Gastroesophageal Reflux In Preterm Infants Research Articles

Gastroesophageal Reflux Disease in Neonates: Facts and Figures.

* 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 …

Diagnosis and treatment of gastroesophageal reflux in premature infants

Gastroesophageal reflux (GER) is a common gastroenterological complication in preterm infants, and which can be divided into physiological GER and pathological GER.Physiological GER generally present no clinical symptoms, while pathological GER manifest as vomiting, milk retention, irritation, and growth retardation.In severe cases apnea, repeated aspiration pneumonia, reflux esophagitis or sudden death might happen.Therefore, understanding the etiology of GER, timely diagnosis, and considerate treatment plan would be crucial to reducing severe sequelae of GER in preterm infants. Key words: Gastroesophageal reflux; Etiology; Treatment; Infant, newborn

Gastroesophageal reflux in preterm infants: Neonatal myths versus evidence-based medicine.

Gastroesophageal reflux in preterm infants: Neonatal myths versus evidence-based medicine.

Erythromycin and Reflux Events in Premature Neonates: A Randomized Clinical Trial.

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.

Diagnosis and Management of Gastroesophageal Reflux in Preterm Infants.

Gastroesophageal reflux (GER), generally defined as the passage of gastric contents into the esophagus, is an almost universal phenomenon in preterm infants. It is a common diagnosis in the NICU; however, there is large variation in its treatment across NICU sites. In this clinical report, the physiology, diagnosis, and symptomatology in preterm infants as well as currently used treatment strategies in the NICU are examined. Conservative measures to control reflux, such as left lateral body position, head elevation, and feeding regimen manipulation, have not been shown to reduce clinically assessed signs of GER in the preterm infant. In addition, preterm infants with clinically diagnosed GER are often treated with pharmacologic agents; however, a lack of evidence of efficacy together with emerging evidence of significant harm (particularly with gastric acid blockade) strongly suggest that these agents should be used sparingly, if at all, in preterm infants.

Nasogastric Feeding Tubes May Not Contribute to Gastroesophageal Reflux in Preterm Infants.

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.

High Frecuency of Gastroesophageal Reflux Disease in Symptomatic Preterm Infants

Introduction: Gastroesophageal reflux (GER) occurs commonly in newborn infants and mostly among preterm infants. Gastroesophageal reflux disease (GERD) is clinically significant GER that causes morbidity, such as frequent vomiting, aspiration pneumonia, irritability, and can influence growth, length of hospital stay, and respiratory outcome. Esophageal 24-hours pH monitoring is the most widely employed diagnostic test for GER in preterm infants. Methods: We included 58 consecutive symptomatic neonates (≤1 month old) who underwent esophageal 24- hours pH monitoring from January 2014 to March 2016 in a tertiary refereal center. Each patient had previously fulfilled 3 basic clinical findings supporting GERD diagnosis, including frequent vomiting, failure to thrive and exacerbation of respiratory symptoms. The diagnosis of GERD was made by Boix-Ochoa Score ≥16.6. Frequencies were expressed as percentages. Statistical comparison between groups was performed using X2 and Student's T test. Results: A total of 20 studies were positive for GERD (34.48%). The mean age of the population without GERD was 38.33 weeks of gestation (WOG). Most of the neonates with GERD were male 70% (N=14). The mean age of the population with GERD was 33.92 ± 2.65 weeks of gestation WOG and the mean value of Boix-Ochoa Score was 67.77 ± 65. Most of the reflux events occur in the postprandial period 85% (N=17), and in supine position 70% (N=14). The Symptom Index was positive in 38.9% (N=7) and Symptom Association Probability (SAP) was positive in 55.6% (N=10). There was a significant association between female gender and a positive Symptom Index and between WOG and the presence of GERD p < 0.005. Conclusion: There is an association between prematurity and the diagnosis of GERD. The SAP could be more sensitive to GERD diagnosis in this population.

