (DBI) is an indicator of mucosal integrity; lower values suggest increased permeability. Aims were to characterize the (1) effect of DBI category (<900 Ω, 900-2000 Ω, and >2000 Ω) on sensory-motor characteristics of mid-esophageal provocation-induced motility reflexes, and (2) clinical outcomes among high-risk human infants evaluated for gastroesophageal reflux disease. Symptomatic infants (N = 49, 41 ± 3 weeks postmenstrual age) underwent pH-impedance testing to characterize acid reflux index (ARI) and DBI, and pharyngo-esophageal manometry to examine upper esophageal sphincter (UES), peristaltic, and lower esophageal sphincter (LES) functions. Sensory-motor response characteristics included response threshold (ml), occurrence (%), latency (s), duration (s), and magnitude (mmHg) upon mid-esophageal stimulations (0.1-2.0 ml of air, water, and apple juice). Motility and clinical outcomes were compared among DBI groups. In infants with DBI <900 Ω and 900-2000 Ω (vs. >2000 Ω): (a) Long-term feeding milestones did not differ (p > 0.05); (b) complete peristaltic propagation decreased in 900-2000 Ω (p < 0.05), polymorphic waveforms increased in <900 Ω and 900-2000 Ω (p < 0.05); (c) media effects were noted with liquids (vs. air) wherein UES and esophageal contractility were prolonged in <900 Ω and 900-2000 Ω (p < 0.05), and esophageal sensitivity heightened for <900 Ω with water and for 900-2000 Ω with air (both p < 0.05). ARI was not correlated with DBI in infants with chronic lung disease (r = 0.05, p = 0.82). We conclude that pharyngo-esophageal motility sensory-motor characteristics in infants are modified by DBI category. These preliminary findings pave-the-way for further physiological testing in convalescing high-risk infants to ascertain potential mechanisms of airway-digestive reflex interactions and symptom generation, which may lead to targeted therapies.

Evidence-Based Approaches to Successful Oral Feeding in Infants with Feeding Difficulties.

Infants in the neonatal intensive care unit (NICU) frequently have feeding difficulties with the root cause remaining elusive to identify. Evaluation of the provider/parent/infant feeding process may provide objective clues to sources of feeding difficulty. Specialized testing may be necessary to determine if the infant's swallowing skills are dysfunctional, immature, or maldeveloped, and to determine the risk of feeding failure or chronic tube feeding. Current evidence-based diagnostic and management approaches resulting in successful oral feeding in the NICU infant are discussed.

Characterization of Esophageal and Sphincter Reflexes across Maturation in Dysphagic Infants with Oral Feeding Success vs Infants requiring Gastrostomy.

To test the hypothesis that esophageal and sphincteric sensory-motor reflexes are distinct across maturation in infants with dysphagia receiving gastrostomy-tube (G-tube). This is a retrospective review of 29 dysphagic infants (N = 15 study requiring gastrostomy, N = 14 age matched control achieving oral feeds) that underwent longitudinal pharyngeal-esophageal manometry at 42.3 (37-50.2) weeks postmenstrual age (PMA) and 48.9 (43.3-57.9) weeks PMA. Graded stimuli (0.1-5 mL) of varying media (air, water, and apple juice) tested esophageal peristaltic reflex, upper esophageal sphincter contractile reflex (UESCR), and lower esophageal sphincter relaxation reflex (LESRR). Comparisons were performed between study and controls and across maturation (time-1 vs time-2). Data represented as mean ± SE or OR (95% CI). Across maturation (time-1 vs time-2): Study infants did not exhibit significant differences across in peristaltic, UES, or LES reflexes (all p > 0.05). In contrast, controls exhibited increased UES resting pressure (13 ± 3 vs 17 ± 3 mmHg, p = 0.001), LES resting pressure (22 ± 3 vs 25 ± 3 mmHg, p < 0.009), LES nadir pressure (0.5 ± 1 vs 4.3 ± 1 mmHg, p = 0.001), and esophago-deglutition responses [2.5 (1.23-4.88), p = 0.04], and decreased secondary peristalsis [0.44 (0.31-0.61), p = 0.001], UESCR [0.4 (0.25-0.65), p = 0.001], LESRR [0.4 (0.24-0.75), p = 0.01], and symptoms [0.6 (0.45-0.83), p = 0.005]. Among infants with dysphagia, esophageal provocation induced peristaltic reflex, UESCR, and LESRR advance with longitudinal maturation when infants are oral-fed successfully, but not in those who received gastrostomy. Underlying mechanisms may be related to esophageal sensitivity, afferent or efferent transmission, and coordination of upstream excitation and downstream inhibition, which can be potential therapeutic targets for improving feeding capabilities after gastrostomy placement in infants with dysphagia.

