A systematic review with meta-analysis of the prevalence of gastroesophageal reflux in congenital diaphragmatic hernia pediatric survivors

A systematic review with meta-analysis of the prevalence of gastroesophageal reflux in congenital... Summary Congenital diaphragmatic hernia survivors are a well-known group at risk for developing gastroesophageal reflux disease that may be particularly long-term severe. The aim of this study is to provide a systematic review of the prevalence of gastroesophageal reflux in infant and children survivors treated for congenital diaphragmatic hernia. Electronic and manual searches were performed with keywords related to congenital diaphragmatic hernia, gastroesophageal reflux disease, and epidemiology terms. Summary estimates of the prevalence were calculated. Effect model was chosen depending on heterogeneity (I2). Factors potentially related with the prevalence, including study quality or the diagnostic strategy followed, were assessed by subgroup and meta-regression analyses. Risk of publication bias was studied by funnel plot analysis and the Egger test. The search yielded 140 articles, 26 of which were included in the analyses and provided 34 estimates of prevalence: 21 in patients aged 12 months or younger, and 13 in older children. The overall prevalence of gastroesophageal reflux disease in infants was 52.7% (95% confidence interval [CI]: 43.2% to 62.1%, I2 = 88.7%) and, in children over 1 year old, 35.1% (95% CI: 25.4% to 45.3%, I2 = 73.5%). Significant clinical and statistical heterogeneity was found. The strategy chosen for gastroesophageal reflux diagnosis influenced the reported prevalence. The only estimate obtained with a systematic use of multichannel intraluminal impedance provided a higher prevalence in both age groups: 83.3% (95% CI: 67.2% to 93.6%) and 61.1% (95% CI: 43.5% to 76.9%) respectively. This last prevalence did not significantly differ from that obtained using only low risk of bias estimates. As a conclusion, gastroesophageal reflux disease is commonly observed after congenital diaphragmatic hernia repair and is almost constantly present in the first months of life. It may be underdiagnosed if systematically esophageal monitoring is not performed. This should be considered when proposing follow-up and management protocols for congenital diaphragmatic hernia survivors. INTRODUCTION Congenital diaphragmatic hernia (CDH) is an uncommon anomaly of the diaphragm that affects 1 out of 2500 newborns, typically characterized by abdominal organ herniation into the chest cavity.1 It is frequently combined with pulmonary, neurological, and gastrointestinal comorbidities. Among the last ones, we can find gastroesophageal reflux disease (GERD) in up to 63% adult survivors, coexisting with Barrett's esophagus or esophagitis in 54%.2 The possible mechanisms explaining GERD in CDH survivors are esophageal dysmotility, weakness of the crura, shortening of the esophagus, disruption of the angle of His, intestinal malrotation, a higher postsurgery abdominal pressure, and changes in the anatomy of the region after repair.3 Furthermore, there is evidence of abnormal enteric innervation and it is likely that esophago-gastric peristalsis is impaired.4 Additionally, size of phrenic defect and use of prosthetic patch may increase the incidence of GERD in CDH patients.5 There are no strict recommendations about the optimal follow-up strategy in children with this risk factor, although recent guidelines have recently emphasized the importance of a high index of suspicion for GERD in CDH infants to avoid pulmonary morbidity and esophagitis.6 Nevertheless, GERD can be difficult to suspect as it has no specific clinical presentation, mainly in infants and children.7 It seems necessary to estimate the real extent of GERD in pediatric CDH survivors in order to facilitate clinical decision making while managing them. Our working hypothesis is that GERD may be underdiagnosed in CDH survivors and that the variability of the reported prevalence of the disease in children may be explained by the diagnosis strategy followed. For these reasons, we aimed to conduct a systematic review and meta-analysis of prevalence of GERD in children with this underlying condition, taking into account influencing variables. METHODS This systematic review and meta-analysis have been registered in the PROSPERO International Prospective Register of Systematic Reviews (www.crd.york.ac.uk/PROSPERO, registry number CRD42017054276). Our objective was to perform a meta-analysis of cross-sectional observational studies, following the PRISMA statement8 and the reporting proposal by the Meta-analysis Of Observational Studies in Epidemiology Group (MOOSE).9 Search strategy We carried out a systematic search for publications reporting the prevalence of GERD in CDH survivors between 1990 and 2016. An initial search for studies with a similar objective and methodology was conducted using MEDLINE and The Cochrane Library. No results were obtained. The search strategy consisted firstly in looking for MEDLINE, Tripdatabase and Biblioteca Virtual en Salud articles with the keywords ‘gastroesophageal reflux’ and ‘congenital diaphragmatic hernia’, both as thesauri (Medical Subject Heading in MEDLINE) and free text terms. These were combined, using the set operator AND, with epidemiology studies identified with the terms ‘epidemiology’ or ‘prevalence’ or ‘incidence’ (thesauri and free text terms). It was undertaken in January 2017. A scheme of the full search strategy is provided as supplemental content. Articles originally written in English, Italian, French, German, Portuguese, or Spanish were screened for eligibility if they met these selection criteria: (1) observational design with either retrospective or prospective data retrieval, (2) report of criteria for GERD diagnosis, (3) provision of GERD prevalence regardless its definition, (4) studies carried out in patients under 18 years old with enough data to infer age at the moment of GERD assessment, and (5) patients not repeated from another included study. Two authors (JVAM and CRH) independently reviewed the title and abstract returned by the systematic search and excluded articles by duplicity or according to their objective, relevance or design. The selected articles’ full text was finally read to confirm eligibility. In a second step, the citations provided by the remaining studies were revised and also included in the analysis if fulfilled the inclusion criteria. Additional relevant reports were identified by hand-searching of the Journal of Pediatric Surgery (identified as a frequent source of articles in an initial scoping study) and the Journal of Pediatric Gastroenterology and Nutrition (looking for abstracts from international specialty meetings). To avoid bias in the information abstraction process, primary data collection was also performed independently and double checked by the same two searchers. Disagreements in each stage were resolved by consensus after discussion. Figure 1 depicts the selection process and reasons for exclusion. Fig. 1. View largeDownload slide Flow chart showing the process of inclusion of relevant articles. Fig. 1. View largeDownload slide Flow chart showing the process of inclusion of relevant articles. Quality Assessment As recommended, reporting of quality scoring of the included studies was done.10,11 However, there is no a truly gold standard for assessing the quality of epidemiologic studies.12 An already used modification of the tool developed by Hoy et al. was implemented, enabling us to perform subgroup analysis according to it.13 One risk of bias item requires if studies use an acceptable case definition. As far as GERD is a wide concept meaning the troublesome symptoms or complications caused by the reflux of gastric content, we did not include this item.7 However, we registered the diagnostic reference chosen in each study for subgroup analysis too. The items assessed for risk of bias included representativeness of sample, sampling frame, random selection, nonresponse bias, presence of informants, and measurement of reliability and validity of the diagnostic tool or strategy followed. Response options for each question were forced to a choice between low (‘yes’ answer) or high (‘no’ answer) risk of bias. A high risk of bias was recorded for analysis if the text was unclear. Quality evaluation was done blindly by two researchers (JVAM and CRH), and discrepancies were also solved by debate. A study was considered to have a high risk of bias if 3 or less criteria were met, moderate risk of bias if 4–5 criteria were met, and low risk of bias if 6 or more criteria were met. Data extraction The following information was extracted and entered into an Excel spreadsheet (Microsoft, Redmond, WA): year of publication, GERD diagnosis criteria, age range of participants, number of cases, number of CDH survivors studied, geographical origin of the population, number of patients with patch repair, and scoring of the risk of bias evaluation tool. When reporting of various age groups in the same article, each prevalence data was considered separately and thus, as belonging to different populations and allowing also age subgroup analysis. Statistical analysis Heterogeneity of accuracy measures was explored with the I2 estimate (inconsistency measure) from Cochran Q. A combination of P < 0.10 and I2 > 50% indicated significant heterogeneity.14 When the heterogeneity was significant, the random-effect model was applied. To deal with the potential problems of confidence intervals outside the 0–1 range and variance instability, the double arcsine transformation of prevalence was applied.15 As mentioned before, additional subgroup analyses were conducted to assess impact of age, study quality and GERD diagnostic criteria. To do so, we used the z-test for the logit of the prevalence to examine differences in pooled estimates. These factors were investigated that might be related to prevalence estimation by meta-regression analyses. Publication bias was assessed by funnel plot using the logit of the prevalence and Egger's regression asymmetry tests.16 Statistical significance was set at P < 0.05 with the exception of that of the Egger's regression intercept, which was set at P < 0.1 (one-tailed). All analyses, as well as associated graphic results, were conducted using the Metaprop command for Stata/SE 12.017 (StataCorp, College Station, TX) and the Comprehensive Meta-Analysis Software 3.3.070 (Biostat, Englewood, NJ). RESULTS A total of 26 unique studies were included that contributed 34 estimates of prevalence, 21 of them in infants under 12 months old, and 13 in children from 1 to 17 years old. This includes a population of 1051 infants and 389 children older than 1 year old, studied over 24 years. Study characteristics are depicted in Tables 1 and 2. Geographical distribution of the articles covers only high-income countries from Europe (54%), North America and Asia. Four study categories were identified according to the reference used for the diagnosis of GERD: (1) clinical definition or poor performance examinations (such as upper gastrointestinal contrast series), (2) selective use of pH monitoring in patients with clinical suspicion, (3) systematic use of esophageal pH monitoring, and (4) systematic use of combined pH and multichannel intraluminal impedance (MII) monitoring. The methods used to assess the presence of GERD in CDH survivors varied over time. Most of the articles reporting systematic use of techniques such as esophageal pH or MII monitoring were conducted since 2000. Studies included in the first category were given an unclear or high risk of bias in the question about the reliability and validity of the study instrument. Other two articles were equally classified in this quality item despite reporting use of esophageal pH monitoring due to lack of indication criteria. The question about the use of some form of random sample selection was excluded owing to the fact that all the studies were consecutive case series and thus, it did not contribute to quality discrimination. Among the 34 estimates of prevalence, 29% were at high risk and 32% at moderate risk of bias. Out of the remaining low risk of bias estimates, 54% reached the maximum score in the quality assessment, mainly because of provision of enough information to justify representativeness of the sample and the suitability of the diagnostic protocol. Results of quality assessment questions are shown in Figure 2. Fig. 2. View largeDownload slide Number of prevalence estimates addressing quality scoring questions within low, high and unclear risk of bias. Fig. 2. View largeDownload slide Number of prevalence estimates addressing quality scoring questions within low, high and unclear risk of bias. Table 1. Characteristics of included studies with prevalence estimates in infants under 12 months old. IT: intrathoracic. Study Year of publication World region Risk of bias Diagnostic references Patch (%) IT liver (%) IT stomach (%) GERD cases/CDH survivors Stolar et al.18 1990 North America Moderate Esophageal pH monitoring – – – 9/16 Koot et al.19 1993 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 17/31 – 20/31 17/31 Nagaya et al.20 1994 Japan High Clinical definition, upper gastrointestinal contrast series, manometry, endoscopy and esophageal pH monitoring – – – 10/86 Kieffer et al.21 1995 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 6/74 24/70 40/70 46/74 D’Agostino et al.22 1995 North America High Need of drugs or tube-feeding – – – 13/16 Rais-Bahrami et al.23 1995 North America High Upper gastrointestinal contrast series 14/33 – – 25/33 Fasching et al.24 2000 Europe High Esophagus manometry or esophageal pH monitoring 3/27 9/27 17/27 12/27 Kamiyama et al.25 2002 Japan Low Esophageal pH monitoring 9/26 9/26 15/26 19/26 Cortes et al.26 2005 North America High Need of drugs to treat esophageal reflux 15/16 – – 7/16 Diamond et al.5 2007 Europe Moderate Need of drugs or tube-feeding 25/86 32/86 50/86 38/86 Su et al.27 2007 Europe Moderate Clinical definition 11/39 – 10/39 21/39 Koivusalo et al. 28 2008 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 10/26 – – 11/26 Gischler et al.29 2009 Europe Low Upper gastrointestinal contrast series and esophageal pH monitoring 15/20 – – 18/20 Kawahara et al.30 2010 Japan Low Esophageal pH monitoring 21/52 19/52 32/52 22/52 Peetsold et al.31 2010 Europe Moderate Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 25/67 – 19/56 27/67 Maier et al.32 2011 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 21/35 Valfrè et al.33 2011 Europe Low Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring 15/61 22/61 – 32/61 Caruso et al.34 2013 Europe Low Combined pH-multichannel intraluminal impedance monitoring 12/36 – 26/72 30/36 Verbelen et al.35 2013 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring rarely used 38/62 26/62 – 31/62 Yokotaet al.36 2014 Japan Low Esophageal pH monitoring 25/74 29/74 50/74 28/74 Teruiet al.37 2014 Japan High Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 68/168 41/168 17/168 40/168 Study Year of publication World region Risk of bias Diagnostic references Patch (%) IT liver (%) IT stomach (%) GERD cases/CDH survivors Stolar et al.18 1990 North America Moderate Esophageal pH monitoring – – – 9/16 Koot et al.19 1993 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 17/31 – 20/31 17/31 Nagaya et al.20 1994 Japan High Clinical definition, upper gastrointestinal contrast series, manometry, endoscopy and esophageal pH monitoring – – – 10/86 Kieffer et al.21 1995 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 6/74 24/70 40/70 46/74 D’Agostino et al.22 1995 North America High Need of drugs or tube-feeding – – – 13/16 Rais-Bahrami et al.23 1995 North America High Upper gastrointestinal contrast series 14/33 – – 25/33 Fasching et al.24 2000 Europe High Esophagus manometry or esophageal pH monitoring 3/27 9/27 17/27 12/27 Kamiyama et al.25 2002 Japan Low Esophageal pH monitoring 9/26 9/26 15/26 19/26 Cortes et al.26 2005 North America High Need of drugs to treat esophageal reflux 15/16 – – 7/16 Diamond et al.5 2007 Europe Moderate Need of drugs or tube-feeding 25/86 32/86 50/86 38/86 Su et al.27 2007 Europe Moderate Clinical definition 11/39 – 10/39 21/39 Koivusalo et al. 28 2008 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 10/26 – – 11/26 Gischler et al.29 2009 Europe Low Upper gastrointestinal contrast series and esophageal pH monitoring 15/20 – – 18/20 Kawahara et al.30 2010 Japan Low Esophageal pH monitoring 21/52 19/52 32/52 22/52 Peetsold et al.31 2010 Europe Moderate Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 25/67 – 19/56 27/67 Maier et al.32 2011 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 21/35 Valfrè et al.33 2011 Europe Low Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring 15/61 22/61 – 32/61 Caruso et al.34 2013 Europe Low Combined pH-multichannel intraluminal impedance monitoring 12/36 – 26/72 30/36 Verbelen et al.35 2013 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring rarely used 38/62 26/62 – 31/62 Yokotaet al.36 2014 Japan Low Esophageal pH monitoring 25/74 29/74 50/74 28/74 Teruiet al.37 2014 Japan High Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 68/168 41/168 17/168 40/168 View Large Table 1. Characteristics of included studies with prevalence estimates in infants under 12 months old. IT: intrathoracic. Study Year of publication World region Risk of bias Diagnostic references Patch (%) IT liver (%) IT stomach (%) GERD cases/CDH survivors Stolar et al.18 1990 North America Moderate Esophageal pH monitoring – – – 9/16 Koot et al.19 1993 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 17/31 – 20/31 17/31 Nagaya et al.20 1994 Japan High Clinical definition, upper gastrointestinal contrast series, manometry, endoscopy and esophageal pH monitoring – – – 10/86 Kieffer et al.21 1995 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 6/74 24/70 40/70 46/74 D’Agostino et al.22 1995 North America High Need of drugs or tube-feeding – – – 13/16 Rais-Bahrami et al.23 1995 North America High Upper gastrointestinal contrast series 14/33 – – 25/33 Fasching et al.24 2000 Europe High Esophagus manometry or esophageal pH monitoring 3/27 9/27 17/27 12/27 Kamiyama et al.25 2002 Japan Low Esophageal pH monitoring 9/26 9/26 15/26 19/26 Cortes et al.26 2005 North America High Need of drugs to treat esophageal reflux 15/16 – – 7/16 Diamond et al.5 2007 Europe Moderate Need of drugs or tube-feeding 25/86 32/86 50/86 38/86 Su et al.27 2007 Europe Moderate Clinical definition 11/39 – 10/39 21/39 Koivusalo et al. 28 2008 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 10/26 – – 11/26 Gischler et al.29 2009 Europe Low Upper gastrointestinal contrast series and esophageal pH monitoring 15/20 – – 18/20 Kawahara et al.30 2010 Japan Low Esophageal pH monitoring 21/52 19/52 32/52 22/52 Peetsold et al.31 2010 Europe Moderate Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 25/67 – 19/56 27/67 Maier et al.32 2011 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 21/35 Valfrè et al.33 2011 Europe Low Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring 15/61 22/61 – 32/61 Caruso et al.34 2013 Europe Low Combined pH-multichannel intraluminal impedance monitoring 12/36 – 26/72 30/36 Verbelen et al.35 2013 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring rarely used 38/62 26/62 – 31/62 Yokotaet al.36 2014 Japan Low Esophageal pH monitoring 25/74 29/74 50/74 28/74 Teruiet al.37 2014 Japan High Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 68/168 41/168 17/168 40/168 Study Year of publication World region Risk of bias Diagnostic references Patch (%) IT liver (%) IT stomach (%) GERD cases/CDH survivors Stolar et al.18 1990 North America Moderate Esophageal pH monitoring – – – 9/16 Koot et al.19 1993 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 17/31 – 20/31 17/31 Nagaya et al.20 1994 Japan High Clinical definition, upper gastrointestinal contrast series, manometry, endoscopy and esophageal pH monitoring – – – 10/86 Kieffer et al.21 1995 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 6/74 24/70 40/70 46/74 D’Agostino et al.22 1995 North America High Need of drugs or tube-feeding – – – 13/16 Rais-Bahrami et al.23 1995 North America High Upper gastrointestinal contrast series 14/33 – – 25/33 Fasching et al.24 2000 Europe High Esophagus manometry or esophageal pH monitoring 3/27 9/27 17/27 12/27 Kamiyama et al.25 2002 Japan Low Esophageal pH monitoring 9/26 9/26 15/26 19/26 Cortes et al.26 2005 North America High Need of drugs to treat esophageal reflux 15/16 – – 7/16 Diamond et al.5 2007 Europe Moderate Need of drugs or tube-feeding 25/86 32/86 50/86 38/86 Su et al.27 2007 Europe Moderate Clinical definition 11/39 – 10/39 21/39 Koivusalo et al. 28 2008 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 10/26 – – 11/26 Gischler et al.29 2009 Europe Low Upper gastrointestinal contrast series and esophageal pH monitoring 15/20 – – 18/20 Kawahara et al.30 2010 Japan Low Esophageal pH monitoring 21/52 19/52 32/52 22/52 Peetsold et al.31 2010 Europe Moderate Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 25/67 – 19/56 27/67 Maier et al.32 2011 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 21/35 Valfrè et al.33 2011 Europe Low Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring 15/61 22/61 – 32/61 Caruso et al.34 2013 Europe Low Combined pH-multichannel intraluminal impedance monitoring 12/36 – 26/72 30/36 Verbelen et al.35 2013 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring rarely used 38/62 26/62 – 31/62 Yokotaet al.36 2014 Japan Low Esophageal pH monitoring 25/74 29/74 50/74 28/74 Teruiet al.37 2014 Japan High Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 68/168 41/168 17/168 40/168 View Large Table 2. Characteristics of included studies with prevalence estimates in children from 1 to 17 years old. IT: intrathoracic. Study Year of publication World region Risk of bias Diagnostic references Patch (%) IT Liver (%) IT Stomach (%) GERD cases/CDH survivors Stolar et al.18 1990 North America High Upper gastrointestinal contrast series – – – 4/12 Delepoulle et al.38 1991 Europe High Clinical definition – – 8/17 3/17 D’Agostino et al.22 1995 North America High Need of drugs or tube-feeding – – – 6/13 Jaillard et al.39 2003 Europe Low Esophageal pH monitoring 15/51 – – 14/51 Cortes et al.26 2005 North America High Need of drugs to treat esophageal reflux 15/16 – – 10/16 Chiu et al.40 2006 North America Moderate Clinical definition and need of drugs 13/62 – – 25/62 Koivusalo et al.28 2008 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring – – – 8/15 Arena et al.41 2008 Europe Low Esophageal pH monitoring – – – 6/11 Rocha et al.42 2008 Europe Moderate Upper gastrointestinal contrast series 26/26 – – 3/26 Peetsold et al.31 2011 Europe Moderate Combined pH-multichannel intraluminal impedance monitoring – – – 26/30 Maier et al.32 2011 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 6/29 Valfrè et al.33 2011 Europe Low Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 17/43 Caruso et al.34 2013 Europe Low Combined pH-multichannel intraluminal impedance monitoring 12/36 – 26/72 22/36 Study Year of publication World region Risk of bias Diagnostic references Patch (%) IT Liver (%) IT Stomach (%) GERD cases/CDH survivors Stolar et al.18 1990 North America High Upper gastrointestinal contrast series – – – 4/12 Delepoulle et al.38 1991 Europe High Clinical definition – – 8/17 3/17 D’Agostino et al.22 1995 North America High Need of drugs or tube-feeding – – – 6/13 Jaillard et al.39 2003 Europe Low Esophageal pH monitoring 15/51 – – 14/51 Cortes et al.26 2005 North America High Need of drugs to treat esophageal reflux 15/16 – – 10/16 Chiu et al.40 2006 North America Moderate Clinical definition and need of drugs 13/62 – – 25/62 Koivusalo et al.28 2008 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring – – – 8/15 Arena et al.41 2008 Europe Low Esophageal pH monitoring – – – 6/11 Rocha et al.42 2008 Europe Moderate Upper gastrointestinal contrast series 26/26 – – 3/26 Peetsold et al.31 2011 Europe Moderate Combined pH-multichannel intraluminal impedance monitoring – – – 26/30 Maier et al.32 2011 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 6/29 Valfrè et al.33 2011 Europe Low Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 17/43 Caruso et al.34 2013 Europe Low Combined pH-multichannel intraluminal impedance monitoring 12/36 – 26/72 22/36 View Large Table 2. Characteristics of included studies with prevalence estimates in children from 1 to 17 years old. IT: intrathoracic. Study Year of publication World region Risk of bias Diagnostic references Patch (%) IT Liver (%) IT Stomach (%) GERD cases/CDH survivors Stolar et al.18 1990 North America High Upper gastrointestinal contrast series – – – 4/12 Delepoulle et al.38 1991 Europe High Clinical definition – – 8/17 3/17 D’Agostino et al.22 1995 North America High Need of drugs or tube-feeding – – – 6/13 Jaillard et al.39 2003 Europe Low Esophageal pH monitoring 15/51 – – 14/51 Cortes et al.26 2005 North America High Need of drugs to treat esophageal reflux 15/16 – – 10/16 Chiu et al.40 2006 North America Moderate Clinical definition and need of drugs 13/62 – – 25/62 Koivusalo et al.28 2008 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring – – – 8/15 Arena et al.41 2008 Europe Low Esophageal pH monitoring – – – 6/11 Rocha et al.42 2008 Europe Moderate Upper gastrointestinal contrast series 26/26 – – 3/26 Peetsold et al.31 2011 Europe Moderate Combined pH-multichannel intraluminal impedance monitoring – – – 26/30 Maier et al.32 2011 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 6/29 Valfrè et al.33 2011 Europe Low Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 17/43 Caruso et al.34 2013 Europe Low Combined pH-multichannel intraluminal impedance monitoring 12/36 – 26/72 22/36 Study Year of publication World region Risk of bias Diagnostic references Patch (%) IT Liver (%) IT Stomach (%) GERD cases/CDH survivors Stolar et al.18 1990 North America High Upper gastrointestinal contrast series – – – 4/12 Delepoulle et al.38 1991 Europe High Clinical definition – – 8/17 3/17 D’Agostino et al.22 1995 North America High Need of drugs or tube-feeding – – – 6/13 Jaillard et al.39 2003 Europe Low Esophageal pH monitoring 15/51 – – 14/51 Cortes et al.26 2005 North America High Need of drugs to treat esophageal reflux 15/16 – – 10/16 Chiu et al.40 2006 North America Moderate Clinical definition and need of drugs 13/62 – – 25/62 Koivusalo et al.28 2008 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring – – – 8/15 Arena et al.41 2008 Europe Low Esophageal pH monitoring – – – 6/11 Rocha et al.42 2008 Europe Moderate Upper gastrointestinal contrast series 26/26 – – 3/26 Peetsold et al.31 2011 Europe Moderate Combined pH-multichannel intraluminal impedance monitoring – – – 26/30 Maier et al.32 2011 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 6/29 Valfrè et al.33 2011 Europe Low Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 17/43 Caruso et al.34 2013 Europe Low Combined pH-multichannel intraluminal impedance monitoring 12/36 – 26/72 22/36 View Large Overall prevalence of GERD in CDH survivors The overall, pooled prevalence of GERD in CDH survivors was 46.4% (95% confidence interval [CI]: 39.1% to 53.7%). All articles provided enough data to divide the prevalence estimates into two age groups. The pooled cross-sectional estimate in infants under 12 months old was 52.7% (95% CI: 43.2% to 62.7%) and, in older children, 35.1% (95% CI: 25.4% to 45.3%). The assessment moment in children older than 1 year old was diverse: 3 estimates at a median age around 5 year old, 8 estimates before 5 years old, and two at a mean age of 12 years old. There was significant heterogeneity across all studies in each age group (I2 88.7% and 73.5% in infants and older children respectively). Changes in prevalence using different diagnostic references or tests The pooled prevalence in the two age groups according to diagnostic reference is available in Figures 3 and 4. In infants systematically studied with pH-MII (83.3%, 95% CI: 67.2% to 93.6%), the prevalence significantly differed from that in infants selectively studied with pH-metry (42.3%, 95% CI: 29.0% to 56.2%, P = 0.0002), from that in infants systematically studied with esophageal pH monitoring (59.6%, 95% CI: 39.6% to 78.2%, P = 0.032) and from that in younger patients with a clinically diagnosed GERD (57.2%, 95% CI: 45.1% to 62.1%, P = 0.008). There were not differences between these three last subgroups. Regarding the analysis in children over one year old, the only significant difference among diagnostic reference groups was found between the pooled prevalence in patients systematically studied with pH-MII (61.1%, 95% CI: 43.5% to 76.9%) and that in children in whom a pH esophageal monitoring was performed only if clinical suspicion (29.6%, 95% CI: 14.8% to 