Protocol for an international multicenter randomized controlled trial assessing treatment success and safety of peroral endoscopic myotomy vs endoscopic balloon dilation for the treatment of achalasia in children.

INTRODUCTION: Achalasia is a rare neurodegenerative esophageal motility disorder characterized by incomplete lower esophageal sphincter (LES) relaxation, increased LES tone and absence of esophageal peristalsis. Achalasia requires invasive treatment in all patients. Conventional treatment options include endoscopic balloon dilation (EBD) and laparoscopic Heller's myotomy (LHM). Recently, a less invasive endoscopic therapy has been developed; Peroral Endoscopic Myotomy (POEM). POEM integrates the theoretical advantages of both EBD and LHM (no skin incisions, less pain, short hospital stay, less blood loss and a durable myotomy). Our aim is to compare efficacy and safety of POEM vs. EBD as primary treatment for achalasia in children. METHODS AND ANALYSIS: This multi-center, and center-stratified block-randomized controlled trial will assess safety and efficacy of POEM vs EBD. Primary outcome measure is the need for retreatment due to treatment failure (i.e. persisting symptoms (Eckardt score > 3) with evidence of recurrence on barium swallow and/or HRM within 12 months follow-up) as assed by a blinded end-point committee (PROBE design). DISCUSSION: This RCT will be the first one to evaluate which endoscopic therapy is most effective and safe for treatment of naïve pediatric patients with achalasia.

Development of a Core Outcome Set for Children Aged 1-18 Years with Gastroesophageal Reflux Disease.

OBJECTIVE: To develop a core outcome set for clinical studies assessing gastroesophageal reflux disease (GERD) in children. STUDY DESIGN: This core outcome set was developed using a 2-round Delphi technique and adhering to the Outcome Measures in Rheumatology Initiative (OMERACT 2.0) recommendations. Healthcare professionals (HCPs) and (parents of) children (age 1-18 years) with a GERD diagnosis (ie, the presence of bothersome symptoms), listed up to 5 harmful and/or beneficial outcomes that they considered important in the treatment of GERD. Outcomes mentioned by more than 10% of participants were put forward and rated and prioritized by HCPs, parents, and children in a second round. Outcomes with the highest rank formed the draft core outcome set. The final core outcome set was created during an online consensus meeting between an expert panel. RESULTS: The first round was completed by 118 of 125 HCPs (94%), 146 of 146 parents (100%), and 69 of 70 children (99%). A total of 80 of 118 HCPs (68%), 130 of 140 parents (93%), and 77 children (100%) completed round 2. "Adequate relief," "evidence of esophagitis," "feeding difficulties," "heartburn (≥4 years)," "hematemesis," "regurgitation," "sleeping difficulties," "vomiting," and "adverse events" were included in the final core outcome set for GERD in children aged 1-18 years. CONCLUSIONS: We identified a total set of 9 core outcomes and suggest these outcomes to be minimally measured in clinical studies assessing GERD in children. Implementation of this core outcome set is likely to increase comparison between studies and may thus provide future recommendations to improve treatment of GERD in children.

Clinical Experience With Performing Esophageal Function Testing in Children.

OBJECTIVES: Pediatric high-resolution manometry (HRM) and 24-hour pH-impedance with/without ambulatory manometry (pH-MII+/-mano) tests are generally performed using adult-derived protocols. We aimed to assess the feasibility of these protocols in children, the occurrence of patient-related imperfections and their influence on test interpretability. METHODS: Esophageal function tests performed between 2015 and 2018 were retrospectively analyzed. All tests were subcategorized into uninterpretable or interpretable tests (regardless of occurrence of patient-related imperfections). For HRM, the following patient-related imperfections were scored: patient-related artefacts, multiple swallowing and/or inability to establish baseline characteristics. For pH-MII(+/-mano), incorrect symptom registration and/or premature catheter removal were scored. Results were compared between age-groups (0-3, 4-12, and >12 years). RESULTS: In total 106 HRM, 60 pH-MII, and 23 pH-MII-mano could be fully analyzed. Of these, 94.8% HRM, 91.9% pH-MII, and 95.7% pH-MII-mano were interpretable. Overall, HRM contained imperfections in 78.3% overall and in 8/8 (100%) in the youngest age group, 36/42 (85.7%) in 4 to 12 years and in 37/56 (66.1%) in children above 12 years; P = 0.011. These imperfections led to uninterpretable results in 4 HRM (3.8%), of which 3 were in the youngest age group (3/8, 37.5%). Imperfections were found in 10% of pH-MII and 17.4% of pH-MII-mano. These led to uninterpretable results in 5.0% and 4.3%, respectively. No age-effect was found. CONCLUSIONS: Esophageal function tests in children are interpretable in more than 90% overall. In children under the age of 4 years, all patients had imperfect HRM and 3/8 tests were uninterpretable. HRM in older children and pH-MII+/-mano were interpretable in the vast majority.