Developing a Quality Improvement Feeding Program for NICU Patients.

Practices in NICUs vary widely, particularly when clinical decisions involve complex tasks and multiple disciplines, which occurs with feeding preterm infants. Neonatal feeding difficulties in preterm infants often lead to prolonged tube feeding and therefore lengthened hospital stays. Education and compliance with evidence-based protocols and guidelines are needed on the initiation of feedings and feeding advancement to transform enteral and oral feeding practices and thus reduce practice variation and improve clinical outcomes.

Mechanisms and management considerations of parent-chosen feeding approaches to infants with swallowing difficulties: an observational study.

Videofluoroscopy swallow studies (VFSS) and high-resolution manometry (HRM) methods complement to ascertain mechanisms of infant feeding difficulties. We hypothesized that: (a) an integrated approach (study: parent-preferred feeding therapy based on VFSS and HRM) is superior to the standard-of-care (control: provider-prescribed feeding therapy based on VFSS), and (b) motility characteristics are distinct in infants with penetration or aspiration defined as penetration-aspiration scale (PAS) score ≥ 2. Feeding therapies were nipple flow, fluid thickness, or no modification. Clinical outcomes were oral-feeding success (primary), length of hospital stay and growth velocity. Basal and adaptive HRM motility characteristics were analyzed for study infants. Oral feeding success was 85% [76-94%] in study (N = 60) vs. 63% [50-77%] in control (N = 49), p = 0.008. Hospital-stay and growth velocity did not differ between approaches or PAS ≥ 2 (all P > 0.05). In study infants with PAS ≥ 2, motility metrics differed for increased deglutition apnea during interphase (p = 0.02), symptoms with pharyngeal stimulation (p = 0.02) and decreased distal esophageal contractility (p = 0.004) with barium. In conclusion, an integrated approach with parent-preferred therapy based on mechanistic understanding of VFSS and HRM metrics improves oral feeding outcomes despite the evidence of penetration or aspiration. Implementation of new knowledge of physiology of swallowing and airway protection may be contributory to our findings.

Pharyngoesophageal motility reflex mechanisms in the human neonate: importance of integrative cross-systems physiology.

Swallowing is a critical function for survival and development in human neonates and requires cross-system coordination between neurological, airway, and digestive motility systems. Development of pharyngoesophageal motility is influenced by intra- and extrauterine development, pregnancy complications, and neonatal comorbidities. The primary role of these motility reflex mechanisms is to maintain aerodigestive homeostasis under basal and adaptive biological conditions including oral feeding, gastroesophageal reflux, and sleep. Failure may result in feeding difficulties, airway compromise, dysphagia, aspiration syndromes, and chronic eating difficulties requiring prolonged tube feeding. We review the integration of cross-systems physiology to describe the basis for physiological and pathophysiological neonatal aerodigestive functions.

Prophylactic Indomethacin in extremely preterm infants: association with death or BPD and observed early serum creatinine levels.

OBJECTIVES: To identify the relationship between prophylactic indomethacin (PI) administration and (1) mortality and bronchopulmonary dysplasia (BPD) at 36-week postmenstrual age (PMA) (primary outcome), and (2) to evaluate for PI-associated acute kidney injury. STUDY DESIGN: Retrospective cohort investigation of 22-28 weeks gestation infants (N = 1167) who were admitted to Nationwide Children's Hospital on postnatal days 0-1 between May 2009 and September 2017 and survived ≥24-h postnatal. The associations of PI treatment with mortality or BPD, and other secondary outcomes, were evaluated via multivariable robust-error-variance Poisson regression. RESULTS: The adjusted risks of death or BPD (1.02, 95% CI: 0.83, 1.25), BPD (0.97, 95% CI: 0.77, 1.21), and death 1.33 (95% CI: 0.84, 2.10) by 36-week PMA were unchanged following PI treatment after multivariable adjustment. No changes in mean creatinine levels were detected in exposed versus unexposed infants to suggest PI-induced AKI. CONCLUSION: Prophylactic indomethacin treatment was unrelated to mortality or BPD outcomes.