46.9%), with P = 0.013. Fig. 3. View largeDownload slide Forrest plot of prevalence of gastroesophageal reflux disease (GERD) in congenital diaphragmatic hernia survivors studied in the first year of life. Grouping by diagnostic reference for GERD. Fig. 3. View largeDownload slide Forrest plot of prevalence of gastroesophageal reflux disease (GERD) in congenital diaphragmatic hernia survivors studied in the first year of life. Grouping by diagnostic reference for GERD. Fig. 4. View largeDownload slide Forrest plot of prevalence of gastroesophageal reflux disease (GERD) in congenital diaphragmatic hernia survivors studied after the first year of life. Grouping by diagnostic reference for GERD. Fig. 4. View largeDownload slide Forrest plot of prevalence of gastroesophageal reflux disease (GERD) in congenital diaphragmatic hernia survivors studied after the first year of life. Grouping by diagnostic reference for GERD. In univariate metaregression for studies conducted in infants with less than 12 months old, there was a significant increase in prevalence when presence of GERD was systematically assessed using pH-MII compared with a selective use of esophageal pH monitoring in patients with clinical suspicion (coefficient 1.94, 95% CI: 0.24 to 3.64, P = 0.025). When performing the same analysis in prevalence estimates in children from 1 to 17 years old, the increase of prevalence turned insignificant: 1.31, 95% CI: –0.34 to 2.96, P = 0.120. Impact of other study variables on pooled prevalence estimates for different age groups Results of metaregression showed a significant relationship between pooled prevalence and GERD diagnostic reference in children under 1 year old (Tables 3 and 4). In addition, geographical setting of the study was found to keep its influence in explaining pooled prevalence in the multivariate analysis conducted in this age group. Studies carried out in Japanese infants demonstrated a pooled prevalence of 35.3% (95% CI: 19.5% to 52.8%), in comparison with European and North American articles (58.2%, 95% CI: 50.6% to 65.6%). The hypothesis of equal prevalence was rejected with a P = 0.024. When considering only Japanese studies conducted with either a systematic use of pH monitoring or combined pH-MII, the difference turned out insignificant: 49.7% (95% CI: 31.2% to 68.2%) and P = 0.452. Table 3. Meta-regression analysis for the association between study variables and prevalence estimates of gastroesophageal reflux disease in congenital diaphragmatic hernia infant survivors. Univariate Multivariate analyses with significant analyses predictors (R2 = 0.63) Study variables Coefficient 95% CI P Coefficient 95% CI P World region (RC: Europe) Japan −0.95 −1.68 to 0.23 0.010 −1.46 −2.16 to −0.76 <0.001 North America 0.05 −0.68 to 0.78 0.887 −0.28 −1.19 to 0.64 0.555 Diagnostic reference (RC: Selective use of pH esophageal monitoring) Clinical definition or poor performance explorations 0.64 −0.17 to 1.44 0.124 0.45 −0.46 to 1.436 0.330 Systematic use of esophageal pH monitoring 0.66 −0.21 to 1.54 0.140 1.32 0.57 to 2.08 0.001 Systematic use of pH-multichannel intraluminal impedance monitoring 1.94 0.24 to 3.64 0.025 1.59 0.30 to 2.88 0.016 Risk of bias (RC: moderate or high risk) Low risk of bias 0.52 −0.16 to 1.21 0.135 – – – Univariate Multivariate analyses with significant analyses predictors (R2 = 0.63) Study variables Coefficient 95% CI P Coefficient 95% CI P World region (RC: Europe) Japan −0.95 −1.68 to 0.23 0.010 −1.46 −2.16 to −0.76 <0.001 North America 0.05 −0.68 to 0.78 0.887 −0.28 −1.19 to 0.64 0.555 Diagnostic reference (RC: Selective use of pH esophageal monitoring) Clinical definition or poor performance explorations 0.64 −0.17 to 1.44 0.124 0.45 −0.46 to 1.436 0.330 Systematic use of esophageal pH monitoring 0.66 −0.21 to 1.54 0.140 1.32 0.57 to 2.08 0.001 Systematic use of pH-multichannel intraluminal impedance monitoring 1.94 0.24 to 3.64 0.025 1.59 0.30 to 2.88 0.016 Risk of bias (RC: moderate or high risk) Low risk of bias 0.52 −0.16 to 1.21 0.135 – – – CI, confidence interval; RC, reference category. View Large Table 3. Meta-regression analysis for the association between study variables and prevalence estimates of gastroesophageal reflux disease in congenital diaphragmatic hernia infant survivors. Univariate Multivariate analyses with significant analyses predictors (R2 = 0.63) Study variables Coefficient 95% CI P Coefficient 95% CI P World region (RC: Europe) Japan −0.95 −1.68 to 0.23 0.010 −1.46 −2.16 to −0.76 <0.001 North America 0.05 −0.68 to 0.78 0.887 −0.28 −1.19 to 0.64 0.555 Diagnostic reference (RC: Selective use of pH esophageal monitoring) Clinical definition or poor performance explorations 0.64 −0.17 to 1.44 0.124 0.45 −0.46 to 1.436 0.330 Systematic use of esophageal pH monitoring 0.66 −0.21 to 1.54 0.140 1.32 0.57 to 2.08 0.001 Systematic use of pH-multichannel intraluminal impedance monitoring 1.94 0.24 to 3.64 0.025 1.59 0.30 to 2.88 0.016 Risk of bias (RC: moderate or high risk) Low risk of bias 0.52 −0.16 to 1.21 0.135 – – – Univariate Multivariate analyses with significant analyses predictors (R2 = 0.63) Study variables Coefficient 95% CI P Coefficient 95% CI P World region (RC: Europe) Japan −0.95 −1.68 to 0.23 0.010 −1.46 −2.16 to −0.76 <0.001 North America 0.05 −0.68 to 0.78 0.887 −0.28 −1.19 to 0.64 0.555 Diagnostic reference (RC: Selective use of pH esophageal monitoring) Clinical definition or poor performance explorations 0.64 −0.17 to 1.44 0.124 0.45 −0.46 to 1.436 0.330 Systematic use of esophageal pH monitoring 0.66 −0.21 to 1.54 0.140 1.32 0.57 to 2.08 0.001 Systematic use of pH-multichannel intraluminal impedance monitoring 1.94 0.24 to 3.64 0.025 1.59 0.30 to 2.88 0.016 Risk of bias (RC: moderate or high risk) Low risk of bias 0.52 −0.16 to 1.21 0.135 – – – CI, confidence interval; RC, reference category. View Large Table 4. Meta-regression analysis for the association between study variables and prevalence estimates of gastroesophageal reflux disease in congenital diaphragmatic hernia survivors older than 1 year old. Study variables Univariate analyses Coefficient 95% CI P World region (RC: Europe) North America 0.59 −0.37 to 1.54 0.228 Diagnostic reference (RC: Selective use of pH esophageal monitoring) Clinical definition or poor performance explorations 0.21 −0.81 to 1.23 0.688 Systematic use of esophageal pH monitoring 0.35 −1.00 to 1.70 0.613 Systematic use of pH-multichannel intraluminal impedance monitoring 1.31 0.34 to 2.96 0.120 Risk of bias (RC: moderate or high risk) Low risk of bias 0.74 −0.17 to 1.65 0.113 Study variables Univariate analyses Coefficient 95% CI P World region (RC: Europe) North America 0.59 −0.37 to 1.54 0.228 Diagnostic reference (RC: Selective use of pH esophageal monitoring) Clinical definition or poor performance explorations 0.21 −0.81 to 1.23 0.688 Systematic use of esophageal pH monitoring 0.35 −1.00 to 1.70 0.613 Systematic use of pH-multichannel intraluminal impedance monitoring 1.31 0.34 to 2.96 0.120 Risk of bias (RC: moderate or high risk) Low risk of bias 0.74 −0.17 to 1.65 0.113 CI, confidence interval; RC, reference category. View Large Table 4. Meta-regression analysis for the association between study variables and prevalence estimates of gastroesophageal reflux disease in congenital diaphragmatic hernia survivors older than 1 year old. Study variables Univariate analyses Coefficient 95% CI P World region (RC: Europe) North America 0.59 −0.37 to 1.54 0.228 Diagnostic reference (RC: Selective use of pH esophageal monitoring) Clinical definition or poor performance explorations 0.21 −0.81 to 1.23 0.688 Systematic use of esophageal pH monitoring 0.35 −1.00 to 1.70 0.613 Systematic use of pH-multichannel intraluminal impedance monitoring 1.31 0.34 to 2.96 0.120 Risk of bias (RC: moderate or high risk) Low risk of bias 0.74 −0.17 to 1.65 0.113 Study variables Univariate analyses Coefficient 95% CI P World region (RC: Europe) North America 0.59 −0.37 to 1.54 0.228 Diagnostic reference (RC: Selective use of pH esophageal monitoring) Clinical definition or poor performance explorations 0.21 −0.81 to 1.23 0.688 Systematic use of esophageal pH monitoring 0.35 −1.00 to 1.70 0.613 Systematic use of pH-multichannel intraluminal impedance monitoring 1.31 0.34 to 2.96 0.120 Risk of bias (RC: moderate or high risk) Low risk of bias 0.74 −0.17 to 1.65 0.113 CI, confidence interval; RC, reference category. View Large Taking into account only low risk of bias estimates, the pooled prevalence of GERD in CDH infants survivors was 59.7% (95% CI: 47.7% to 71.2%), with significant heterogeneity (I2 81.9%). This prevalence was not statistically different neither from the pooled prevalence regardless study quality (P = 0.354) nor from the pooled prevalence of low risk of bias estimates obtained only with systematic performance of esophageal pH monitoring or combined pH-MII (P = 0.541). In the case of prevalence estimates in older children, low risk of bias pooled prevalence was 47.6% (95% CI: 28.4% to 67.1%), also with significant heterogeneity (I2 72.9%). No differences from the overall pooled prevalence in this age group (P = 0.252) and from the prevalence of studies with high quality and systematically performed tests in children older than 1 year old (P = 0.933) were obtained either. Cumulative meta-analysis, adding studies from the first to the latest regarding publication date, did not show a trend in pooled prevalence modification over the years in any age group. Publication bias Funnel plot comparing the logit of the prevalence with the estimate standard error was depicted jointly with imputed studies to assess publication bias (Fig. 5). Egger's linear regression method intercept was 4.32 (95% CI: 1.30 to 7.33) with a significant one-tailed P value of 0.004 in estimates in infants under one year old. When excluding moderate or high risk of bias estimates, the intercept slightly changed to 4.32 (95% CI: –0.11 to 8.76) and remained significant: P = 0.027. The same analysis with all the studies carried out in children aged from 1 to 17, demonstrated a non-significant asymmetry: intercept –0.52 (95% CI: –4.38 to 3.34) and P = 0.386. Fig. 5. View largeDownload slide Funnel plot of standard error by the logit of the prevalence with observed estimates (white spots) and imputed estimates (black spots). Panel A: estimates in children under 1 year old. Panel B: estimates in children from 1 to 17 years old. Fig. 5. View largeDownload slide Funnel plot of standard error by the logit of the prevalence with observed estimates (white spots) and imputed estimates (black spots). Panel A: estimates in children under 1 year old. Panel B: estimates in children from 1 to 17 years old. DISCUSSION Advances in neonatal intensive care and surgical technique have led to an improvement in the survival rate of newborns with CDH. Consequently the interest is currently also focused in long-term comorbidity.4 GERD is an expected potential pathology in CDH survivors as far the nature of the disease and its surgical solution interfere in the innate antireflux mechanisms.3 In fact, prevalence of GERD in this group of patients is reported in more than a half adult survivors, often related to preneoplastic lesions.2,4 Specific management is still under debate and current follow-up protocols suggest investigating GERD in presence of typical symptoms only.6 However, recent reports indicate that pediatric CDH patients develop GERD not only more often than thought, but frequently complicated with endoscopically confirmed silent esophagitis.43 Thus, concerns about the right timing, and what kind of complementary explorations should be performed in asymptomatic patients, need to be properly defined, as already done in a similar condition such as esophageal atresia.44 This has relevant therapeutic implications. Satisfactory improvement in clinical parameters has been reported in patients under medical treatment,6 but on the other hand, antireflux surgery is frequently performed, even in a prophylactic way.45 A better knowledge of the epidemiology of this association and the optimal diagnostic approach may help in the development of clinical prediction rules for the management of GERD in CDH survivors. We have conducted, to our knowledge, the first systematic review and meta-analysis investigating the prevalence of GERD in CDH survivors. Bagolan and Morini carried out a review on the topic, among other comorbidities, that was published in 2007.46 However, criteria for the inclusion of articles were not reported and their aim was not to aggregate prevalence estimates through meta-analysis. Estimates were all obtained from single-center retrospective case series with the exception of those from Peetsold (two Dutch hospitals)31 and Terui (nine Japanese institutions).37 Some included articles did not provide enough information about use of patch repair or proportion of patients with intrathoracic position of liver or stomach. For this reason, we could not study its relationship with GERD prevalence. However it is still controversial if these features behave as predictors of GERD.3,46 It has been reported that there is a positive association between the diaphragmatic standardized defect size and the proportion of patients with gastrointestinal morbidity, defined as the need for supplemental feeding or having GERD.47 We could not assess the influence of the number of survivors with larger defects on GERD prevalence either due to lack of data. Furthermore, it is unlikely that CDH-related clinical features were significantly different between primary studies as they all provide nonselected series of patients in the extracorporeal membrane oxygenation era. The main clinical sources for heterogeneity, as demonstrated by subgroups analysis, were the age of the participants and the diagnostic strategy followed for GERD diagnosis. Combined pH-MII monitoring have been the diagnostic standard that lead to the highest prevalence of GERD when used systematically in CDH survivors, both in infants and in older children. Influence of the study's country of origin on the pooled prevalence is probably confused by diagnostic reference, as it disappeared taking into account only estimates with systematic esophageal monitoring. In fact, Japanese studies’ pooled prevalence in infants is strongly influenced by the effect of a single low-quality estimate, that deviates the summary proportion towards low values. This outlier is indeed the lowest prevalence included in the analysis and belongs