Neonatal microbiota development and the effect of early life antibiotics are determined by two distinct settler types.

The neonatal period, during which the initial gut microbiota is acquired, is a critical phase. The healthy development of the infant's microbiome can be interrupted by external perturbations, like antibiotics, which are associated with profound effects on the gut microbiome and various disorders later in life. The aim of this study was to investigate the development of intestinal microbiota and the effect of antibiotic exposure during the first three months of life in term infants. Fecal samples were collected from healthy infants and infants who received antibiotics in the first week of life at one week, one month, and three months after birth. Microbial composition was analyzed using IS-pro and compared between antibiotics-treated and untreated infants. In total, 98 infants, divided into four groups based on feeding type and delivery mode, were analyzed. At one week of age, samples clustered into two distinct groups, which were termed "settler types", based on their Bacteroidetes abundance. Caesarean-born infants belonged to the low-Bacteroidetes settler type, but vaginally-born infants were divided between the two groups. The antibiotics effect was assessed within a subgroup of 45 infants, vaginally-born and exclusively breastfed, to minimize the effect of other confounders. Antibiotics administration resulted in lower Bacteroidetes diversity and/or a delay in Bacteroidetes colonization, which persisted for three months, and in a differential development of the microbiota. Antibiotics resulted in pronounced effects on the Bacteroidetes composition and dynamics. Finally, we hypothesize that stratification of children's cohorts based on settler types may reveal group effects that might otherwise be masked.

High-resolution esophageal manometry in pediatrics: Effect of esophageal length on diagnostic measures.

BACKGROUND: High-resolution esophageal manometry (HREM), derived esophageal pressure topography metrics (EPT), integrated relaxation pressure (IRP), and distal latency (DL) are influenced by age and size. Combined pressure and intraluminal impedance also allow derivation of metrics that define distension pressure and bolus flow timing. We prospectively investigated the effects of esophageal length on these metrics to determine whether adjustment strategies are required for children. METHODS: Fifty-five children (12.3 ± 4.5 years) referred for HREM, and 30 healthy adult volunteers (46.9 ± 3.8 years) were included. Studies were performed using the MMS system and a standardized protocol including 10 × 5 mL thin liquid bolus swallows (SBM kit, Trisco Foods) and analyzed via Swallow Gateway (www.swallowgateway.com). Esophageal distension pressures and swallow latencies were determined in addition to EGJ resting pressure and standard EPT metrics. Effects of esophageal length were examined using partial correlation, correcting for age. Adult-derived upper limits were adjusted for length using the slopes of the identified linear equations. KEY RESULTS: Mean esophageal length in children was 16.8 ± 2.8 cm and correlated significantly with age (r = 0.787, P = .000). Shorter length correlated with higher EGJ resting pressure and 4-s integrated relaxation pressures (IRP), distension pressures, and shorter contraction latencies. Ten patients had an IRP above the adult upper limit. Adjustment for esophageal length reduced the number of patients with elevated IRP to three. CONCLUSIONS & INFERENCES: We prospectively confirmed that certain EPT metrics, as well as potential useful adjunct pressure-impedance measures such as distension pressure, are substantially influenced by esophageal length and require adjusted diagnostic thresholds specifically for children.

Definitions of Pediatric Functional Abdominal Pain Disorders and Outcome Measures: A Systematic Review.