Differentiating esophageal sensitivity phenotypes using pH-impedance in intensive care unit infants referred for gastroesophageal reflux symptoms.

BACKGROUND: To identify esophageal sensitivity phenotypes relative to acid (SAcid), bolus (SBolus), acid and bolus (SAcid+Bolus), and none (SNone) exposures in infants suspected with gastroesophageal reflux disease (GERD). METHODS: Symptomatic infants (N = 279) were evaluated for GERD at 42 (40-45) weeks postmenstrual age using 24-h pH-impedance. Symptom-associated probability (SAP) for acid and bolus components defined esophageal sensitivity: (1) SAcid as SAP ≥ 95% for acid (pH < 4), (2) SBolus as SAP ≥ 95% for bolus, (3) SAcid+Bolus as SAP ≥ 95% for acid and bolus, or (4) SNone as SAP < 95% for acid and bolus. RESULTS: Esophageal sensitivity prevalence (SAcid, SBolus, SAcid+Bolus, SNone) was 28 (10%), 94 (34%), 65 (23%), and 92 (33%), respectively. Emesis occurred more in SBolus and SAcid+Bolus vs SNone (p < 0.05). Magnitude (#/day) of cough and emesis events increased with SBolus and SAcid+Bolus vs SNone (p < 0.05). SAcid+Bolus had increased acid exposure vs SNone (p < 0.05). Distributions of feeding and breathing methods were distinct in infants with SBolus vs SNone (both, p < 0.05). Multivariate analysis revealed that arching and irritability events/day were lesser at higher PMAs (p < 0.001) and greater for infants on NCPAP (p < 0.01) with SBolus and SAcid+Bolus (p < 0.05). Coughs/day was greater at higher PMAs (p < 0.001) for infants with gavage and transitional feeding methods (p < 0.02) with SBolus and SAcid+Bolus (p < 0.05) but lesser with Trach (p < 0.001). Number of emesis events/day were greater with SBolus and SAcid+Bolus (p < 0.001). Sneezes/day decreased for infants on Trach (p = 0.02). CONCLUSIONS: Feeding and breathing methods can influence the frequency and type of aerodigestive symptoms. We differentiated esophageal sensitivity phenotypes in NICU infants referred for GERD symptoms using pH-impedance. Acid sensitivity alone was rare, which may explain poor response to acid suppressives; aerodigestive symptoms were predominantly linked with bolus spread. Magnitude of esophageal acid exposure and esophageal sensitivity to bolus spread may explain the pathophysiological basis for symptoms. IMPACT: Objective GERD diagnosis and reasons for symptoms in NICU infants remains unclear. Differentiation of esophageal sensitivities by acid and bolus components of GER reveal distinct symptom profiles, specifically the bolus component of GER significantly contributes to symptom occurrence. Acid only sensitivity to GER is rare, and acid-suppressive therapy alone may not improve symptoms in a majority of NICU infants. Magnitude of esophageal acid exposure and esophageal sensitivity to any bolus spread may explain the pathophysiological basis for symptoms. Feeding and breathing methods can influence the frequency and type of aerodigestive symptoms. GERD treatments should be individualized to the patient's GERD phenotype and likely also target the bolus component of GER.

Role of feeding strategy bundle with acid-suppressive therapy in infants with esophageal acid reflux exposure: a randomized controlled trial.