to an article published in 1994 with selective use of pH-metry. The single study providing a prevalence estimate with systematic use of pH-MII mentioned what criteria were used to diagnose the presence of GERD.34 Because normal values for children have not been established yet, results were compared with those obtained in children with esophageal atresia and children with and without GERD, already published by Di Pace et al.48,49 Another reference by the same study group could have been introduced in the analysis if it were not for the fact that the patients were also included in the already selected work.50 In both, esophageal monitoring was done systematically and without the influence of acid-inhibitor drugs. Even so, 60% of alkaline reflux was detected even in noninfant survivors.34 They also report performing a visual and manual revision of the tracings. This is particularly advisable in CDH survivors as it is known that patients with esophagitis or motility disorders (conditions potentially present in these patients) have lower baseline impedances than controls, which may cause underreporting of reflux.51 Pooled prevalences from studies with clinically diagnosed GERD or selective use of pH-metry were closed to that from estimates with systematic use of pH-metry. Nevertheless, we consider the last one as more reliable. In fact, all the estimates proportioned by articles with high risk of bias belonged to the less reliable diagnostic reference categories (those with nonsystematic approach). Similarity of those pooled prevalences may not indicate a comparable diagnostic capability between both strategies as it is unclear how many patients were false positive or false negative. No publication bias effect was found for prevalences in children older than one year old. However, we detected a tendency to underpublication of low estimates in infants. This is difficult to interpret as many articles included in the analysis were not intended to study GERD prevalence as their main objective. This research has been based on a compilation of the results of an exhaustive literature search in major databases. Recovered studies were critically appraised according to methodological aspects and data was extracted independently by different authors in those articles providing enough information to endorse a reliable estimate of GERD prevalence in CDH survivors under 18 years old. Absence of complementary test to study nonsymptomatic patients or inappropriate diagnosis strategy followed by the authors of original articles were not considered to rule out possible biased estimates as far as our intention was to study its influence in subgroup pooled prevalences. After the recovery of data from finally selected articles, we managed to label all estimates’ diagnostic reference under four categories. We consider that truly reliable pooled prevalences are those from low risk of bias estimates from articles assessing GERD with systematically performed tests, regardless its clinical expression. Is highly likely that other pooled estimates can be misleading due to clinical and statistical heterogeneity. For this reason, we believe that they should be interpreted with extreme caution. In conclusion, this systematic review has found that GERD is a very common comorbidity in CDH survivors, that can be diagnosed almost constantly in infants (near 83% of patients) and persist in up to 61% children and teenagers when performing pH-MII to study gastroesophageal function. Despite demonstrated from a low risk of bias source, this statement must also be taken with caution because is based in the results from only one study. Other diagnostic approaches imply reporting of lower prevalences, even when using systematically 24-hour pH-metry, not only in infants, but also in older children. We interpret these findings as that combined pH-MII is the most appropriate nonendoscopical tool to study GERD in CDH survivors, as a test with high sensitivity is required to avoid underdiagnosing patients at risk of developing silent complications like esophagitis or Barrett's esophagus in the long run as already described.43 Monitoring gastroesophageal function with pH-MII seems to be advisable even in asymptomatic patients and further studies may explore its utility in selecting patients in whom perform endoscopic surveillance for silent esophagitis. In addition, reflux events and its severity are equally as likely to be caused by non-acid gastric content as acid reflux, mainly in infants, children on acid-inhibitor medication or on continuous feeding.7 Despite there are no effective medications to treat non-acid reflux, these findings may support systematic pharmacological treatment for GERD in CDH survivors during the first year of life, until controlled trials are carried out on this topic, as it has been proposed for managing GERD risk in infants with esophageal atresia.44 Similarly, it may be advisable to perform periodic pH-MII to guide decision-making in children older than one year old. Nevertheless, to make general decisions in this clinical scenario, we suggest using the Pauker–Kassirer model,52,53 where knowing the pre-test probability of the disease is necessary. To this effect, more studies on the costs and benefits of treatment and complementary explorations need to be done. Notes Conflicts of interest: Neither conflicts of interest nor need for disclosure of funding. Specific author contributions: Sergio Pinillos Pisón and Javier Martin de Carpi proposed the idea. José Vicente Arcos-Machancoses designed the methods and wrote the paper. José Vicente Arcos-Machancoses and Carlos Ruiz Hernández conducted an initial literature research, the systematic review in full and the quality evaluation of the primary studies. Sergio Pinillos Pisón, Carlos Ruiz Hernández, and Javier Martin de Carpi contributed to the design and interpretation of the study and to further drafts. Sergio Pinillos Pisón and Javier Martin de Carpi are the guarantors. References 1 Lally K P . Congenital diaphragmatic hernia . Curr Opin Pediatr 2002 ; 14 : 486 – 90 . Google Scholar CrossRef Search ADS PubMed 2 Vanamo K , Rintala R J , Lindahl H , Louhimo I . Long-term gastrointestinal morbidity in patients with congenital diaphragmatic defects . J Pediatr Surg 1996 ; 31 : 551 – 4 . Google Scholar CrossRef Search ADS PubMed 3 Marseglia L , Manti S , D’Angelo G et al. Gastroesophageal reflux and congenital gastrointestinal malformations . World J Gastroenterol 2015 ; 21 : 8508 – 15 . Google Scholar CrossRef Search ADS PubMed 4 Tovar J A . Congenital diaphragmatic hernia . Orphanet J Rare Dis 2012 ; 7 : 1 . Google Scholar CrossRef Search ADS PubMed 5 Diamond I R , Mah K , Kim P C W , Bohn D , Gerstle J T , Wales P W . Predicting the need for fundoplication at the time of congenital diaphragmatic hernia repair . J Pediatr Surg 2007 ; 42 : 1066 – 70 . Google Scholar CrossRef Search ADS PubMed 6 American Academy of Pediatrics Section on Surgery American Academy of Pediatrics Committee on Fetus and Newborn Lally K P , Engle W . Postdischarge follow-up of infants with congenital diaphragmatic hernia . Pediatrics 2008 ; 121 : 627 – 32 . Google Scholar CrossRef Search ADS PubMed 7 Vandenplas Y , Rudolph C D , Di Lorenzo C et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) . J Pediatr Gastroenterol Nutr 2009 ; 49 : 498 – 547 . Google Scholar CrossRef Search ADS PubMed 8 Moher D , Liberati A , Tetzlaff J , Altman D G PRISMA Group . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement . PLoS Med 2009 ; 6 : e1000097 . Google Scholar CrossRef Search ADS PubMed 9 Stroup D F , Berlin J A , Morton S C et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group . JAMA 2000 ; 283 : 2008 – 12 . Google Scholar CrossRef Search ADS PubMed 10 Friedenreich C M , Brant R F , Riboli E . Influence of methodologic factors in a pooled analysis of 13 case-control studies of colorectal cancer and dietary fiber . Epidemiology 1994 ; 5 : 66 – 79 . Google Scholar CrossRef Search ADS PubMed 11 Stroup D F , Berlin J A , Morton S C et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group . JAMA 2000 ; 283 : 2008 – 12 . Google Scholar CrossRef Search ADS PubMed 12 Sanderson S , Tatt I D , Higgins J P T . Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography . Int J Epidemiol 2007 ; 36 : 666 – 76 . Google Scholar CrossRef Search ADS PubMed 13 Hoy D , Brooks P , Woolf A et al. Assessing risk of bias in prevalence studies: modification of an existing tool and evidence of interrater agreement . J Clin Epidemiol 2012 ; 65 : 934 – 9 . Google Scholar CrossRef Search ADS PubMed 14 Higgins J P T , Thompson S G . Quantifying heterogeneity in a meta-analysis . Stat Med 2002 ; 21 : 1539 – 58 . Google Scholar CrossRef Search ADS PubMed 15 Barendregt J J , Doi S A , Lee Y Y , Norman R E , Vos T . Meta-analysis of prevalence . J Epidemiol Community Health 2013 ; 67 : 974 – 8 . Google Scholar CrossRef Search ADS PubMed 16 Egger M , Davey Smith G , Schneider M , Minder C . Bias in meta-analysis detected by a simple, graphical test . BMJ 1997 ; 315 : 629 – 34 . Google Scholar CrossRef Search ADS PubMed 17 Nyaga V N , Arbyn M , Aerts M . Metaprop: a Stata command to perform meta-analysis of binomial data . Arch Public Health 2014 ; 72 : 39 . Google Scholar CrossRef Search ADS PubMed 18 Stolar C J , Levy J P , Dillon P W , Reyes C , Belamarich P , Berdon W E . Anatomic and functional abnormalities of the esophagus in infants surviving congenital diaphragmatic hernia . Am J Surg 1990 ; 159 : 204 – 7 . Google Scholar CrossRef Search ADS PubMed 19 Koot V C , Bergmeijer J H , Bos A P , Molenaar J C . Incidence and management of gastroesophageal reflux after repair of congenital diaphragmatic hernia . J Pediatr Surg 1993 ; 28 : 48 – 52 . Google Scholar CrossRef Search ADS PubMed 20 Nagaya M , Akatsuka H , Kato J . Gastroesophageal reflux occurring after repair of congenital diaphragmatic hernia . J Pediatr Surg 1994 ; 29 : 1447 – 51 . Google Scholar CrossRef Search ADS PubMed 21 Kieffer J , Sapin E , Berg A , Beaudoin S , Bargy F , Helardot P G . Gastroesophageal reflux after repair of congenital diaphragmatic hernia . J Pediatr Surg 1995 ; 30 : 1330 – 3 . Google Scholar CrossRef Search ADS PubMed 22 D’Agostino J A , Bernbaum J C , Gerdes M et al. Outcome for infants with congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation: the first year . J Pediatr Surg 1995 ; 30 : 10 – 5 . Google Scholar CrossRef Search ADS PubMed 23 Rais-Bahrami K , Robbins S T , Reed V L , Powell D M , Short B L . Congenital diaphragmatic hernia. Outcome of preoperative extracorporeal membrane oxygenation . Clin Pediatr 1995 ; 34 : 471 – 4 . Google Scholar CrossRef Search ADS 24 Fasching G , Huber A , Uray E , Sorantin E , Lindbichler F , Mayr J . Gastroesophageal reflux and diaphragmatic motility after repair of congenital diaphragmatic hernia . Eur J Pediatr Surg 2000 ; 10 : 360 – 4 . Google Scholar CrossRef Search ADS PubMed 25 Kamiyama M , Kawahara H , Okuyama H et al. Gastroesophageal reflux after repair of congenital diaphragmatic hernia . J Pediatr Surg 2002 ; 37 : 1681 – 4 . Google Scholar CrossRef Search ADS PubMed 26 Cortes R A , Keller R L , Townsend T et al. Survival of severe congenital diaphragmatic hernia has morbid consequences . J Pediatr Surg 2005 ; 40 : 36-45-6 . Google Scholar CrossRef Search ADS 27 Su W , Berry M , Puligandla P S , Aspirot A , Flageole H , Laberge J-M . Predictors of gastroesophageal reflux in neonates with congenital diaphragmatic hernia . J Pediatr Surg 2007 ; 42 : 1639 – 43 . Google Scholar CrossRef Search ADS PubMed 28 Koivusalo A I , Pakarinen M P , Lindahl H G , Rintala R J . The cumulative incidence of significant gastroesophageal reflux in patients with congenital diaphragmatic hernia-a systematic clinical, pH-metric, and endoscopic follow-up study . J Pediatr Surg 2008 ; 43 : 279 – 82 . Google Scholar CrossRef Search ADS PubMed 29 Gischler S J , van der Cammen-van Zijp M H M , Mazer P et al. A prospective comparative evaluation of persistent respiratory morbidity in esophageal atresia and congenital diaphragmatic hernia survivors . J Pediatr Surg 2009 ; 44 : 1683 – 90 . Google Scholar CrossRef Search ADS PubMed 30 Kawahara H , Okuyama H , Nose K et al. Physiological and clinical characteristics of gastroesophageal reflux after congenital diaphragmatic hernia repair . J Pediatr Surg 2010 ; 45 : 2346 – 50 . Google Scholar CrossRef Search ADS PubMed 31 Peetsold M G , Kneepkens C M F , Heij H A , IJsselstijn H , Tibboel D , Gemke R J B J . Congenital diaphragmatic hernia: long-term risk of gastroesophageal reflux disease . J Pediatr Gastroenterol Nutr 2010 ; 51 : 448 – 53 . Google Scholar CrossRef Search ADS PubMed 32 Maier S , Zahn K , Wessel L M , Schaible T , Brade J , Reinshagen K . Preventive antireflux surgery in neonates with congenital diaphragmatic hernia: a single-blinded prospective study . J Pediatr Surg 2011 ; 46 : 1510 – 5 . Google Scholar CrossRef Search ADS PubMed 33 Valfrè L , Braguglia A , Conforti A et al. Long term follow-up in high-risk congenital diaphragmatic hernia survivors: patching the diaphragm affects the outcome . J Pediatr Surg 2011 ; 46 : 52 – 6 . Google Scholar CrossRef Search ADS PubMed 34 Caruso A M , Di Pace M R , Catalano P et al. Gastroesophageal reflux in patients treated for congenital diaphragmatic hernia: short- and long-term evaluation with multichannel intraluminal impedance . Pediatr Surg Int 2013 ; 29 : 553 – 9 . Google Scholar CrossRef Search ADS PubMed 35 Verbelen T , Lerut T , Coosemans W et al. Antireflux surgery after congenital diaphragmatic hernia repair: a plea for a tailored approach . Eur J Cardiothorac Surg 2013 ; 44 : 263 – 7 ; discussion 268 . Google Scholar CrossRef Search ADS PubMed 36 Yokota K , Uchida H , Kaneko K et al. Surgical complications, especially gastroesophageal reflux disease, intestinal adhesion obstruction, and diaphragmatic hernia recurrence, are major sequelae in survivors of congenital diaphragmatic hernia . Pediatr Surg Int 2014 ; 30 : 895 – 9 . Google Scholar CrossRef Search ADS PubMed 37 Terui K , Taguchi T , Goishi K et al. Prognostic factors of gastroesophageal reflux disease in congenital diaphragmatic hernia: a multicenter study . Pediatr Surg Int 2014 ; 30 : 1129 – 34 . Google Scholar CrossRef Search ADS PubMed 38 Delepoulle F , Martinot A , Leclerc F et al. Long-term outcome of congenital diaphragmatic hernia. A study of 17 patients . Arch Fr Pediatr 1991 ; 48 : 703 – 7 . Google Scholar PubMed 39 Jaillard S M , Pierrat V , Dubois A et al. Outcome at 2 years of infants with congenital diaphragmatic hernia: a population-based study . Ann Thorac Surg 2003 ; 75 : 250 – 6 . Google Scholar CrossRef Search ADS PubMed 40 Chiu P P L , Sauer C , Mihailovic A et al. The price of success in the management of congenital diaphragmatic hernia: is improved survival accompanied by an increase in long-term morbidity? J Pediatr Surg 2006 ; 41 : 888 – 92 . Google Scholar CrossRef Search ADS PubMed 41 Arena F , Romeo C , Baldari S et al. Gastrointestinal sequelae in survivors of congenital diaphragmatic hernia . Pediatr Int 2008 ; 50 : 76 – 80 . Google Scholar CrossRef Search ADS PubMed 42 Rocha G M , Bianchi R F , Severo M et al. Congenital Diaphragmatic Hernia. The Post-neonatal period. Part II . Eur J Pediatr Surg 2008 ; 18 : 307 – 12 . Google Scholar CrossRef Search ADS PubMed 43 Morandi A , Macchini F , Zanini A et al. Endoscopic surveillance for congenital diaphragmatic hernia: unexpected prevalence of silent esophagitis . Eur J Pediatr Surg 2016 ; 26 : 291 – 5 . Google Scholar CrossRef Search ADS PubMed 44 Krishnan U , Mousa H , Dall’Oglio L et al. ESPGHAN-NASPGHAN Guidelines for the Evaluation and Treatment of Gastrointestinal and Nutritional Complications in Children With Esophageal Atresia-Tracheoesophageal Fistula . J Pediatr Gastroenterol Nutr 2016 ; 63 : 550 – 70 . Google Scholar CrossRef Search ADS PubMed 45 Dariel A , Rozé J-C , Piloquet H , Podevin G French CDH Study Group . Impact of prophylactic fundoplication on survival without growth disorder in left congenital diaphragmatic hernia requiring a patch repair . J Pediatr 2010 ; 157 : 688 – 90 , 690.e1 . Google Scholar CrossRef Search ADS PubMed 46 Bagolan P , Morini F . Long-term follow up of infants with congenital diaphragmatic hernia . Semin Pediatr Surg 2007 ; 16 : 134 – 44 . Google Scholar CrossRef Search ADS PubMed 47 Putnam L R , Harting M T , Tsao K et al. Congenital diaphragmatic hernia defect size and infant morbidity at discharge . Pediatrics 2016 ; 138: e20162043. 