Gastroesophageal Reflux in the Preterm Neonate

Background: Transient lower oesophageal sphincter relaxation (TLOSR) is the predominant mechanism of gastro-oesophageal reflux (GOR) in healthy infants but the mechanisms of GOR in infants with GOR disease (GORD) are...

Gastroesophageal reflux disease (GERD) in premature neonates may manifest as apnea, bradycardia, growth failure, aspiration, or feeding intolerance. Erythromycin ethylsuccinate (EES), is often used as a pro-kinetic in the management of GERD, despite lack of evidence or safety from randomized controlled trials. We sought to study the efficacy of enteral EES at a dose of 50 mg · kg · day in decreasing the frequency of gastroesophageal reflux events as determined by pH-multichannel intraluminal impedance (pH-MII) monitoring. In a randomized, double-blind, placebo-controlled trial, eligible premature neonates with clinical signs of GERD underwent 24-hour pH-MII monitoring. If >5 reflux events were identified on pH-MII, then subjects were randomized to receive either EES or placebo. Repeat 24-hour pH-MII was performed on day 7 of study treatment and compared to initial pH-MII. Forty-three premature neonates were enrolled. Of those, 31 neonates were randomized, 15 to EES and 16 to placebo with a median (IQR) pretreatment total reflux events per 24 hours of 23 (16-40) and 29 (12-40), respectively. Day 7 total events per 24 hours decreased by 4 events in the EES group to 19 (15-33) and by 10 events in the placebo group to 19 (11-26) (P = 0.09). There were no differences in pretreatment and day 7 acidic and nonacidic reflux, proximal reflux, total or percent reflux time, median or longest bolus clearance time, or nurse-reported apnea events between groups. Enteral EES did not decrease reflux events on 24-hour pH-MII at the dose studied. Therefore, it may be ineffective in the treatment of GERD in premature neonates.

Inhibition of Transient Lower Esophageal Sphincter Relaxation and Gastroesophageal Reflux by Metabotropic Glutamate Receptor Ligands

We present the first study using 24-hour impedance-pH recordings in asymptomatic premature neonates. Previous studies that used pH-metry suggested that neonatal cardiorespiratory symptoms could be related to acid gastroesophageal reflux. However, pH-metry could not detect accurately weakly acidic or nonacid reflux. Our healthy premature neonates had approximately 70 reflux events in 24 hours, 25% of which were acid, 73% were weakly acidic, and 2% were weakly alkaline. The number of reflux events per hour (2-3 per hour) was slightly lower than that described in premature neonates with cardiorespiratory events (4 per hour). We confirmed that weakly acidic reflux is more prevalent than acid reflux, particularly so during the feeding periods. In contrast, similar to healthy adults, weakly alkaline reflux was very rare. We confirmed findings from previous studies in which most reflux events were pure liquid during both fasting and during postprandial periods and gas reflux was very rare. As in neonates with cardiorespiratory symptoms, the majority of reflux events in asymptomatic preterms reached the proximal esophagus or pharynx, and there were no differences between acid and weakly acidic reflux. The lack of differences between asymptomatic and diseased infants contravenes the hypothesis for macro- or microaspiration but does not exclude hypersensitivity to reflux as a cause for respiratory symptoms. The acid exposure that was related to reflux events and detected by impedance was significantly lower than the total acid exposure during 24 hours. Increased acid exposure could be attributable to pH-only reflux events or, less frequently, to slow drifts of pH from baselines at approximately 5 to values < 4. These changes were not accompanied by a typical impedance pattern of reflux but by slow drifts in impedance in 1 or 2 channels. Our findings confirm the need for the use of impedance together with pH-metry for diagnosis of all gastroesophageal reflux events. The relationship between gastroesophageal reflux and cardiorespiratory events in neonates and older infants has been studied extensively. The current evidence for such a relationship is controversial. This study provides values of impedance-pH monitoring for acid, weakly acidic, and weakly alkaline reflux from healthy preterm neonates that can be used for comparison when evaluating gastroesophageal reflux in preterm infants with a cardiorespiratory disease.