OBJECTIVE: To systematically review definitions of functional abdominal pain orders (FAPDs) and outcome measures used in therapeutic randomized controlled trials in pediatric FAPDs adhering to the Outcome Measures in Rheumatology recommendations. STUDY DESIGN: Cochrane, MEDLINE, Embase, and Cinahl databases were systematically searched from inception to April 2018. English-written therapeutic randomized controlled trials concerning FAPDs in children aged 4-18 years were included. Definitions of FAPDs, interventions, outcome measures, measurement instruments, and outcome assessors of each study were tabulated descriptively. Quality was assessed using the Delphi List. RESULTS: A total of 4771 articles were found, of which 64 articles were included (n = 25, 39% of high methodologic quality). The Rome III (50%), Rome II (17%), Apley (16%), and author-defined (17%) criteria were used to define FAPDs. Fourteen studies (22%) assessed a pharmacologic, 25 (39%) a dietary, and 25 (39%) a psychosocial intervention. Forty-four studies (69%) predefined their primary outcomes. In total, 211 reported predefined outcome measures were grouped into 23 different outcome domains; the majority being patient-reported (n = 27, 61%). Of the 14 studies that evaluated a pharmacologic intervention, 12 (86%) reported on adverse events. CONCLUSIONS: Studies on pediatric FAPDs are of limited methodologic quality and show large heterogeneity and inconsistency in defining FAPDs and outcome measures used. Development of a core outcome set is needed to make comparison between intervention studies possible.

Prevalence of Gastroesophageal Reflux Disease Symptoms in Infants and Children: A Systematic Review.

OBJECTIVES: Gastroesophageal reflux disease (GERD) is defined as gastroesophageal reflux causing troublesome symptoms or complications. In this study we reviewed the literature regarding the prevalence of GERD symptoms in infants and children. METHODS: Databases of PubMed, EMBASE, and Cochrane were systematically searched from inception to June 26, 2018. English-written studies based on birth cohort, school-based, or general population samples of ≥50 children aged 0 to 21 years were included. Convenience samples were excluded. RESULTS: In total, 3581 unique studies were found, of which 25 studies (11 in infants and 14 in children) were included with data on the prevalence of GERD symptoms comprising a total population of 487,969 children. In infants (0-18 months), GERD symptoms are present in more than a quarter of infants on a daily basis and show a steady decline in frequency with almost complete disappearance of symptoms at the age of 12 months. In children older than 18 months, GERD symptoms show large variation in prevalence between studies (range 0%-38% of study population) and overall, are present in >10% and in 25% on respectively a weekly and monthly basis. Of the risk factors assessed, higher body mass index and the use of alcohol and tobacco were associated with higher GERD symptom prevalence. CONCLUSIONS: This systematic review demonstrates that the reported prevalence of GERD symptoms varies considerably, depending on method of data collection and criteria used to define symptoms. Nevertheless, the high reported prevalence rates support better investment of resources and educational campaigns focused on prevention.

Oesophageal atresia.

Oesophageal atresia (EA) is a congenital abnormality of the oesophagus that is caused by incomplete embryonic compartmentalization of the foregut. EA commonly occurs with a tracheo-oesophageal fistula (TEF). Associated birth defects or anomalies, such as VACTERL association, trisomy 18 or 21 and CHARGE syndrome, occur in the majority of patients born with EA. Although several studies have revealed signalling pathways and genes potentially involved in the development of EA, our understanding of the pathophysiology of EA lags behind the improvements in surgical and clinical care of patients born with this anomaly. EA is treated surgically to restore the oesophageal interruption and, if present, ligate and divide the TEF. Survival is now ~90% in those born with EA with severe associated anomalies and even higher in those born with EA alone. Despite these achievements, long-term gastrointestinal and respiratory complications and comorbidities in patients born with EA are common and lead to decreased quality of life. Oesophageal motility disorders are probably ubiquitous in patients after undergoing EA repair and often underlie these complications and comorbidities. The implementation of several new diagnostic and screening tools in clinical care, including high-resolution impedance manometry, pH-multichannel intraluminal impedance testing and disease-specific quality of life questionnaires now provide better insight into these problems and may contribute to better long-term outcomes in the future.

Development of a Core Outcome Set for Infant Gastroesophageal Reflux Disease.