48 Di Pace M R , Caruso A M , Catalano P , Casuccio A , De Grazia E . Evaluation of esophageal motility using multichannel intraluminal impedance in healthy children and children with gastroesophageal reflux . J Pediatr Gastroenterol Nutr 2011 ; 52 : 26 – 30 . Google Scholar CrossRef Search ADS PubMed 49 Di Pace M R , Caruso A M , Catalano P , Casuccio A , Cimador M , De Grazia E . Evaluation of esophageal motility and reflux in children treated for esophageal atresia with the use of combined multichannel intraluminal impedance and pH monitoring . J Pediatr Surg 2011 ; 46 : 443 – 51 . Google Scholar CrossRef Search ADS PubMed 50 Di Pace M R , Caruso A M , Farina F , Casuccio A , Cimador M , De Grazia E . Evaluation of esophageal motility and reflux in children treated for congenital diaphragmatic hernia with the use of combined multichannel intraluminal impedance and pH monitoring . J Pediatr Surg 2011 ; 46 : 1881 – 6 . Google Scholar CrossRef Search ADS PubMed 51 Fröhlich T , Otto S , Weber P et al. Combined esophageal multichannel intraluminal impedance and pH monitoring after repair of esophageal atresia . J Pediatr Gastroenterol Nutr 2008 ; 47 : 443 – 9 . Google Scholar CrossRef Search ADS PubMed 52 Pauker S G , Kassirer J P . Therapeutic decision making: a cost-benefit analysis . N Engl J Med 1975 ; 293 : 229 – 34 . Google Scholar CrossRef Search ADS PubMed 53 Pauker S G , Kassirer J P . The threshold approach to clinical decision making . N Engl J Med 1980 ; 302 : 1109 – 17 . Google Scholar CrossRef Search ADS PubMed © The Authors 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

A systematic review with meta-analysis of the prevalence of gastroesophageal reflux in congenital diaphragmatic hernia pediatric survivors

Loading next page...
 
/lp/ou_press/a-systematic-review-with-meta-analysis-of-the-prevalence-of-6wM09Pe0uZ
Publisher
The International Society for Diseases of the Esophagus
Copyright
© The Authors 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.
ISSN
1120-8694
eISSN
1442-2050
D.O.I.
10.1093/dote/dox158
Publisher site
See Article on Publisher Site

Abstract

Summary Congenital diaphragmatic hernia survivors are a well-known group at risk for developing gastroesophageal reflux disease that may be particularly long-term severe. The aim of this study is to provide a systematic review of the prevalence of gastroesophageal reflux in infant and children survivors treated for congenital diaphragmatic hernia. Electronic and manual searches were performed with keywords related to congenital diaphragmatic hernia, gastroesophageal reflux disease, and epidemiology terms. Summary estimates of the prevalence were calculated. Effect model was chosen depending on heterogeneity (I2). Factors potentially related with the prevalence, including study quality or the diagnostic strategy followed, were assessed by subgroup and meta-regression analyses. Risk of publication bias was studied by funnel plot analysis and the Egger test. The search yielded 140 articles, 26 of which were included in the analyses and provided 34 estimates of prevalence: 21 in patients aged 12 months or younger, and 13 in older children. The overall prevalence of gastroesophageal reflux disease in infants was 52.7% (95% confidence interval [CI]: 43.2% to 62.1%, I2 = 88.7%) and, in children over 1 year old, 35.1% (95% CI: 25.4% to 45.3%, I2 = 73.5%). Significant clinical and statistical heterogeneity was found. The strategy chosen for gastroesophageal reflux diagnosis influenced the reported prevalence. The only estimate obtained with a systematic use of multichannel intraluminal impedance provided a higher prevalence in both age groups: 83.3% (95% CI: 67.2% to 93.6%) and 61.1% (95% CI: 43.5% to 76.9%) respectively. This last prevalence did not significantly differ from that obtained using only low risk of bias estimates. As a conclusion, gastroesophageal reflux disease is commonly observed after congenital diaphragmatic hernia repair and is almost constantly present in the first months of life. It may be underdiagnosed if systematically esophageal monitoring is not performed. This should be considered when proposing follow-up and management protocols for congenital diaphragmatic hernia survivors. INTRODUCTION Congenital diaphragmatic hernia (CDH) is an uncommon anomaly of the diaphragm that affects 1 out of 2500 newborns, typically characterized by abdominal organ herniation into the chest cavity.1 It is frequently combined with pulmonary, neurological, and gastrointestinal comorbidities. Among the last ones, we can find gastroesophageal reflux disease (GERD) in up to 63% adult survivors, coexisting with Barrett's esophagus or esophagitis in 54%.2 The possible mechanisms explaining GERD in CDH survivors are esophageal dysmotility, weakness of the crura, shortening of the esophagus, disruption of the angle of His, intestinal malrotation, a higher postsurgery abdominal pressure, and changes in the anatomy of the region after repair.3 Furthermore, there is evidence of abnormal enteric innervation and it is likely that esophago-gastric peristalsis is impaired.4 Additionally, size of phrenic defect and use of prosthetic patch may increase the incidence of GERD in CDH patients.5 There are no strict recommendations about the optimal follow-up strategy in children with this risk factor, although recent guidelines have recently emphasized the importance of a high index of suspicion for GERD in CDH infants to avoid pulmonary morbidity and esophagitis.6 Nevertheless, GERD can be difficult to suspect as it has no specific clinical presentation, mainly in infants and children.7 It seems necessary to estimate the real extent of GERD in pediatric CDH survivors in order to facilitate clinical decision making while managing them. Our working hypothesis is that GERD may be underdiagnosed in CDH survivors and that the variability of the reported prevalence of the disease in children may be explained by the diagnosis strategy followed. For these reasons, we aimed to conduct a systematic review and meta-analysis of prevalence of GERD in children with this underlying condition, taking into account influencing variables. METHODS This systematic review and meta-analysis have been registered in the PROSPERO International Prospective Register of Systematic Reviews (www.crd.york.ac.uk/PROSPERO, registry number CRD42017054276). Our objective was to perform a meta-analysis of cross-sectional observational studies, following the PRISMA statement8 and the reporting proposal by the Meta-analysis Of Observational Studies in Epidemiology Group (MOOSE).9 Search strategy We carried out a systematic search for publications reporting the prevalence of GERD in CDH survivors between 1990 and 2016. An initial search for studies with a similar objective and methodology was conducted using MEDLINE and The Cochrane Library. No results were obtained. The search strategy consisted firstly in looking for MEDLINE, Tripdatabase and Biblioteca Virtual en Salud articles with the keywords ‘gastroesophageal reflux’ and ‘congenital diaphragmatic hernia’, both as thesauri (Medical Subject Heading in MEDLINE) and free text terms. These were combined, using the set operator AND, with epidemiology studies identified with the terms ‘epidemiology’ or ‘prevalence’ or ‘incidence’ (thesauri and free text terms). It was undertaken in January 2017. A scheme of the full search strategy is provided as supplemental content. Articles originally written in English, Italian, French, German, Portuguese, or Spanish were screened for eligibility if they met these selection criteria: (1) observational design with either retrospective or prospective data retrieval, (2) report of criteria for GERD diagnosis, (3) provision of GERD prevalence regardless its definition, (4) studies carried out in patients under 18 years old with enough data to infer age at the moment of GERD assessment, and (5) patients not repeated from another included study. Two authors (JVAM and CRH) independently reviewed the title and abstract returned by the systematic search and excluded articles by duplicity or according to their objective, relevance or design. The selected articles’ full text was finally read to confirm eligibility. In a second step, the citations provided by the remaining studies were revised and also included in the analysis if fulfilled the inclusion criteria. Additional relevant reports were identified by hand-searching of the Journal of Pediatric Surgery (identified as a frequent source of articles in an initial scoping study) and the Journal of Pediatric Gastroenterology and Nutrition (looking for abstracts from international specialty meetings). To avoid bias in the information abstraction process, primary data collection was also performed independently and double checked by the same two searchers. Disagreements in each stage were resolved by consensus after discussion. Figure 1 depicts the selection process and reasons for exclusion. Fig. 1. View largeDownload slide Flow chart showing the process of inclusion of relevant articles. Fig. 1. View largeDownload slide Flow chart showing the process of inclusion of relevant articles. Quality Assessment As recommended, reporting of quality scoring of the included studies was done.10,11 However, there is no a truly gold standard for assessing the quality of epidemiologic studies.12 An already used modification of the tool developed by Hoy et al. was implemented, enabling us to perform subgroup analysis according to it.13 One risk of bias item requires if studies use an acceptable case definition. As far as GERD is a wide concept meaning the troublesome symptoms or complications caused by the reflux of gastric content, we did not include this item.7 However, we registered the diagnostic reference chosen in each study for subgroup analysis too. The items assessed for risk of bias included representativeness of sample, sampling frame, random selection, nonresponse bias, presence of informants, and measurement of reliability and validity of the diagnostic tool or strategy followed. Response options for each question were forced to a choice between low (‘yes’ answer) or high (‘no’ answer) risk of bias. A high risk of bias was recorded for analysis if the text was unclear. Quality evaluation was done blindly by two researchers (JVAM and CRH), and discrepancies were also solved by debate. A study was considered to have a high risk of bias if 3 or less criteria were met, moderate risk of bias if 4–5 criteria were met, and low risk of bias if 6 or more criteria were met. Data extraction The following information was extracted and entered into an Excel spreadsheet (Microsoft, Redmond, WA): year of publication, GERD diagnosis criteria, age range of participants, number of cases, number of CDH survivors studied, geographical origin of the population, number of patients with patch repair, and scoring of the risk of bias evaluation tool. When reporting of various age groups in the same article, each prevalence data was considered separately and thus, as belonging to different populations and allowing also age subgroup analysis. Statistical analysis Heterogeneity of accuracy measures was explored with the I2 estimate (inconsistency measure) from Cochran Q. A combination of P < 0.10 and I2 > 50% indicated significant heterogeneity.14 When the heterogeneity was significant, the random-effect model was applied. To deal with the potential problems of confidence intervals outside the 0–1 range and variance instability, the double arcsine transformation of prevalence was applied.15 As mentioned before, additional subgroup analyses were conducted to assess impact of age, study quality and GERD diagnostic criteria. To do so, we used the z-test for the logit of the prevalence to examine differences in pooled estimates. These factors were investigated that might be related to prevalence estimation by meta-regression analyses. Publication bias was assessed by funnel plot using the logit of the prevalence and Egger's regression asymmetry tests.16 Statistical significance was set at P < 0.05 with the exception of that of the Egger's regression intercept, which was set at P < 0.1 (one-tailed). All analyses, as well as associated graphic results, were conducted using the Metaprop command for Stata/SE 12.017 (StataCorp, College Station, TX) and the Comprehensive Meta-Analysis Software 3.3.070 (Biostat, Englewood, NJ). RESULTS A total of 26 unique studies were included that contributed 34 estimates