There is widespread concern about gastroesophageal reflux (GER) in preterm infants. This article reviews the evidence for this concern. GER is common in infants, which is related to their large fluid intake (corresponding to 14 L/day in an adult) and supine body position, resulting in the gastroesophageal junction's being constantly "under water." pH monitoring, the standard for reflux detection, is of limited use in preterm infants whose gastric pH is >4 for 90% of the time. New methods such as the multiple intraluminal impedance technique and micromanometric catheters may be promising alternatives but require careful evaluation before applying them to clinical practice. A critical review of the evidence for potential sequelae of GER in preterm infants shows that 1) apnea is unrelated to GER in most infants, 2) failure to thrive practically does not occur with GER, and 3) a relationship between GER and chronic airway problems has not yet been confirmed in preterm infants. Thus, there is currently insufficient evidence to justify the apparently widespread practice of treating GER in infants with symptoms such as recurrent apnea or regurgitation or of prolonging their hospital stay, unless there is unequivocal evidence of complications, eg, recurrent aspiration or cyanosis during vomiting. Objective criteria that help to identify those presumably few infants who do require treatment for GER disease are urgently needed.

The objective was to determine if the presence of a nasogastric (NG) feeding tube is associated with increased gastroesophageal reflux (GER) and acid exposure in preterm infants. This is a retrospective study on preterm infants [gestational age (GA) <37 weeks] who were evaluated by multichannel intraluminal impedance and pH monitoring (MII-pH) between October 2009 and March 2016. Infants were divided into two groups, NG tube present and no feeding tube. GER events per hour and the percent of time with pH <4 during a 24-hour period were then compared. Eighty-three infants were included, 41 had an NG tube present and 42 did not. The group without an NG tube had significantly more reflux events per hour (2.3 ± 2.9 vs. 1.3 ± 0.8, p < 0.05) even after adjusting for differences in birth weight, GA, corrected GA, and total fluid intake. There was no significant difference in acidic events per hour and acid exposure time between the two groups. The presence of a 5-French NG tube is not associated with an increase in GER or acid exposure in preterm infants. In fact, it appears that infants fed through an NG tube have fewer episodes of GER.

Gastroesophageal Reflux

C olic usually affects babies in the first few weeks of their lives and persists for about 4 months. Crying can be intense and furious and it may last for several hours per day for several weeks. Although crying can occur at any time, it is usually worse in the late afternoon and evening, and occasionally affects the baby’s sleep. Infantile colic is not considered a disease, fulfilling instead criteria for a functional disorder. Research shows that babies with colic continue to eat and gain weight appropriately, despite the crying (1). The main risk for these babies relates to the stress and anxiety that the condition creates at home, especially when it affects the first child. The cause of colic is not known. Painful flatus may contribute to colic, but there is little evidence to prove that it is linked to digestive problems (2). Another theory is that while the digestive system is maturing, some babies are more sensitive to substances such as lactose ingested through breast-feeding and formula milk; however, evidence to support this hypothesis also is limited. Other possible causes relate to the baby’s behavior and temperament. Among the gastrointestinal (GI) factors, we focus on non-nutritive pathophysiology such as the relation of colic to gastroesophageal reflux (GER), GI motility disorders, the role of gut hormones, and intestinal microflora.

Proton pump inhibitor (PPI) therapy is increasingly being used to treat premature infants with gastroesophageal reflux disease (GERD); however, the efficacy of PPI on acid production in this population has yet to be assessed in this patient group. The aim of this study was to determine the effect of 0.7 mg/kg/d omeprazole on gastric acidity and acid gastroesophageal reflux in preterm infants with reflux symptoms and pathological acid reflux on 24-h pH probe. A randomized, double blind, placebo-controlled, crossover design trial of omeprazole therapy was performed in 10 preterm infants (34-40 weeks postmenstrual age). Infants were given omeprazole for 7 d and then placebo for 7 d in randomized order. Twenty-four-hour esophageal and gastric pH monitoring was performed on days 7 and 14 of the trial. Compared to placebo, omeprazole therapy significantly reduced gastric acidity (%time pH <4, 54% vs 14%, P < 0.0005), esophageal acid exposure (%time pH <4, 19% vs 5%, P < 0.01) and number of acid GER episodes (119 vs 60 episodes, P < 0.05). Omeprazole is effective in reducing esophageal acid exposure in premature infants with pathological acid reflux on 24-h pH probe; however, the far more complex issues of safety and efficacy have yet to be addressed.