Nonpharmacological therapy of gastroesophageal reflux in preterm infants

Gastroesophageal reflux (GER) was very common among preterm infants, which could cause several complications and severely affects the prognosis. The standardization of diagnosis and treatment of gastroesophageal reflux was very important for preterm infants. Due to less adverse reactions, nonpharmacological therapy was the most advisable choice in preterm infants with GER. In this paper, nonpharmacological therapies including body positioning, feeding frequency and modality, changing food patterns, gastric tube, and nonnutritive sucking were reviewed. Body positioning was the safest and most effective nonpharmacological therapy. Other nonpharmacological strategies such as changes of feeding frequency and modality might also be useful. The role of some strategies was still controversial, thereby needing to be further investigated. Selection of what kind of specific nonpharmacological therapy should be based on the specific conditions. Key words: Infant, premature; Gastroesophageal reflux; Review

Detection of pepsin in mouth swab: correlation with clinical gastroesophageal reflux in preterm infants

Objective: To study the relationship between pepsinogen/pepsin in a mouth swab and clinical gastroesophageal reflux (GER) in preterm infants.Methods: Preterm infants (birth weight ≤ 2000 g) on full enteral feeds were enrolled. Mouth swabs from cheek and below the tongue were collected one, two and three hours after feeding. An enzymatic assay with substrate fluorescein isothiocyanate-casein was used to detect pepsin A and C activities with further confirmation by western blot. Blinded investigators reviewed the infant’s medical record to clinically diagnose GER.Results: A total of 101 premature infants were enrolled. Pepsinogen/pepsin was detected in 45/101 (44.5%) infants in at least one sample. A clinical diagnosis of GER was made in 36/101 (35.6%) infants. Mouth swabs were positive in 26/36 (72%) infants with clinical GER and only 19/65 (29%) infants without GER (p < 0.001). Similarly, the levels of pepsinogen/pepsin A and C were higher in the mouth swabs of infants with clinical GER.Conclusion: The detection of pepsinogen/pepsin in a mouth swab correlates with clinical GER in premature infants.

Association of Inhibitors of Gastric Acid Secretion and Higher Incidence of Necrotizing Enterocolitis in Preterm Very Low-Birth-Weight Infants

Inhibitors of gastric acid (IGA) are used for upper gastrointestinal bleeding or gastroesophageal reflux in preterm infants. The resultant increase in gastric pH may enhance the growth of pathogens and increase the risk of necrotizing enterocolitis (NEC). Our systematic review examined the association between IGA and NEC in preterm infants. Standard methodology of systematic reviews was followed. PubMed, Embase, Cochrane, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were searched in August 2012. One case-control and one prospective cohort study (n = 11,346), both evaluating H2-blockers as IGA, were included. Meta-analysis showed a significant association between NEC and IGA (odds ratio [OR]: 1.78, 95% confidence interval [CI]: 1.4, 2.27, p < 0.00001). The prospective cohort study found higher incidence of infection (sepsis, pneumonia, urinary tract infection) with IGA (37.4% versus 9.8%, OR: 5.5, 95% CI: 2.9 to 10.4, p < 0.001). Exposure to H2 receptor antagonists may be associated with increased risk of NEC and infections in preterm infants.

Diagnosis and Management of Gastroesophageal Reflux Disease

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

Nonpharmacological Management of Gastroesophageal Reflux in Preterm Infants

Gastroesophageal reflux (GOR) is very common among preterm infants, due to several physiological mechanisms. Although GOR should not be usually considered a pathological condition, its therapeutic management still represents a controversial issue among neonatologists; pharmacological overtreatment, often unuseful and potentially harmful, is increasingly widespread. Hence, a stepwise approach, firstly promoting conservative strategies such as body positioning, milk thickening, or changes of feeding modalities, should be considered the most advisable choice in preterm infants with GOR. This review focuses on the conservative management of GOR in the preterm population, aiming to provide a complete overview, based on currently available evidence, on potential benefits and adverse effects of nonpharmacological measures. Nonpharmacological management of GOR might represent a useful tool for neonatologists to reduce the use of antireflux medications, which should be limited to selected cases of symptomatic babies.

