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.

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.

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.

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.

Predictive ability of postnatal growth failure for adverse feeding-related outcomes in preterm infants: an exploratory study comparing Fenton with INTERGROWTH-21st preterm growth charts.

BACKGROUND: Postnatal growth failure (PGF) can impact the short- and long-term health outcomes in preterm infants. However, PGF rates vary according to the way it is defined and the growth chart used to monitor the postnatal growth. Fenton-2013 growth charts which suggest following intrauterine fetal growth compared to INTERGROWTH-21st, one specifically constructed for monitoring preterm extrauterine growth. OBJECTIVE: Exploratory study to determine the PGF definition at first per oral (PO) that is most predictive of adverse oral feeding-related outcomes in preterm infants. METHODS: Prospectively collected data of preterm infants 24-32 weeks gestation, who were started on cue-based oral feeds at ≤34 weeks gestation were reviewed. Anthropometric data at first PO (weight, length, and head circumference) were compared according to Fenton and INTERGROWTH-21st growth charts. PGF was defined either as <10th percentile, Z-score change (ZSC) of ≥-1.5 from birth, or ZSC of ≥-2.0. Top-quartile (Q4) of feeding-related outcomes (days from first PO to full PO, post-menstrual age at full PO, days from first PO to discharge, and length of hospital stay) was considered as adverse outcome. RESULTS: Of the 125 infants included, the median birth gestation and weight were 29.4 weeks and 1235 g, respectively. Incidence of appropriate, small, and large for gestational age was similar at birth by both growth charts. ZSC -1.5 for weight by Fenton was significantly higher at first PO vs. INTERGROWTH-21st (p=.02), while percentile <10th and ZSC -2.0 rates were similar. The PGF definition based on individual anthropometrics at first PO that has the best area under the curve (AUC) for adverse feeding-related outcomes was used to create a combined PGF definition for each growth chart. The AUC for the combined PGF for the Fenton and INTERGROWTH-21st was similar (p>.05) and both have moderate sensitivity and negative predictive value, but have low specificity, positive predictive value, and positive likelihood ratio for adverse feeding-related outcomes. CONCLUSIONS: The tested definitions of PGF at first PO have only small to moderate predictive ability for adverse feeding-related outcomes in preterm infants.

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.

Body adiposity and oral feeding outcomes in infants: a pilot study.

BACKGROUND: Prevalence of oral feeding difficulties in high-risk infants is increasing. Desire to take orally can be influenced by hunger and satiety, which may influence growth and body fat. OBJECTIVE: To determine the association between body adiposity and infant oral feeding. METHODS: Retrospective case-control study of infants ≥37-week postmenstrual age (PMA). Infants on tube feeding (cases) compared to birth gestation-matched infants on full oral feeding (controls). Body composition was determined by air displacement plethysmography. RESULTS: Overall, 16 cases vs. 16 controls. At study, cases vs. controls had similar PMA, weight and length z-scores, and calorie intake. The mean oral intake was significantly less in cases vs. controls (66 vs. 168 ml/kg/day, p < 0.001). Cases had significantly higher percentage of fat mass (18.7 vs. 10.9) and fat-mass z-score (1.62 vs. 0.08) (p < 0.05), but similar fat-free mass vs. controls. Five case infants required gastrostomy. CONCLUSIONS: Higher body adiposity may worsen the infant oral feeding outcomes.

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.

Diagnostic utility of impedance-pH monitoring in infants of diabetic mothers with oral feeding difficulties.

OBJECTIVE: To determine the diagnostic utility of impedance-pH monitoring in infants of diabetic mothers (IDM) with oral feeding difficulties. STUDY DESIGN: Retrospective review of a consecutive sample of 50 IDM who had impedance-pH monitoring for objective gastroesophageal reflux disease (GERD) diagnosis. Acid reflux index (ARI) ≥ 7 was considered pathological (ARI+). RESULTS: Impedance-pH monitoring was performed at 42.1-week postmenstrual age. Twenty infants (40%) with ARI+ compared to 30 with ARI < 7 (ARI-). ARI+ had lower weight at study vs. ARI- (p < 0.05). ARI+ had significantly higher reflux parameters but had similar symptom burden and symptom-association scores vs. ARI-. All ARI+ received proton-pump inhibitors (PPI) vs. 7 (23.3%) in ARI- (p < 0.05), but oral feeding outcomes, gastrostomy rate, growth, and hospital length of stay were similar in both groups. CONCLUSIONS: The diagnostic yield of impedance-pH monitoring in IDM is about 40%. However, GERD diagnosis or treatment with PPI did not modify short-term clinical outcomes.