Gastroesophageal reflux disease (GERD) is one of the most common disorders in medical practice. It is the most common gastrointestinal diagnosis recorded during visits to outpatient clinics in the United States. Apart from the economic burden of the disease and its impact on quality of life, GERD is the most common predisposing factor for esophageal adenocarcinoma [1]. Recently, many important issues have emerged regarding the classification, pathogenesis, natural history, and treatment of GERD. Although use of proton-pump inhibitor (PPI) is the treatment of choice for GERD, approximately, one-third of patients with GERD fail to response symptomatically to a standard-dose proton-pump inhibitor (PPI), either partially or completely [2]. Additionally, most GERD patients need long-term treatment for frequent relapses after discontinuing acid inhibition therapy. This has led to great interest in new endoscopic therapies for the treatment of this disease. With regard to the diagnosis of GERD, patients with refractory reflux symptoms and normal upper endoscopy are more difficult to diagnose and treat. Combined 24-hour pH and impedance monitoring allows classifying the patients as having true nonerosive reflux disease (NERD), hypersensitive esophagus, or functional heartburn and is helpful for further management of the patients [3]. The main focus of this special issue is on recent advances in the treatment of erosive esophagitis, NERD and Barrett's esophagus. In addition, the emerging diagnostic methods, pharmacological treatments, and endoscopic therapies for GERD are also discussed. The paper entitled “The frequencies of gastroesophageal and extragastroesophageal symptoms in patients with mild erosive esophagitis, severe erosive esophagitis, and Barrett's esophagus, in Taiwan” is the first work simultaneously assessing the differences in reflux symptom profiles among the three different categories of GERD. The data showed that the frequencies of some esophageal and extraesophageal symptoms in patients with Los Angeles grade A/B erosive esophagitis were higher than those in patients with Los Angeles grade C/D erosive esophagitis and Barrett's esophagus. In the paper entitled “Current pharmacological management of gastroesophageal reflux disease,” Y.-K. Wang et al. present the current and developing therapeutic agents for GERD treatment. The efficacies of PPIs and potassium-competitive acid blocker in GERD therapy are well reviewed. Additionally, the article summarizes the development of novel therapeutic agents focusing on the underlying mechanisms of GERD. In the paper entitled “Pharmacological therapy of gastroesophageal reflux in preterm infants,” L. Corvaglia et al. review the pathogenesis, presentation, diagnosis, and treatment of gastroesophageal reflux in preterm infants. A stepwise approach is advisable for the treatment of gastroesophageal reflux in preterm infants, firstly, promoting nonpharmacological interventions and secondly, limiting drugs to selected infants unresponsive to the conservative measures or who are suffering from severe gastroesophageal reflux with clinical complications. In the paper entitled “Stretta radiofrequency treatment for GERD: a safe and effective modality,” M. Franciosa et al. focus on the safety, efficacy, and durability of the Stretta radiofrequency treatment for GERD therapy. The novel endoscopic treatment reduces esophageal acid exposure, decreases the frequency of transient lower esophageal relaxation, decreases medication use and improves quality of life in GERD patients. In the paper entitled “Duodenal tube feeding: an alternative approach for effectively promoting weight gain in children with gastroesophageal reflux and congenital heart disease,” S. Kuwata et al. showed that duodenal tube feeding improves the weight gain of infants with gastroesophageal reflux who need treatment for congenital-heart-disease-associated heart failure. In the paper entitled “Changes in ghrelin-related factors in gastroesophageal reflux disease in rats,” M. Nahata et al. examined gastrointestinal hormone profiles and functional changes in rats with GERD. The results suggest that aberrantly increased secretion of peripheral ghrelin and decreased ghrelin responsiveness may occur in GERD rats. In the paper entitled “Surgical management of pediatric gastroesophageal reflux disease,” H. T. Jackson and T. D. Kane review the clinical presentation of GERD in pediatric population and discuss the options for surgical management and outcome in these patients. In the paper entitled “Current advances in the diagnosis and treatment of nonerosive reflux disease,” C. L. Chen and P. I. Hsu, review the literature about the pathogenesis, natural history, diagnosis and treatment of NERD. The authors suggest that a combination of 24-hour esophageal impedance and pH monitoring is indicated to differentiate acid-reflux-related NERD, weakly acid reflux-related NERD (hypersensitive esophagus), nonacid-reflux-related NERD, and functional heartburn in patients with poor response to appropriate PPI treatment. In the paper entitled “Antireflux endoluminal therapies: past and present,” K. C. Yew et al. and S.-K. Chuah review, highlight, and discuss three commonly employed antireflux endoluminal procedures: fundoplication or suturing techniques (EndoCinch, NDO, EsophyX), intramural injection or implant techniques (enhancing LES volume and/or strengthening compliance of the LES-EnteryX, Gatekeeper), and radiofrequency ablation of lower esophageal sphincter and cardia (the Stretta system). Ping-I Hsu Nayoung Kim Khean Lee Goh Deng-Chyang Wu