Pharmacological therapy of gastroesophageal reflux in preterm infants.

Although gastroesophageal reflux (GER) is a very common phenomenon among preterm infants, its therapeutic management is still an issue of debate among neonatologists. A step-wise approach should be advisable, firstly promoting nonpharmacological interventions and limiting drugs to selected infants unresponsive to the conservative measures or who are suffering from severe GER with clinical complications. Despite of this, a concerning pharmacological overtreatment has been increasingly reported. Most of the antireflux drugs, however, have not been specifically assessed in preterm infants; moreover, serious adverse effects have been noticed in association to their administration. This review mainly aims to draw the state of the art regarding the pharmacological management of GER in preterm infants, analyzing the best piecies of evidence currently available on the most prescribed anti-reflux drugs. Although further trials are required, sodium alginate-based formulations might be considered promising; however, data regarding their safety are still limited. Few piecies of evidence on the efficacy of histamine-2 receptor blockers and proton pump inhibitors in preterm infants with GER are currently available. Nevertheless, a significantly increased risk of necrotizing enterocolitis and infections has been largely reported in association with their use, thereby leading to an unfavorable risk-benefit ratio. The efficacy of metoclopramide in GER's improvement still needs to be clarified. Other prokinetic agents, such as domperidone and erythromycin, have been reported to be ineffective, whereas cisapride has been withdrawn due to its remarkable cardiac adverse effects.

Gastroesophageal reflux and apnea of prematurity--coincidence, not causation. Commentary on L. Corvaglia et Al.: A thickened formula does not reduce apneas related to gastroesophageal reflux in preterm infants

Gastroesophageal reflux and apnea of prematurity--coincidence, not causation. Commentary on L. Corvaglia et Al.: A thickened formula does not reduce apneas related to gastroesophageal reflux in preterm infants

A Thickened Formula Does Not Reduce Apneas Related to Gastroesophageal Reflux in Preterm Infants

Background: Apnea of prematurity (AOP) occurs frequently in preterm infants and a variable proportion of AOP can be induced by gastroesophageal reflux (GER). Conservative treatment, including dietary modifications, should be the first-line approach for both GER and GER-related apneas in this population. Objectives: To evaluate the efficacy of a starch-thickened preterm formula (PF) in reducing the frequency of apneas related to GER. Methods: Preterm infants with AOP were studied by combined impedance and pH monitoring and polysomnography. The 6-hour study period included two feeds, one of a commercially available PF and one of the same formula thickened with amylopectin (TPF). GER indexes, apneas and GER-related apneas detected after TPF and PF feeds were compared by Wilcoxon signed-rank test. Results: 24 infants were studied. During 140 h of registration, 289 apneas (147 after TPF and 142 after PF; p = 0.876), and 861 GER episodes (400 after TPF and 461 after PF; p = 0.465) were recorded. No difference in the number of AOP was found between TPF and PF. A significant reduction in acid exposure was found after TPF; there was no influence on non-acid GER indexes. The frequency of GER-related apneas did not differ between TPF and PF. Conclusions: A formula thickened with amylopectin did not reduce the number of AOP or GER-related apneas. It reduced acid GER features but had no effect on non-acid GER indexes. Future research should focus on exploring different conservative strategies to treat GER-related apneas in preterm infants.

Gastroesophageal Reflux Disease in the Neonatal Intensive Care Unit

Gastroesophageal reflux (GER), commonly diagnosed in preterm infants in neonatal intensive care units (NICUs), is a cause of morbidity and is known to prolong hospital stay. Pharmacological treatment of presumed or proven GER is increasingly being used in NICUs; this attitude is concerning, owing to an association between pharmacological treatment of GER and serious adverse events, which has recently been demonstrated (i.e., ranitidine and necrotizing enterocolitis). Furthermore, a wide variability exists among NICUs in the proportion of infants treated for GER, which suggests a serious lack of evidence in this field. Thus, there is a need to develop safe and effective treatment options for GER in preterm infants is a critical issue for future research.