OBJECTIVE: In therapeutic trials for infant gastroesophageal reflux disease (GERD), ways to define GERD and measure and report study outcomes vary widely. The aim of this study was to develop a core outcome set (COS) for infant GERD. METHODS: The COS was developed using the Delphi technique, adhering to the Outcome Measures in Rheumatology Initiative 2.0 recommendations. Healthcare professionals (HCPs) (predominantly pediatric gastroenterologists and general pediatricians) and parents of infants (age 0-12 months) with GERD, listed up to 5 primary goals of therapy from their perspective and up to 5 persistent signs or symptoms that would signify inadequate treatment. Outcomes mentioned by >10% of participants were included in 2 shortlists. Next, HCPs and parents rated and prioritized outcomes on these shortlists. Outcomes with the highest rank formed the draft COS. The final COS was created after 2 consensus meetings between an expert panel and patient representatives. RESULTS: In total, 125 of 165 HCPs (76%) and 139 of 143 parents (97%) of infants with GERD completed the first phase. The second phase was completed by 83 of 139 HCPs (60%) and 127 of 142 different parents (89%). Outcomes of these phases were discussed during the consensus meetings and a 9-item COS was formed: "Adequate Growth," "Adequate Relief," "Adverse events,", "Crying," "Evidence of Esophagitis," "Feeding Difficulties," "Hematemesis," "No Escalation of Therapy," and "Sleep Problems." CONCLUSIONS: We developed a COS for infant GERD consisting of 9 items that should minimally be measured in future therapeutic trials to decrease study heterogeneity and ease comparability of results.

Measurement of Salivary Pepsin to Detect Gastroesophageal Reflux Disease Is Not Ready for Clinical Application.

A noninvasive test for gastroesophageal reflux disease (GERD) is desirable for adults and children. Salivary pepsin measurement has been proposed as such a test.1-3 A previous study from our group demonstrated that a maximal salivary pepsin cutoff of >210 ng/mL using the PepTest device (RD Biomed, Hull, United Kingdom) had excellent specificity of 96% but modest sensitivity of 44% to diagnose GERD,4 leading to optimism about its potential use. In this study, we aimed to confirm the previously reported sensitivity and specificity in healthy volunteers and patients with heartburn, evaluate the association between a positive PepTest and response to proton pump inhibitor (PPI) therapy, assess if test-sensitivity can be improved for GERD when samples are taken over a 72-hour sampling period, and establish normal values of salivary pepsin in infants.

High-resolution impedance manometry parameters in the evaluation of esophageal function of non-obstructive dysphagia patients.

BACKGROUND: High-resolution impedance manometry (HRIM) allows evaluation of esophageal bolus retention, flow, and pressurization. We explored novel HRIM measures and assessed their temporal relationship to dysphagia symptoms for boluses of different volume and consistency in non-obstructive dysphagia (NOD) patients. METHODS: Thirty-three NOD patients (n = 19 minor or no disorder of peristalsis ("Normal") and n = 14 esophagogastric junction outflow obstruction ("EGJOO")) were evaluated with HRIM. Patients were administered 5 and 10 mL liquid, semisolid, and 2 and 4 cm solid boluses and indicated bolus perception during individual swallows using a 5-point Likert scale. HRIM was analyzed to assess Chicago Classification and pressure flow metrics, esophageal impedance integral (EII) ratio, and bolus flow time (BFT). KEY RESULTS: Overall, bolus perception increased with increasing bolus consistency (P < 0.001), but did not differ significantly between EGJOO and Normal patients. EGJOO patients had higher IRP4, higher levels of bolus residual (ie, EII ratio and IR), and restricted esophageal emptying. The results for linking semisolid bolus perception to semisolid-derived measures revealed more biomechanically plausible and consistent patterns when compared to those derived for liquid boluses. In Normal patients, perception of boluses of heavier viscosity was related to higher bolus flow resistance during transport, whilst in EGJOO, perception was related to restriction of esophageal emptying. CONCLUSION & INFERENCES: These novel pressure-impedance measures may aid in the evaluation of NOD patients by revealing abnormal motor patterns, which may explain symptom generation. Future studies are needed to evaluate which of these measures are worthy of calculation and to establish protocol settings that allow for their meaningful interpretation.

Clinical Management of Pediatric Achalasia: A Survey of Current Practice.

OBJECTIVES: Pediatric achalasia is a rare neurodegenerative disorder of the esophagus that requires treatment. Different diagnostic and treatment modalities are available, but there are no data that show how children can best be diagnosed and treated. We aimed to identify current practices regarding the diagnostic and therapeutic approach toward children with achalasia. METHODS: Information on the current practice regarding the management of pediatric achalasia was collected by an online-based survey sent to members of the European and North American Societies for Pediatric Gastroenterology Hepatology and Nutrition involved in pediatric achalasia care. RESULTS: The survey was completed by 38 centers from 24 countries. Within these centers, 108 children were diagnosed with achalasia in the last year (median 2, range 0-15). Achalasia was primarily managed by a pediatric gastroenterologist (76%) and involved a multidisciplinary team in 84% of centers, also including a surgeon (87%), radiologist (61%), dietician (37%), speech pathologist (8%), and psychologist (5%). Medical history taking and physical examination were considered most important to establish the diagnosis (50%), followed by (a combination of) manometry (45%) or contrast swallow (21%). Treatment of first choice was Heller myotomy (58%), followed by pneumatic dilation (46%) and peroral endoscopic myotomy (29%). CONCLUSION: This study shows a great heterogeneity in the management of pediatric achalasia amongst different centers worldwide. These findings stress the need for well-designed intervention trials in children with achalasia. Given the rarity of this disease, we recommend that achalasia care should be managed in centers with access to appropriate diagnostic and treatment modalities.