OBJECTIVE: To test the hypothesis that a feeding bundle concurrent with acid suppression is superior to acid suppression alone in improving gastroesophageal reflux disease (GERD) attributed-symptom scores and feeding outcomes in neonatal ICU infants. METHODS: Infants (N = 76) between 34 and 60 weeks' postmenstrual age with acid reflux index > 3% were randomly allocated to study (acid-suppressive therapy + feeding bundle) or conventional (acid-suppressive therapy only) arms for 4 weeks. Feeding bundle included: total fluid volume < 140 mL/kg/day, fed over 30 min in right lateral position, and supine postprandial position. Primary outcome was independent oral feeding and/or ≥6-point decrease in symptom score (I-GERQ-R). Secondary outcomes included growth (weight, length, head circumference), length of hospital stay (LOHS, days), airway (oxygen at discharge), and developmental (Bayley scores) milestones. RESULTS: Of 688 screened: 76 infants were randomized and used for the primary outcome as intent-to-treat, and secondary outcomes analyzed for 72 infants (N = 35 conventional, N = 37 study). For study vs. conventional groups, respectively: (a) 33% (95% CI, 19-49%) vs. 44% (95% CI, 28-62%), P = 0.28 achieved primary outcome success, and (b) secondary outcomes did not significantly differ (P > 0.05). CONCLUSIONS: Feeding strategy modifications concurrent with acid suppression are not superior to PPI alone in improving GERD symptoms or discharge feeding, short-term and long-term outcomes. IMPACT: Conservative feeding therapies are thought to modify GERD symptoms and its consequences. However, in this randomized controlled trial in convalescing neonatal ICU infants with GERD symptoms, when controlling for preterm or full-term birth and severity of esophageal acid reflux index, the effectiveness of acid suppression plus a feeding modification bundle (volume restriction, intra- and postprandial body positions, and prolonged feeding periods) vs. acid suppression alone, administered over a 4-week period was not superior in improving symptom scores or feeding outcomes. Restrictive feeding strategies are of no impact in modifying GERD symptoms or clinically meaningful outcomes. Further studies are needed to define true GERD and to identify effective therapies in modifying pathophysiology and outcomes. The improvement in symptoms and feeding outcomes over time irrespective of feeding modifications may suggest a maturational effect. This study justifies the use of placebo-controlled randomized clinical trial among NICU infants with objectively defined GERD.

Impact of Feeding Strategies With Acid Suppression on Esophageal Reflexes in Human Neonates With Gastroesophageal Reflux Disease: A Single-Blinded Randomized Clinical Trial.

INTRODUCTION: Aims were to test hypothesis that esophageal provocation-induced reflexes are superior with acid suppression plus feeding modifications vs acid suppression alone among infants treated for gastroesophageal reflux disease (GERD). METHODS: Infants (N = 49, 41.3 ± 2.6 of postmenstrual age) with acid reflux index >3% underwent longitudinal motility testing (weeks 0 and 5) with graded midesophageal provocation to test randomly allocated therapies (4 weeks' proton pump inhibitor [PPI] ± feeding modifications) on sensory-motor aerodigestive reflexes. Feeding modification included restricted fluid volume <140 mL/kg per day, fed over 30 minutes in right lateral position and supine postprandial position. Primary motility outcome was frequency-occurrence of peristaltic reflex. Secondary outcomes included upper esophageal sphincter contractile reflex, lower esophageal sphincter (LES) relaxation reflex, respiratory change, and symptom characteristics. RESULTS: Treatment groups did not differ for primary outcome (odds ratio = 0.8, 95% confidence interval 0.4-1.6, P = 0.99) or secondary outcomes (all P > 0.05). For both treatment groups at follow-up, distal esophageal contraction and LES tone decreased, and LES relaxation reflex occurrence is less frequent (all P < 0.05). In a subgroup analysis, comparing infants with PPI washout (N = 40) vs with continued (N = 9) PPI therapy, no differences were noted for aerodigestive reflex response frequency-occurrence (all P > 0.05). DISCUSSION: In infants with GERD, feeding modification with acid suppression is not superior to acid suppression alone in modifying aerodigestive reflexes (frequency, sensation, or magnitude). Contiguous areas targeted by GER, i.e., LES and distal esophageal functions, worsened at follow-up for both groups despite PPI therapy. Maturation is likely the key factor for GERD resolution in infants, justifying the use of placebo in clinical trials for objectively determined GERD.