Characterization of cardiorespiratory events following gastroesophageal reflux in preterm infants

ObjectiveTo characterize cardiorespiratory events in preterm infants following both acid and non-acid GER as detected by pH and multiple intraluminal impedance (MII).Study DesignTwelve hour overnight studies were performed in 71 preterm infants (gestational age 29.4±3.0 wks, birth weight 1319±496 gm). Apnea ≥10 seconds in duration, bradycardia ≤80 bpm and oxygen desaturation ≤85% that occurred within 30 seconds after the initiation of GER were classified as associated with GER.Result12,957 cardiorespiratory events and 4164 GER episodes were documented. Less than 3% of all cardiorespiratory events were preceded by GER constituting 3.4% of apnea, 2.8% of oxygen desaturation and 2.9% of bradycardia events. GER did not prolong cardiorespiratory event duration or increase severity. In contrast, GER was associated with a shorter duration of oxygen desaturation events (7.8±4.6 vs 6.3±5.6 sec, p<.05).ConclusionGER is rarely associated with cardiorespiratory events, and has no detrimental effect on cardiorespiratory event duration or severity.

Cross-Over Trial of Treatment for Bradycardia Attributed to Gastroesophageal Reflux in Preterm Infants

Cross-Over Trial of Treatment for Bradycardia Attributed to Gastroesophageal Reflux in Preterm Infants

Protein Content and Fortification of Human Milk Influence Gastroesophageal Reflux in Preterm Infants

: Preterm human milk (HM) may provide insufficient energy and nutrients and thus may need to be fortified. Our aim was to determine whether fat content, protein content, and osmolality of HM before and after fortification may affect gastroesophageal reflux (GER) in symptomatic preterm infants. : Gastroesophageal reflux was evaluated in 17 symptomatic preterm newborns fed naïve and fortified HM by combined pH/intraluminal-impedance monitoring (pH-MII). Human milk fat and protein content was analysed by a near-infrared reflectance analysis. Human milk osmolality was tested before and after fortification. Gastroesophageal reflux indexes measured before and after fortification were compared and were also related to HM fat and protein content and osmolality before and after fortification. : An inverse correlation was found between naïve HM protein content and acid reflux index (RIpH: P = 0.041, rho =-0.501). After fortification, osmolality often exceeded the values recommended for infant feeds; furthermore, a statistically significant (P < 0.05) increase in nonacid reflux indexes was observed. : Protein content of naïve HM may influence acid GER in preterm infants. A standard fortification of HM may worsen nonacid GER indexes and, due to the extreme variability in HM composition, may overcome both recommended protein intake and HM osmolality. Thus, an individualised fortification, based on the analysis of the composition of naïve HM, could optimise both nutrient intake and feeding tolerance.

Cross-Over Trial of Treatment for Bradycardia Attributed to Gastroesophageal Reflux in Preterm Infants

To determine whether anti-reflux medications reduce bradycardia episodes attributed to clinically suspected gastroesophageal reflux (GER). We conducted a masked trial comparing metoclopramide, 0.2 mg/kg/dose q 6 hours, and ranitidine, 2 mg/kg/dose q 8 hours, with saline placebo. Each infant served as his own control. Preterm infants having >3 bradycardia episodes per 2 days were eligible if the clinician intended to begin anti-reflux medications for bradycardia attributed to GER. The mean (SD) birth weight was 1238 (394) g and gestational age was 29 (3) weeks. Eighteen infants were enrolled at 35 (22) days of age. There were 4.6 (3.1) and 3.6 (2.7) bradycardia episodes per day in the drug and placebo periods, respectively. The mean difference (drug minus placebo) was 0.94 (95% CI, 0.04 to 1.95) (P = .04 by t test). There was a decrease in bradycardia episodes over time (P < .001 by nonparametric repeated-measures analysis of variance). Anti-reflux medications did not reduce, and may have increased, bradycardia episodes in preterm infants with GER. Because there was an improvement of bradycardia episodes over time, unrelated to treatment, unmasked therapeutic trials of medications are likely to lead to misleading conclusions.