of prevalence, 21 of them in infants under 12 months old, and 13 in children from 1 to 17 years old. This includes a population of 1051 infants and 389 children older than 1 year old, studied over 24 years. Study characteristics are depicted in Tables 1 and 2. Geographical distribution of the articles covers only high-income countries from Europe (54%), North America and Asia. Four study categories were identified according to the reference used for the diagnosis of GERD: (1) clinical definition or poor performance examinations (such as upper gastrointestinal contrast series), (2) selective use of pH monitoring in patients with clinical suspicion, (3) systematic use of esophageal pH monitoring, and (4) systematic use of combined pH and multichannel intraluminal impedance (MII) monitoring. The methods used to assess the presence of GERD in CDH survivors varied over time. Most of the articles reporting systematic use of techniques such as esophageal pH or MII monitoring were conducted since 2000. Studies included in the first category were given an unclear or high risk of bias in the question about the reliability and validity of the study instrument. Other two articles were equally classified in this quality item despite reporting use of esophageal pH monitoring due to lack of indication criteria. The question about the use of some form of random sample selection was excluded owing to the fact that all the studies were consecutive case series and thus, it did not contribute to quality discrimination. Among the 34 estimates of prevalence, 29% were at high risk and 32% at moderate risk of bias. Out of the remaining low risk of bias estimates, 54% reached the maximum score in the quality assessment, mainly because of provision of enough information to justify representativeness of the sample and the suitability of the diagnostic protocol. Results of quality assessment questions are shown in Figure 2. Fig. 2. View largeDownload slide Number of prevalence estimates addressing quality scoring questions within low, high and unclear risk of bias. Fig. 2. View largeDownload slide Number of prevalence estimates addressing quality scoring questions within low, high and unclear risk of bias. Table 1. Characteristics of included studies with prevalence estimates in infants under 12 months old. IT: intrathoracic. Study Year of publication World region Risk of bias Diagnostic references Patch (%) IT liver (%) IT stomach (%) GERD cases/CDH survivors Stolar et al.18 1990 North America Moderate Esophageal pH monitoring – – – 9/16 Koot et al.19 1993 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 17/31 – 20/31 17/31 Nagaya et al.20 1994 Japan High Clinical definition, upper gastrointestinal contrast series, manometry, endoscopy and esophageal pH monitoring – – – 10/86 Kieffer et al.21 1995 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 6/74 24/70 40/70 46/74 D’Agostino et al.22 1995 North America High Need of drugs or tube-feeding – – – 13/16 Rais-Bahrami et al.23 1995 North America High Upper gastrointestinal contrast series 14/33 – – 25/33 Fasching et al.24 2000 Europe High Esophagus manometry or esophageal pH monitoring 3/27 9/27 17/27 12/27 Kamiyama et al.25 2002 Japan Low Esophageal pH monitoring 9/26 9/26 15/26 19/26 Cortes et al.26 2005 North America High Need of drugs to treat esophageal reflux 15/16 – – 7/16 Diamond et al.5 2007 Europe Moderate Need of drugs or tube-feeding 25/86 32/86 50/86 38/86 Su et al.27 2007 Europe Moderate Clinical definition 11/39 – 10/39 21/39 Koivusalo et al. 28 2008 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 10/26 – – 11/26 Gischler et al.29 2009 Europe Low Upper gastrointestinal contrast series and esophageal pH monitoring 15/20 – – 18/20 Kawahara et al.30 2010 Japan Low Esophageal pH monitoring 21/52 19/52 32/52 22/52 Peetsold et al.31 2010 Europe Moderate Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 25/67 – 19/56 27/67 Maier et al.32 2011 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 21/35 Valfrè et al.33 2011 Europe Low Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring 15/61 22/61 – 32/61 Caruso et al.34 2013 Europe Low Combined pH-multichannel intraluminal impedance monitoring 12/36 – 26/72 30/36 Verbelen et al.35 2013 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring rarely used 38/62 26/62 – 31/62 Yokotaet al.36 2014 Japan Low Esophageal pH monitoring 25/74 29/74 50/74 28/74 Teruiet al.37 2014 Japan High Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 68/168 41/168 17/168 40/168 Study Year of publication World region Risk of bias Diagnostic references Patch (%) IT liver (%) IT stomach (%) GERD cases/CDH survivors Stolar et al.18 1990 North America Moderate Esophageal pH monitoring – – – 9/16 Koot et al.19 1993 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 17/31 – 20/31 17/31 Nagaya et al.20 1994 Japan High Clinical definition, upper gastrointestinal contrast series, manometry, endoscopy and esophageal pH monitoring – – – 10/86 Kieffer et al.21 1995 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 6/74 24/70 40/70 46/74 D’Agostino et al.22 1995 North America High Need of drugs or tube-feeding – – – 13/16 Rais-Bahrami et al.23 1995 North America High Upper gastrointestinal contrast series 14/33 – – 25/33 Fasching et al.24 2000 Europe High Esophagus manometry or esophageal pH monitoring 3/27 9/27 17/27 12/27 Kamiyama et al.25 2002 Japan Low Esophageal pH monitoring 9/26 9/26 15/26 19/26 Cortes et al.26 2005 North America High Need of drugs to treat esophageal reflux 15/16 – – 7/16 Diamond et al.5 2007 Europe Moderate Need of drugs or tube-feeding 25/86 32/86 50/86 38/86 Su et al.27 2007 Europe Moderate Clinical definition 11/39 – 10/39 21/39 Koivusalo et al. 28 2008 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 10/26 – – 11/26 Gischler et al.29 2009 Europe Low Upper gastrointestinal contrast series and esophageal pH monitoring 15/20 – – 18/20 Kawahara et al.30 2010 Japan Low Esophageal pH monitoring 21/52 19/52 32/52 22/52 Peetsold et al.31 2010 Europe Moderate Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 25/67 – 19/56 27/67 Maier et al.32 2011 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 21/35 Valfrè et al.33 2011 Europe Low Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring 15/61 22/61 – 32/61 Caruso et al.34 2013 Europe Low Combined pH-multichannel intraluminal impedance monitoring 12/36 – 26/72 30/36 Verbelen et al.35 2013 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring rarely used 38/62 26/62 – 31/62 Yokotaet al.36 2014 Japan Low Esophageal pH monitoring 25/74 29/74 50/74 28/74 Teruiet al.37 2014 Japan High Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 68/168 41/168 17/168 40/168 View Large Table 1. Characteristics of included studies with prevalence estimates in infants under 12 months old. IT: intrathoracic. Study Year of publication World region Risk of bias Diagnostic references Patch (%) IT liver (%) IT stomach (%) GERD cases/CDH survivors Stolar et al.18 1990 North America Moderate Esophageal pH monitoring – – – 9/16 Koot et al.19 1993 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 17/31 – 20/31 17/31 Nagaya et al.20 1994 Japan High Clinical definition, upper gastrointestinal contrast series, manometry, endoscopy and esophageal pH monitoring – – – 10/86 Kieffer et al.21 1995 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 6/74 24/70 40/70 46/74 D’Agostino et al.22 1995 North America High Need of drugs or tube-feeding – – – 13/16 Rais-Bahrami et al.23 1995 North America High Upper gastrointestinal contrast series 14/33 – – 25/33 Fasching et al.24 2000 Europe High Esophagus manometry or esophageal pH monitoring 3/27 9/27 17/27 12/27 Kamiyama et al.25 2002 Japan Low Esophageal pH monitoring 9/26 9/26 15/26 19/26 Cortes et al.26 2005 North America High Need of drugs to treat esophageal reflux 15/16 – – 7/16 Diamond et al.5 2007 Europe Moderate Need of drugs or tube-feeding 25/86 32/86 50/86 38/86 Su et al.27 2007 Europe Moderate Clinical definition 11/39 – 10/39 21/39 Koivusalo et al. 28 2008 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 10/26 – – 11/26 Gischler et al.29 2009 Europe Low Upper gastrointestinal contrast series and esophageal pH monitoring 15/20 – – 18/20 Kawahara et al.30 2010 Japan Low Esophageal pH monitoring 21/52 19/52 32/52 22/52 Peetsold et al.31 2010 Europe Moderate Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 25/67 – 19/56 27/67 Maier et al.32 2011 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 21/35 Valfrè et al.33 2011 Europe Low Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring 15/61 22/61 – 32/61 Caruso et al.34 2013 Europe Low Combined pH-multichannel intraluminal impedance monitoring 12/36 – 26/72 30/36 Verbelen et al.35 2013 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring rarely used 38/62 26/62 – 31/62 Yokotaet al.36 2014 Japan Low Esophageal pH monitoring 25/74 29/74 50/74 28/74 Teruiet al.37 2014 Japan High Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 68/168 41/168 17/168 40/168 Study Year of publication World region Risk of bias Diagnostic references Patch (%) IT liver (%) IT stomach (%) GERD cases/CDH survivors Stolar et al.18 1990 North America Moderate Esophageal pH monitoring – – – 9/16 Koot et al.19 1993 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 17/31 – 20/31 17/31 Nagaya et al.20 1994 Japan High Clinical definition, upper gastrointestinal contrast series, manometry, endoscopy and esophageal pH monitoring – – – 10/86 Kieffer et al.21 1995 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 6/74 24/70 40/70 46/74 D’Agostino et al.22 1995 North America High Need of drugs or tube-feeding – – – 13/16 Rais-Bahrami et al.23 1995 North America High Upper gastrointestinal contrast series 14/33 – – 25/33 Fasching et al.24 2000 Europe High Esophagus manometry or esophageal pH monitoring 3/27 9/27 17/27 12/27 Kamiyama et al.25 2002 Japan Low Esophageal pH monitoring 9/26 9/26 15/26 19/26 Cortes et al.26 2005 North America High Need of drugs to treat esophageal reflux 15/16 – – 7/16 Diamond et al.5 2007 Europe Moderate Need of drugs or tube-feeding 25/86 32/86 50/86 38/86 Su et al.27 2007 Europe Moderate Clinical definition 11/39 – 10/39 21/39 Koivusalo et al. 28 2008 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 10/26 – – 11/26 Gischler et al.29 2009 Europe Low Upper gastrointestinal contrast series and esophageal pH monitoring 15/20 – – 18/20 Kawahara et al.30 2010 Japan Low Esophageal pH monitoring 21/52 19/52 32/52 22/52 Peetsold et al.31 2010 Europe Moderate Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 25/67 – 19/56 27/67 Maier et al.32 2011 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 21/35 Valfrè et al.33 2011 Europe Low Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring 15/61 22/61 – 32/61 Caruso et al.34 2013 Europe Low Combined pH-multichannel intraluminal impedance monitoring 12/36 – 26/72 30/36 Verbelen et al.35 2013 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring rarely used 38/62 26/62 – 31/62 Yokotaet al.36 2014 Japan Low Esophageal pH monitoring 25/74 29/74 50/74 28/74 Teruiet al.37 2014 Japan High Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring 68/168 41/168 17/168 40/168 View Large Table 2. Characteristics of included studies with prevalence estimates in children from 1 to 17 years old. IT: intrathoracic. Study Year of publication World region Risk of bias Diagnostic references Patch (%) IT Liver (%) IT Stomach (%) GERD cases/CDH survivors Stolar et al.18 1990 North America High Upper gastrointestinal contrast series – – – 4/12 Delepoulle et al.38 1991 Europe High Clinical definition – – 8/17 3/17 D’Agostino et al.22 1995 North America High Need of drugs or tube-feeding – – – 6/13 Jaillard et al.39 2003 Europe Low Esophageal pH monitoring 15/51 – – 14/51 Cortes et al.26 2005 North America High Need of drugs to treat esophageal reflux 15/16 – – 10/16 Chiu et al.40 2006 North America Moderate Clinical definition and need of drugs 13/62 – – 25/62 Koivusalo et al.28 2008 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring – – – 8/15 Arena et al.41 2008 Europe Low Esophageal pH monitoring – – – 6/11 Rocha et al.42 2008 Europe Moderate Upper gastrointestinal contrast series 26/26 – – 3/26 Peetsold et al.31 2011 Europe Moderate Combined pH-multichannel intraluminal impedance monitoring – – – 26/30 Maier et al.32 2011 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 6/29 Valfrè et al.33 2011 Europe Low Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 17/43 Caruso et al.34 2013 Europe Low Combined pH-multichannel intraluminal impedance monitoring 12/36 – 26/72 22/36 Study Year of publication World region Risk of bias Diagnostic references Patch (%) IT Liver (%) IT Stomach (%) GERD cases/CDH survivors Stolar et al.18 1990 North America High Upper gastrointestinal contrast series – – – 4/12 Delepoulle et al.38 1991 Europe High Clinical definition – – 8/17 3/17 D’Agostino et al.22 1995 North America High Need of drugs or tube-feeding – – – 6/13 Jaillard et al.39 2003 Europe Low Esophageal pH monitoring 15/51 – – 14/51 Cortes et al.26 2005 North America High Need of drugs to treat esophageal reflux 15/16 – – 10/16 Chiu et al.40 2006 North America Moderate Clinical definition and need of drugs 13/62 – – 25/62 Koivusalo et al.28 2008 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring – – – 8/15 Arena et al.41 2008 Europe Low Esophageal pH monitoring – – – 6/11 Rocha et al.42 2008 Europe Moderate Upper gastrointestinal contrast series 26/26 – – 3/26 Peetsold et al.31 2011 Europe Moderate Combined pH-multichannel intraluminal impedance monitoring – – – 26/30 Maier et al.32 2011 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 6/29 Valfrè et al.33 2011 Europe Low Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 17/43 Caruso et al.34 2013 Europe Low Combined pH-multichannel intraluminal impedance monitoring 12/36 – 26/72 22/36 View Large Table 2. Characteristics of included studies with prevalence estimates in children from 1 to 17 years old. IT: intrathoracic. Study Year of publication World region Risk of bias Diagnostic references Patch (%) IT Liver (%) IT Stomach (%) GERD cases/CDH survivors Stolar et al.18 1990 North America High Upper gastrointestinal contrast series – – – 4/12 Delepoulle et al.38 1991 Europe High Clinical definition – – 8/17 3/17 D’Agostino et al.22 1995 North America High Need of drugs or tube-feeding – – – 6/13 Jaillard et al.39 2003 Europe Low Esophageal pH monitoring 