Thickened infant formula: What to know.

OBJECTIVES: This study aimed to provide an overview of the characteristics of thickened formulas to aid health care providers manage infants with regurgitations. METHODS: The indications, properties, and efficacy of different thickening agents and thickened formulas on regurgitation and gastroesophageal reflux in infants were reviewed. PubMed and the Cochrane database were searched up to December 2016. RESULTS: Based on the literature review, thickened formulas reduce regurgitation, may improve reflux-associated symptoms, and increase weight gain. However, clinical efficacy is related to the characteristics of the formula and of the infant. Commercial thickened formulas are preferred over the supplementation of standard formulas with thickener because of the better viscosity, digestibility, and nutritional balance. Rice and corn starch, carob bean gum, and soy bean polysaccharides are available as thickening agents. Hydrolyzed formulas have recently shown promising additional benefit. CONCLUSIONS: Thickened formulas reduce the frequency and severity of regurgitation and are indicated in formula-fed infants with persisting symptoms despite reassurance and appropriate feeding volume intake.

Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

This document serves as an update of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) 2009 clinical guidelines for the diagnosis and management of gastroesophageal reflux disease (GERD) in infants and children and is intended to be applied in daily practice and as a basis for clinical trials. Eight clinical questions addressing diagnostic, therapeutic and prognostic topics were formulated. A systematic literature search was performed from October 1, 2008 (if the question was addressed by 2009 guidelines) or from inception to June 1, 2015 using Embase, MEDLINE, the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Clinical Trials. The approach of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was applied to define and prioritize outcomes. For therapeutic questions, the quality of evidence was also assessed using GRADE. Grading the quality of evidence for other questions was performed according to the Quality Assessment of Studies of Diagnostic Accuracy (QUADAS) and Quality in Prognostic Studies (QUIPS) tools. During a 3-day consensus meeting, all recommendations were discussed and finalized. In cases where no randomized controlled trials (RCT; therapeutic questions) or diagnostic accuracy studies were available to support the recommendations, expert opinion was used. The group members voted on each recommendation, using the nominal voting technique. With this approach, recommendations regarding evaluation and management of infants and children with GERD to standardize and improve quality of care were formulated. Additionally, 2 algorithms were developed, 1 for infants <12 months of age and the other for older infants and children.

Clinical management of pediatric achalasia.

INTRODUCTION: Achalasia is a rare esophageal motility disorder. Much of the literature is based on the adult population. In adults, guidance of therapeutic approach by manometric findings has led to improvement in patient outcome. Promising results have been achieved with novel therapies such as PerOral Endoscopic Myotomy (POEM). Areas covered: In this review, we provide an overview of the novel diagnostic and therapeutic tools for achalasia management and in what way they will relate to the future management of pediatric achalasia. We performed a PubMed and EMBASE search of English literature on achalasia using the keywords 'children', 'achalasia', 'pneumatic dilation', 'myotomy' and 'POEM'. Cohort studies < 10 cases and studies describing patients ≥ 20 years were excluded. Data regarding patient characteristics, treatment outcome and adverse events were extracted and presented descriptively, or pooled when possible. Expert commentary: Available data report that pneumatic dilation and laparoscopic Heller's myotomy are effective in children, with certain studies suggesting lower success rates in pneumatic dilation. POEM is increasingly used in the pediatric setting with promising short-term results. Gastro-esophageal reflux disease (GERD) may occur post-achalasia intervention due to disruption of the LES and therefore requires diligent follow-up, especially in children treated with POEM.

Pediatric Gastroesophageal Reflux Disease: Systematic Review on Prognosis and Prognostic Factors.