Objective. To examine the temporal relationship between apnea and gastroesophageal reflux (GER) and to assess the effect of GER on apnea duration. Methods. A total of 119 preterm infants underwent 12-hour cardiorespiratory monitoring studies using respiratory inductance plethysmography, heart rate, oxygen saturation (SaO 2 ), and esophageal pH. The studies were scored for GER (pH <4 for ≥5 seconds) and apnea ≥15 seconds or ≥10 seconds that occurred within 30 seconds of GER. Apnea ≥10 seconds was used to assess whether GER would prolong apnea duration. Results. There were 6255 episodes of GER. Only 1% of GER episodes were associated with apnea ≥15 seconds, and there was no difference in apnea rate before, during, or after GER. There was also no difference in rate of apnea ≥10 seconds before versus during GER; however, there was a decrease in apnea rate immediately after GER. The presence of GER during apnea did not prolong apnea duration, and GER had no effect on the lowest SaO 2 or heart rate during apnea. Conclusion. There is no evidence of a temporal relationship between acid-based GER and apnea in preterm infants. In addition, GER does not prolong apnea duration and does not exacerbate the resultant decrease in heart rate and SaO 2 .

Persistent Reflux Symptoms in the Proton Pump Inhibitor Era: The Changing Face of Gastroesophageal Reflux Disease

To examine the temporal relationship between apnea and gastroesophageal reflux (GER) and to assess the effect of GER on apnea duration. A total of 119 preterm infants underwent 12-hour cardiorespiratory monitoring studies using respiratory inductance plethysmography, heart rate, oxygen saturation (SaO2), and esophageal pH. The studies were scored for GER (pH <4 for > or =5 seconds) and apnea > or =15 seconds or > or =10 seconds that occurred within 30 seconds of GER. Apnea > or =10 seconds was used to assess whether GER would prolong apnea duration. There were 6255 episodes of GER. Only 1% of GER episodes were associated with apnea > or =15 seconds, and there was no difference in apnea rate before, during, or after GER. There was also no difference in rate of apnea > or =10 seconds before versus during GER; however, there was a decrease in apnea rate immediately after GER. The presence of GER during apnea did not prolong apnea duration, and GER had no effect on the lowest SaO2 or heart rate during apnea. There is no evidence of a temporal relationship between acid-based GER and apnea in preterm infants. In addition, GER does not prolong apnea duration and does not exacerbate the resultant decrease in heart rate and SaO2.