15/51 – – 14/51 Cortes et al.26 2005 North America High Need of drugs to treat esophageal reflux 15/16 – – 10/16 Chiu et al.40 2006 North America Moderate Clinical definition and need of drugs 13/62 – – 25/62 Koivusalo et al.28 2008 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring – – – 8/15 Arena et al.41 2008 Europe Low Esophageal pH monitoring – – – 6/11 Rocha et al.42 2008 Europe Moderate Upper gastrointestinal contrast series 26/26 – – 3/26 Peetsold et al.31 2011 Europe Moderate Combined pH-multichannel intraluminal impedance monitoring – – – 26/30 Maier et al.32 2011 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 6/29 Valfrè et al.33 2011 Europe Low Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 17/43 Caruso et al.34 2013 Europe Low Combined pH-multichannel intraluminal impedance monitoring 12/36 – 26/72 22/36 Study Year of publication World region Risk of bias Diagnostic references Patch (%) IT Liver (%) IT Stomach (%) GERD cases/CDH survivors Stolar et al.18 1990 North America High Upper gastrointestinal contrast series – – – 4/12 Delepoulle et al.38 1991 Europe High Clinical definition – – 8/17 3/17 D’Agostino et al.22 1995 North America High Need of drugs or tube-feeding – – – 6/13 Jaillard et al.39 2003 Europe Low Esophageal pH monitoring 15/51 – – 14/51 Cortes et al.26 2005 North America High Need of drugs to treat esophageal reflux 15/16 – – 10/16 Chiu et al.40 2006 North America Moderate Clinical definition and need of drugs 13/62 – – 25/62 Koivusalo et al.28 2008 Europe Low Clinical definition, upper gastrointestinal contrast series, endoscopy and esophageal pH monitoring – – – 8/15 Arena et al.41 2008 Europe Low Esophageal pH monitoring – – – 6/11 Rocha et al.42 2008 Europe Moderate Upper gastrointestinal contrast series 26/26 – – 3/26 Peetsold et al.31 2011 Europe Moderate Combined pH-multichannel intraluminal impedance monitoring – – – 26/30 Maier et al.32 2011 Europe Moderate Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 6/29 Valfrè et al.33 2011 Europe Low Clinical definition, upper gastrointestinal contrast series and esophageal pH monitoring – – – 17/43 Caruso et al.34 2013 Europe Low Combined pH-multichannel intraluminal impedance monitoring 12/36 – 26/72 22/36 View Large Overall prevalence of GERD in CDH survivors The overall, pooled prevalence of GERD in CDH survivors was 46.4% (95% confidence interval [CI]: 39.1% to 53.7%). All articles provided enough data to divide the prevalence estimates into two age groups. The pooled cross-sectional estimate in infants under 12 months old was 52.7% (95% CI: 43.2% to 62.7%) and, in older children, 35.1% (95% CI: 25.4% to 45.3%). The assessment moment in children older than 1 year old was diverse: 3 estimates at a median age around 5 year old, 8 estimates before 5 years old, and two at a mean age of 12 years old. There was significant heterogeneity across all studies in each age group (I2 88.7% and 73.5% in infants and older children respectively). Changes in prevalence using different diagnostic references or tests The pooled prevalence in the two age groups according to diagnostic reference is available in Figures 3 and 4. In infants systematically studied with pH-MII (83.3%, 95% CI: 67.2% to 93.6%), the prevalence significantly differed from that in infants selectively studied with pH-metry (42.3%, 95% CI: 29.0% to 56.2%, P = 0.0002), from that in infants systematically studied with esophageal pH monitoring (59.6%, 95% CI: 39.6% to 78.2%, P = 0.032) and from that in younger patients with a clinically diagnosed GERD (57.2%, 95% CI: 45.1% to 62.1%, P = 0.008). There were not differences between these three last subgroups. Regarding the analysis in children over one year old, the only significant difference among diagnostic reference groups was found between the pooled prevalence in patients systematically studied with pH-MII (61.1%, 95% CI: 43.5% to 76.9%) and that in children in whom a pH esophageal monitoring was performed only if clinical suspicion (29.6%, 95% CI: 14.8% to 46.9%), with P = 0.013. Fig. 3. View largeDownload slide Forrest plot of prevalence of gastroesophageal reflux disease (GERD) in congenital diaphragmatic hernia survivors studied in the first year of life. Grouping by diagnostic reference for GERD. Fig. 3. View largeDownload slide Forrest plot of prevalence of gastroesophageal reflux disease (GERD) in congenital diaphragmatic hernia survivors studied in the first year of life. Grouping by diagnostic reference for GERD. Fig. 4. View largeDownload slide Forrest plot of prevalence of gastroesophageal reflux disease (GERD) in congenital diaphragmatic hernia survivors studied after the first year of life. Grouping by diagnostic reference for GERD. Fig. 4. View largeDownload slide Forrest plot of prevalence of gastroesophageal reflux disease (GERD) in congenital diaphragmatic hernia survivors studied after the first year of life. Grouping by diagnostic reference for GERD. In univariate metaregression for studies conducted in infants with less than 12 months old, there was a significant increase in prevalence when presence of GERD was systematically assessed using pH-MII compared with a selective use of esophageal pH monitoring in patients with clinical suspicion (coefficient 1.94, 95% CI: 0.24 to 3.64, P = 0.025). When performing the same analysis in prevalence estimates in children from 1 to 17 years old, the increase of prevalence turned insignificant: 1.31, 95% CI: –0.34 to 2.96, P = 0.120. Impact of other study variables on pooled prevalence estimates for different age groups Results of metaregression showed a significant relationship between pooled prevalence and GERD diagnostic reference in children under 1 year old (Tables 3 and 4). In addition, geographical setting of the study was found to keep its influence in explaining pooled prevalence in the multivariate analysis conducted in this age group. Studies carried out in Japanese infants demonstrated a pooled prevalence of 35.3% (95% CI: 19.5% to 52.8%), in comparison with European and North American articles (58.2%, 95% CI: 50.6% to 65.6%). The hypothesis of equal prevalence was rejected with a P = 0.024. When considering only Japanese studies conducted with either a systematic use of pH monitoring or combined pH-MII, the difference turned out insignificant: 49.7% (95% CI: 31.2% to 68.2%) and P = 0.452. Table 3. Meta-regression analysis for the association between study variables and prevalence estimates of gastroesophageal reflux disease in congenital diaphragmatic hernia infant survivors. Univariate Multivariate analyses with significant analyses predictors (R2 = 0.63) Study variables Coefficient 95% CI P Coefficient 95% CI P World region (RC: Europe) Japan −0.95 −1.68 to 0.23 0.010 −1.46 −2.16 to −0.76 <0.001 North America 0.05 −0.68 to 0.78 0.887 −0.28 −1.19 to 0.64 0.555 Diagnostic reference (RC: Selective use of pH esophageal monitoring) Clinical definition or poor performance explorations 0.64 −0.17 to 1.44 0.124 0.45 −0.46 to 1.436 0.330 Systematic use of esophageal pH monitoring 0.66 −0.21 to 1.54 0.140 1.32 0.57 to 2.08 0.001 Systematic use of pH-multichannel intraluminal impedance monitoring 1.94 0.24 to 3.64 0.025 1.59 0.30 to 2.88 0.016 Risk of bias (RC: moderate or high risk) Low risk of bias 0.52 −0.16 to 1.21 0.135 – – – Univariate Multivariate analyses with significant analyses predictors (R2 = 0.63) Study variables Coefficient 95% CI P Coefficient 95% CI P World region (RC: Europe) Japan −0.95 −1.68 to 0.23 0.010 −1.46 −2.16 to −0.76 <0.001 North America 0.05 −0.68 to 0.78 0.887 −0.28 −1.19 to 0.64 0.555 Diagnostic reference (RC: Selective use of pH esophageal monitoring) Clinical definition or poor performance explorations 0.64 −0.17 to 1.44 0.124 0.45 −0.46 to 1.436 0.330 Systematic use of esophageal pH monitoring 0.66 −0.21 to 1.54 0.140 1.32 0.57 to 2.08 0.001 Systematic use of pH-multichannel intraluminal impedance monitoring 1.94 0.24 to 3.64 0.025 1.59 0.30 to 2.88 0.016 Risk of bias (RC: moderate or high risk) Low risk of bias 0.52 −0.16 to 1.21 0.135 – – – CI, confidence interval; RC, reference category. View Large Table 3. Meta-regression analysis for the association between study variables and prevalence estimates of gastroesophageal reflux disease in congenital diaphragmatic hernia infant survivors. Univariate Multivariate analyses with significant analyses predictors (R2 = 0.63) Study variables Coefficient 95% CI P Coefficient 95% CI P World region (RC: Europe) Japan −0.95 −1.68 to 0.23 0.010 −1.46 −2.16 to −0.76 <0.001 North America 0.05 −0.68 to 0.78 0.887 −0.28 −1.19 to 0.64 0.555 Diagnostic reference (RC: Selective use of pH esophageal monitoring) Clinical definition or poor performance explorations 0.64 −0.17 to 1.44 0.124 0.45 −0.46 to 1.436 0.330 Systematic use of esophageal pH monitoring 0.66 −0.21 to 1.54 0.140 1.32 0.57 to 2.08 0.001 Systematic use of pH-multichannel intraluminal impedance monitoring 1.94 0.24 to 3.64 0.025 1.59 0.30 to 2.88 0.016 Risk of bias (RC: moderate or high risk) Low risk of bias 0.52 −0.16 to 1.21 0.135 – – – Univariate Multivariate analyses with significant analyses predictors (R2 = 0.63) Study variables Coefficient 95% CI P Coefficient 95% CI P World region (RC: Europe) Japan −0.95 −1.68 to 0.23 0.010 −1.46 −2.16 to −0.76 <0.001 North America 0.05 −0.68 to 0.78 0.887 −0.28 −1.19 to 0.64 0.555 Diagnostic reference (RC: Selective use of pH esophageal monitoring) Clinical definition or poor performance explorations 0.64 −0.17 to 1.44 0.124 0.45 −0.46 to 1.436 0.330 Systematic use of esophageal pH monitoring 0.66 −0.21 to 1.54 0.140 1.32 0.57 to 2.08 0.001 Systematic use of pH-multichannel intraluminal impedance monitoring 1.94 0.24 to 3.64 0.025 1.59 0.30 to 2.88 0.016 Risk of bias (RC: moderate or high risk) Low risk of bias 0.52 −0.16 to 1.21 0.135 – – – CI, confidence interval; RC, reference category. View Large Table 4. Meta-regression analysis for the association between study variables and prevalence estimates of gastroesophageal reflux disease in congenital diaphragmatic hernia survivors older than 1 year old. Study variables Univariate analyses Coefficient 95% CI P World region (RC: Europe) North America 0.59 −0.37 to 1.54 0.228 Diagnostic reference (RC: Selective use of pH esophageal monitoring) Clinical definition or poor performance explorations 0.21 −0.81 to 1.23 0.688 Systematic use of esophageal pH monitoring 0.35 −1.00 to 1.70 0.613 Systematic use of pH-multichannel intraluminal impedance monitoring 1.31 0.34 to 2.96 0.120 Risk of bias (RC: moderate or high risk) Low risk of bias 0.74 −0.17 to 1.65 0.113 Study variables Univariate analyses Coefficient 95% CI P World region (RC: Europe) North America 0.59 −0.37 to 1.54 0.228 Diagnostic reference (RC: Selective use of pH esophageal monitoring) Clinical definition or poor performance explorations 0.21 −0.81 to 1.23 0.688 Systematic use of esophageal pH monitoring 0.35 −1.00 to 1.70 0.613 Systematic use of pH-multichannel intraluminal impedance monitoring 1.31 0.34 to 2.96 0.120 Risk of bias (RC: moderate or high risk) Low risk of bias 0.74 −0.17 to 1.65 0.113 CI, confidence interval; RC, reference category. View Large Table 4. Meta-regression analysis for the association between study variables and prevalence estimates of gastroesophageal reflux disease in congenital diaphragmatic hernia survivors older than 1 year old. Study variables Univariate analyses Coefficient 95% CI P World region (RC: Europe) North America 0.59 −0.37 to 1.54 0.228 Diagnostic reference (RC: Selective use of pH esophageal monitoring) Clinical definition or poor performance explorations 0.21 −0.81 to 1.23 0.688 Systematic use of esophageal pH monitoring 0.35 −1.00 to 1.70 0.613 Systematic use of pH-multichannel intraluminal impedance monitoring 1.31 0.34 to 2.96 0.120 Risk of bias (RC: moderate or high risk) Low risk of bias 0.74 −0.17 to 1.65 0.113 Study variables Univariate analyses Coefficient 95% CI P World region (RC: Europe) North America 0.59 −0.37 to 1.54 0.228 Diagnostic reference (RC: Selective use of pH esophageal monitoring) Clinical definition or poor performance explorations 0.21 −0.81 to 1.23 0.688 Systematic use of esophageal pH monitoring 0.35 −1.00 to 1.70 0.613 Systematic use of pH-multichannel intraluminal impedance monitoring 1.31 0.34 to 2.96 0.120 Risk of bias (RC: moderate or high risk) Low risk of bias 0.74 −0.17 to 1.65 0.113 CI, confidence interval; RC, reference category. View Large Taking into account only low risk of bias estimates, the pooled prevalence of GERD in CDH infants survivors was 59.7% (95% CI: 47.7% to 71.2%), with significant heterogeneity (I2 81.9%). This prevalence was not statistically different neither from the pooled prevalence regardless study quality (P = 0.354) nor from the pooled prevalence of low risk of bias estimates obtained only with systematic performance of esophageal pH monitoring or combined pH-MII (P = 0.541). In the case of prevalence estimates in older children, low risk of bias pooled prevalence was 47.6% (95% CI: 28.4% to 67.1%), also with significant heterogeneity (I2 72.9%). No differences from the overall pooled prevalence in this age group (P = 0.252) and from the prevalence of studies with high quality and systematically performed tests in children older than 1 year old (P = 0.933) were obtained either. Cumulative meta-analysis, adding studies from the first to the latest regarding publication date, did not show a trend in pooled prevalence modification over the years in any age group. Publication bias Funnel plot comparing the logit of the prevalence with the estimate standard error was depicted jointly with imputed studies to assess publication bias (Fig. 5). Egger's linear regression method intercept was 4.32 (95% CI: 1.30 to 7.33) with a significant one-tailed P value of 0.004 in estimates in infants under one year old. When excluding moderate or high risk of bias estimates, the intercept slightly changed to 4.32 (95% CI: –0.11 to 8.76) and remained significant: P = 0.027. The same analysis with all the studies carried out in children aged from 1 to 17, demonstrated a non-significant asymmetry: intercept –0.52 (95% CI: –4.38 to 3.34) and P = 0.386. Fig. 5. View largeDownload slide Funnel plot of standard error by the logit of the prevalence with observed estimates (white spots) and imputed estimates (black spots). Panel A: estimates in children under 1 year old. Panel B: estimates in children from 1 to 17 years old. Fig. 5. View largeDownload slide Funnel plot of standard error