In this systematic review, we summarize the evidence on prognosis and prognostic factors of pediatric gastroesophageal reflux disease (GERD). A structured search of Embase and MEDLINE/PubMed (inception to April 2016) yielded 5365 references; 4 publications met our inclusion criteria (risk of bias moderate-high). Definitions and outcome measures varied widely between studies. The percentage of children with a diagnosis of GERD with esophagitis that had persisting symptoms and/or were on antireflux medication at follow-up (12 months to >5 years) ranged from 23% (weekly symptoms) to 68% (antireflux medication), depending on definition used. In children with a diagnosis of GERD without esophagitis, 1.4% developed esophagitis at follow-up (>5 years); none developed Barrett esophagus. In conclusion, prognostic studies on pediatric GERD are of limited quality and show large methodological heterogeneity. Based on these studies, we are unable to identify those children at risk for unfavorable outcome with regards to GERD symptoms or endoscopic complications.

Novel Pressure-Impedance Parameters for Evaluating Esophageal Function in Pediatric Achalasia.

OBJECTIVE: In achalasia, absent peristalsis and reduced esophagogastric junction (EGJ) relaxation and compliance underlie dysphagia symptoms. Novel high-resolution impedance manometry variables, that is, bolus presence time (BPT) and trans-EGJ-bolus flow time (BFT) have been developed to estimate the duration of EGJ opening and trans-EGJ bolus flow. The aim of this study was to evaluate esophageal motor function and bolus flow in children diagnosed with achalasia using these variables. METHODS: High-resolution impedance manometry recordings from 20 children who fulfilled the Chicago Classification (V3) criteria for achalasia were compared with recordings of 15 children with normal esophageal high-resolution manometry findings and no other evidence suggestive of achalasia. Matlab-based analysis software was used to calculate BPT and BFT. RESULTS: Both BPT and BFT were significantly reduced in achalasia patients compared with children with normal esophageal motility (BPT 3.3 s vs 5.1 s P < 0.01; BFT 1.4 s vs 4.3 s P < 0.001). BFT was significantly lower than BPT (achalasia difference 1.9 s ±â€Š1.3 s, P = 0.001 and normal difference 0.9 ±â€Š0.3 s, P = 0.001). Overall, there was a significant correlation between BPT and BFT (r = 0.825, P < 0.001). We observed a 2-way differentiation of achalasia patients; those in whom the BPT and BFT were proportional, but significantly lower than in patients with normal peristalsis, and those in whom BFT was disproportionately lower than BPT. CONCLUSIONS: Calculation of BPT and BFT may help determine whether esophageal bolus transport to the EGJ and/or esophageal emptying through the EGJ are aberrant. For achalasia, this may detect flow resistance at the EGJ, potentially improving both diagnosis and objective assessment of therapeutic effects.

Variations in Definitions and Outcome Measures in Gastroesophageal Reflux Disease: A Systematic Review.

CONTEXT: Gastroesophageal reflux (GER) is defined as GER disease (GERD) when it leads to troublesome symptoms and/or complications. We hypothesized that definitions and outcome measures in randomized controlled trials (RCTs) on pediatric GERD would be heterogeneous. OBJECTIVES: Systematically assess definitions and outcome measures in RCTs in this population. DATA SOURCES: Data were obtained through Cochrane, Embase, Medline, and Pubmed databases. STUDY SELECTION: We selected English-written therapeutic RCTs concerning GERD in children 0 to 18 years old. DATA EXTRACTION: Data were tabulated and presented descriptively. Each individual parameter or set of parameters with unique criteria for interpretation was considered a single definition for GER(D). Quality was assessed by using the Delphi score. RESULTS: A total of 2410 unique articles were found; 46 articles were included. Twenty-six (57%) studies defined GER by using 25 different definitions and investigated 25 different interventions. GERD was defined in 21 (46%) studies, all using a unique definition and investigating a total of 23 interventions. Respectively 87 and 61 different primary outcome measures were reported by the studies in GER and GERD. Eight (17%) studies did not report on side effects. Of the remaining 38 (83%) studies that did report on side effects, 18 (47%) included this as predefined outcome measure of which 4 (22%) as a primary outcome measure. Sixteen studies (35%) were of good methodological quality. LIMITATIONS: Only English-written studies were included. CONCLUSIONS: Inconsistency and heterogeneity exist in definitions and outcome measures used in RCTs on pediatric GER and GERD; therefore, we recommend the development of a core outcome set.