Pharyngeal contractile and regulatory characteristics are distinct during nutritive oral stimulus in preterm-born infants: Implications for clinical and research applications.

BACKGROUND: Maturation of pharyngeal swallowing during neonatal oral feeding is unknown. Our objective was to evaluate pharyngeal functioning using high-resolution manometry (HRM) during nutritive oral stimulus and test the hypothesis that pharyngeal contractility and regulation are distinct in preterm-born infants. METHODS: High-resolution manometry data during oral milk feeding were analyzed for pharyngeal contractile (PhCI, mm Hg cm s) and regulatory (number and frequency of pharyngeal contractions and bursts, pharyngeal activity-to-quiescence ratio, upper esophageal sphincter nadir pressure) characteristics in 23 preterm (<38 weeks' gestation) and 18 full-term-born infants at term maturation. Mixed linear models and stepwise regression methods were used. RESULTS: Despite more oral feeding experiences (P < 0.05), preterm infants (vs full-term), consumed less milk volume (P < 0.001), had lesser pharyngeal contractions within bursts (P = 0.04), lower pharyngeal contraction frequency (P < 0.01), and lower pharyngeal activity (P = 0.03), but higher PhCI per individual contraction (P = 0.01). PhCI is higher for longer PMA (P < 0.05), higher UES nadir pressures (P < 0.05), and lower pharyngeal contraction frequency (P < 0.05). CONCLUSIONS: Nutritive oral milk stimulus provoked pharyngeal contractility characteristics is distinct in preterm-born. Despite more oral nutritive experiences, preterm infants had underdeveloped excitatory and inhibitory rhythmic activity. Cranial nerve IX and X effects on sensory-motor responses and feedback (excitation-inhibitory rhythm regulation) remain immature among preterm-born even at full-term maturational status. We speculate the relationship between PhCI and UES regulatory activity contributes to the observed differences in preterm and full-term infants.

The Effect of Additives for Reflux or Dysphagia Management on Osmolality in Ready-to-Feed Preterm Formula: Practice Implications.

BACKGROUND: A common osmolality threshold for feedings is to stay <450 mOsm/kg for normal infants. Preterm formulas are frequently modified to improve growth, modify nutrition, and manage gastroesophageal reflux (GER) or dysphagia. Relationships between osmolality and additives to ready-to-feed preterm formulas are unclear. Our aims were to evaluate and compare the effects of caloric density, thickening agent recipes, and supplements to ready-to-feed preterm formula on osmolality. METHODS: A freezing point osmometer was used to measure the osmolality of 47 preterm infant formula combinations with varying caloric densities (ready-to-feed 22 and 30 cal/oz), thickening agents (rice vs oatmeal cereal), thickener amounts (0.0, 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0 tsp/oz), and combinations of supplements (saline, iron, vitamin D, or multivitamin). Ten samples per combination were tested using a 10-µL pipette. Comparisons were made using analysis of variance and t-tests for group and pair-wise comparisons, respectively. RESULTS: A total of 470 osmolality samples were analyzed: (1) raters had high agreement (r = 0.98; P < .001); (2) for every 0.5 tsp/oz of thickener, the osmolality increases by 30 mOsm/kg (P < .001); (3) osmolality was higher with the oatmeal (vs rice) thickening agent (P < .001); and (4) vitamin and electrolyte supplement combinations increase osmolality. CONCLUSIONS: Alteration of ready-to-feed preterm formulas may significantly increase osmolality and have unintended consequences. Caution and monitoring should be exercised with modifying ready-to-feed preterm formulas for regurgitation, rumination, GER, dysphagia, feeding intolerance, or emesis. This study supports the concept of achieving volume tolerance before further manipulation of additives.