Currently, thickened feeds are increasingly being used to treat infants with gastroesophageal reflux, driven in large part by the baby food industry. Previous meta-analyses have shown that although thickened formulas do not seem to reduce measurable reflux, they may reduce vomiting. However, because data are limited, there is still uncertainty regarding the use of thickening agents. Our goal was to systematically evaluate and update data from randomized, controlled trials on the efficacy and safety of thickened feeds for the treatment of gastroesophageal reflux in healthy infants. The Cochrane Library, Medline, Embase, and CINAHL databases and proceedings of the European and North American pediatric gastroenterology conferences (from 2000) were searched in May 2008; additional references were obtained from reviewed articles. Only randomized, controlled trials that evaluated thickened feeds used in infants for at least several days for the treatment of gastroesophageal reflux were considered for inclusion. Three reviewers independently performed data extraction by using standard data-extraction forms. Discrepancies between reviewers were resolved by discussion between all authors. Only the consensus data were entered. Fourteen randomized, controlled trials with a parallel or crossover design, some with methodologic limitations, were included. Use of thickened formulas compared with standard formula significantly increased the percentage of infants with no regurgitation, slightly reduced the number of episodes of regurgitation and vomiting per day (assessed jointly or separately), and increased weight gain per day; it had no effect on the reflux index, number of acid gastroesophageal reflux episodes per hour, or number of reflux episodes lasting >5 minutes but significantly reduced the duration of the longest reflux episode of pH<4. No definitive data showed that one particular thickening agent is more effective than another. No serious adverse effects were noted. This meta-analysis shows that thickened food is only moderately effective in treating gastroesophageal reflux in healthy infants.

* Abbreviations: AAP: : American Academy of Pediatrics BPD: : bronchopulmonary dysplasia CMPA: : cow milk protein allergy GEJ: : gastroesophageal junction GER: : gastroesophageal reflux GERD: : gastroesophageal reflux disease H2RA: : histamine 2 receptor antagonist LES: : lower esophageal sphincter NASPGHAN: : North American Society of Pediatric Gastroenterology, Hepatology and Nutrition pH-MII: : multichannel intraluminal pH impedance PPI: : proton pump inhibitor SLESR: : swallow-associated lower esophageal sphincter relaxation SSI: : symptom sensitivity index TLESR: : transient lower esophageal sphincter relaxation VLBW: : very low-birthweight Clinicians caring for premature infants need to recognize the natural history and pathophysiology of gastroesophageal reflux (GER) and GER disease. Clinicians also need to make the most out of the diagnostic tools available in their clinical settings and offer the most appropriate therapy for these conditions, which constitute a significant burden to patients and to our health care system. After completing this article, readers should be able to: 1. Explain the terminology, mechanisms, and controversies surrounding gastroesophageal reflux (GER) and gastroesophageal reflux disease (GERD) in neonates. 2. Describe the epidemiology, pathophysiology, and risk factors of GER and GERD in neonates. 3. Explain the approach to evaluate, diagnose, and manage GERD in neonates. Gastroesophageal reflux (GER) is a normal physiologic process that occurs in all age groups. In healthy preterm infants, an average of 2 to 3 reflux events occur per hour, as has been reported using 24-hour pH impedance monitoring. (1) GER has historically been associated with a wide variety of behaviors commonly attributed to “GERD-like” symptoms in infants. (2) However, the association between a specific symptom and GER needs supporting data. (3) In the NICU infant, many of these symptoms may have multisystemic etiologies related to prematurity, chronic lung disease, and neuropathology, among others, rather than solely GER. Over the years, GER has remained a controversial topic for clinicians because of the challenges that entail its accurate diagnosis, as well as the uncertainty of treatment efficacy in symptomatic neonates. Furthermore, various studies have shown that histamine 2 receptor antagonists (H2RAs), proton pump inhibitors (PPIs), and prokinetics therapy may be associated with serious adverse outcomes in preterm infants. (4)(5)(6)(7) In addition, the American Academy of Pediatrics (AAP) through the “Choosing Wisely in Newborn Medicine” initiative highlighted routine use of antireflux medications in symptomatic GER in preterm infants …