by the logit of the prevalence with observed estimates (white spots) and imputed estimates (black spots). Panel A: estimates in children under 1 year old. Panel B: estimates in children from 1 to 17 years old. DISCUSSION Advances in neonatal intensive care and surgical technique have led to an improvement in the survival rate of newborns with CDH. Consequently the interest is currently also focused in long-term comorbidity.4 GERD is an expected potential pathology in CDH survivors as far the nature of the disease and its surgical solution interfere in the innate antireflux mechanisms.3 In fact, prevalence of GERD in this group of patients is reported in more than a half adult survivors, often related to preneoplastic lesions.2,4 Specific management is still under debate and current follow-up protocols suggest investigating GERD in presence of typical symptoms only.6 However, recent reports indicate that pediatric CDH patients develop GERD not only more often than thought, but frequently complicated with endoscopically confirmed silent esophagitis.43 Thus, concerns about the right timing, and what kind of complementary explorations should be performed in asymptomatic patients, need to be properly defined, as already done in a similar condition such as esophageal atresia.44 This has relevant therapeutic implications. Satisfactory improvement in clinical parameters has been reported in patients under medical treatment,6 but on the other hand, antireflux surgery is frequently performed, even in a prophylactic way.45 A better knowledge of the epidemiology of this association and the optimal diagnostic approach may help in the development of clinical prediction rules for the management of GERD in CDH survivors. We have conducted, to our knowledge, the first systematic review and meta-analysis investigating the prevalence of GERD in CDH survivors. Bagolan and Morini carried out a review on the topic, among other comorbidities, that was published in 2007.46 However, criteria for the inclusion of articles were not reported and their aim was not to aggregate prevalence estimates through meta-analysis. Estimates were all obtained from single-center retrospective case series with the exception of those from Peetsold (two Dutch hospitals)31 and Terui (nine Japanese institutions).37 Some included articles did not provide enough information about use of patch repair or proportion of patients with intrathoracic position of liver or stomach. For this reason, we could not study its relationship with GERD prevalence. However it is still controversial if these features behave as predictors of GERD.3,46 It has been reported that there is a positive association between the diaphragmatic standardized defect size and the proportion of patients with gastrointestinal morbidity, defined as the need for supplemental feeding or having GERD.47 We could not assess the influence of the number of survivors with larger defects on GERD prevalence either due to lack of data. Furthermore, it is unlikely that CDH-related clinical features were significantly different between primary studies as they all provide nonselected series of patients in the extracorporeal membrane oxygenation era. The main clinical sources for heterogeneity, as demonstrated by subgroups analysis, were the age of the participants and the diagnostic strategy followed for GERD diagnosis. Combined pH-MII monitoring have been the diagnostic standard that lead to the highest prevalence of GERD when used systematically in CDH survivors, both in infants and in older children. Influence of the study's country of origin on the pooled prevalence is probably confused by diagnostic reference, as it disappeared taking into account only estimates with systematic esophageal monitoring. In fact, Japanese studies’ pooled prevalence in infants is strongly influenced by the effect of a single low-quality estimate, that deviates the summary proportion towards low values. This outlier is indeed the lowest prevalence included in the analysis and belongs to an article published in 1994 with selective use of pH-metry. The single study providing a prevalence estimate with systematic use of pH-MII mentioned what criteria were used to diagnose the presence of GERD.34 Because normal values for children have not been established yet, results were compared with those obtained in children with esophageal atresia and children with and without GERD, already published by Di Pace et al.48,49 Another reference by the same study group could have been introduced in the analysis if it were not for the fact that the patients were also included in the already selected work.50 In both, esophageal monitoring was done systematically and without the influence of acid-inhibitor drugs. Even so, 60% of alkaline reflux was detected even in noninfant survivors.34 They also report performing a visual and manual revision of the tracings. This is particularly advisable in CDH survivors as it is known that patients with esophagitis or motility disorders (conditions potentially present in these patients) have lower baseline impedances than controls, which may cause underreporting of reflux.51 Pooled prevalences from studies with clinically diagnosed GERD or selective use of pH-metry were closed to that from estimates with systematic use of pH-metry. Nevertheless, we consider the last one as more reliable. In fact, all the estimates proportioned by articles with high risk of bias belonged to the less reliable diagnostic reference categories (those with nonsystematic approach). Similarity of those pooled prevalences may not indicate a comparable diagnostic capability between both strategies as it is unclear how many patients were false positive or false negative. No publication bias effect was found for prevalences in children older than one year old. However, we detected a tendency to underpublication of low estimates in infants. This is difficult to interpret as many articles included in the analysis were not intended to study GERD prevalence as their main objective. This research has been based on a compilation of the results of an exhaustive literature search in major databases. Recovered studies were critically appraised according to methodological aspects and data was extracted independently by different authors in those articles providing enough information to endorse a reliable estimate of GERD prevalence in CDH survivors under 18 years old. Absence of complementary test to study nonsymptomatic patients or inappropriate diagnosis strategy followed by the authors of original articles were not considered to rule out possible biased estimates as far as our intention was to study its influence in subgroup pooled prevalences. After the recovery of data from finally selected articles, we managed to label all estimates’ diagnostic reference under four categories. We consider that truly reliable pooled prevalences are those from low risk of bias estimates from articles assessing GERD with systematically performed tests, regardless its clinical expression. Is highly likely that other pooled estimates can be misleading due to clinical and statistical heterogeneity. For this reason, we believe that they should be interpreted with extreme caution. In conclusion, this systematic review has found that GERD is a very common comorbidity in CDH survivors, that can be diagnosed almost constantly in infants (near 83% of patients) and persist in up to 61% children and teenagers when performing pH-MII to study gastroesophageal function. Despite demonstrated from a low risk of bias source, this statement must also be taken with caution because is based in the results from only one study. Other diagnostic approaches imply reporting of lower prevalences, even when using systematically 24-hour pH-metry, not only in infants, but also in older children. We interpret these findings as that combined pH-MII is the most appropriate nonendoscopical tool to study GERD in CDH survivors, as a test with high sensitivity is required to avoid underdiagnosing patients at risk of developing silent complications like esophagitis or Barrett's esophagus in the long run as already described.43 Monitoring gastroesophageal function with pH-MII seems to be advisable even in asymptomatic patients and further studies may explore its utility in selecting patients in whom perform endoscopic surveillance for silent esophagitis. In addition, reflux events and its severity are equally as likely to be caused by non-acid gastric content as acid reflux, mainly in infants, children on acid-inhibitor medication or on continuous feeding.7 Despite there are no effective medications to treat non-acid reflux, these findings may support systematic pharmacological treatment for GERD in CDH survivors during the first year of life, until controlled trials are carried out on this topic, as it has been proposed for managing GERD risk in infants with esophageal atresia.44 Similarly, it may be advisable to perform periodic pH-MII to guide decision-making in children older than one year old. Nevertheless, to make general decisions in this clinical scenario, we suggest using the Pauker–Kassirer model,52,53 where knowing the pre-test probability of the disease is necessary. To this effect, more studies on the costs and benefits of treatment and complementary explorations need to be done. Notes Conflicts of interest: Neither conflicts of interest nor need for disclosure of funding. Specific author contributions: Sergio Pinillos Pisón and Javier Martin de Carpi proposed the idea. José Vicente Arcos-Machancoses designed the methods and wrote the paper. José Vicente Arcos-Machancoses and Carlos Ruiz Hernández conducted an initial literature research, the systematic review in full and the quality evaluation of the primary studies. Sergio Pinillos Pisón, Carlos Ruiz Hernández, and Javier Martin de Carpi contributed to the design and interpretation of the study and to further drafts. Sergio Pinillos Pisón and Javier Martin de Carpi are the guarantors. References 1 Lally K P . Congenital diaphragmatic hernia . Curr Opin Pediatr 2002 ; 14 : 486 – 90 . Google Scholar CrossRef Search ADS PubMed 2 Vanamo K , Rintala R J , Lindahl H , Louhimo I . Long-term gastrointestinal morbidity in patients with congenital diaphragmatic defects . J Pediatr Surg 1996 ; 31 : 551 – 4 . Google Scholar CrossRef Search ADS PubMed 3 Marseglia L , Manti S , D’Angelo G et al. Gastroesophageal reflux and congenital gastrointestinal malformations . World J Gastroenterol 2015 ; 21 : 8508 – 15 . Google Scholar CrossRef Search ADS PubMed 4 Tovar J A . Congenital diaphragmatic hernia . Orphanet J Rare Dis 2012 ; 7 : 1 . Google Scholar CrossRef Search ADS PubMed 5 Diamond I R , Mah K , Kim P C W , Bohn D , Gerstle J T , Wales P W . Predicting the need for fundoplication at the time of congenital diaphragmatic hernia repair . J Pediatr Surg 2007 ; 42 : 1066 – 70 . Google Scholar CrossRef Search ADS PubMed 6 American Academy of Pediatrics Section on Surgery American Academy of Pediatrics Committee on Fetus and Newborn Lally K P , Engle W . Postdischarge follow-up of infants with congenital diaphragmatic hernia . Pediatrics 2008 ; 121 : 627 – 32 . Google Scholar CrossRef Search ADS PubMed 7 Vandenplas Y , Rudolph C D , Di Lorenzo C et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) . J Pediatr Gastroenterol Nutr 2009 ; 49 : 498 – 547 . Google Scholar CrossRef Search ADS PubMed 8 Moher D , Liberati A , Tetzlaff J , Altman D G PRISMA Group . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement . PLoS Med 2009 ; 6 : e1000097 . Google Scholar CrossRef Search ADS PubMed 9 Stroup D F , Berlin J A , Morton S C et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group . JAMA 2000 ; 283 : 2008 – 12 . Google Scholar CrossRef Search ADS PubMed 10 Friedenreich C M , Brant R F , Riboli E . Influence of methodologic factors in a pooled analysis of 13 case-control studies of colorectal cancer and dietary fiber . Epidemiology 1994 ; 5 : 66 – 79 . Google Scholar CrossRef Search ADS PubMed 11 Stroup D F , Berlin J A , Morton S C et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group . JAMA 2000 ; 283 : 2008 – 12 . Google Scholar CrossRef Search ADS PubMed 12 Sanderson S , Tatt I D , Higgins J P T . Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography . Int J Epidemiol 2007 ; 36 : 666 – 76 . Google Scholar CrossRef Search ADS PubMed 13 Hoy D , Brooks P , Woolf A et al. Assessing risk of bias in prevalence studies: modification of an existing tool and evidence of interrater agreement . J Clin Epidemiol 2012 ; 65 : 934 – 9 . Google Scholar CrossRef Search ADS PubMed 14 Higgins J P T , Thompson S G . Quantifying heterogeneity in a meta-analysis . Stat Med 2002 ; 21 : 1539 – 58 . Google Scholar CrossRef Search ADS PubMed 15 Barendregt J J , Doi S A , Lee Y Y , Norman R E , Vos T . Meta-analysis of prevalence . J Epidemiol Community Health 2013 ; 67 : 974 – 8 . Google Scholar CrossRef Search ADS PubMed 16 Egger M , Davey Smith G , Schneider M , Minder C . Bias in meta-analysis detected by a simple, graphical test . BMJ 1997 ; 315 : 629 – 34 . Google Scholar CrossRef Search ADS PubMed 17 Nyaga V N , Arbyn M , Aerts M . Metaprop: a Stata command to perform meta-analysis of binomial data . Arch Public Health 2014 ; 72 : 39 . Google Scholar CrossRef Search ADS PubMed 18 Stolar C J , Levy J P , Dillon P W , Reyes C , Belamarich P , Berdon W E . Anatomic and functional abnormalities of the esophagus in infants surviving congenital diaphragmatic hernia . Am J Surg 1990 ; 159 : 204 – 7 . Google Scholar CrossRef Search ADS PubMed 19 Koot V C , Bergmeijer J H , Bos A P , Molenaar J C . Incidence and management of gastroesophageal reflux after repair of congenital diaphragmatic hernia . J Pediatr Surg 1993 ; 28 : 48 – 52 . Google Scholar CrossRef Search ADS PubMed 20 Nagaya M , Akatsuka H , Kato J . Gastroesophageal reflux occurring after repair of congenital diaphragmatic hernia . J Pediatr Surg 1994 ; 29 : 1447 – 51 . Google Scholar CrossRef Search ADS PubMed 21 Kieffer J , Sapin E , Berg A , Beaudoin S , Bargy F , Helardot P G . Gastroesophageal reflux after repair of congenital diaphragmatic hernia . J Pediatr Surg 1995 ; 30 : 1330 – 3 . Google Scholar CrossRef Search ADS PubMed 22 D’Agostino J A , Bernbaum J C , Gerdes M et al. Outcome for infants with congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation: the first year . J Pediatr Surg 1995 ; 30 : 10 – 5 . Google Scholar CrossRef Search ADS PubMed 23 Rais-Bahrami K , Robbins S T , Reed V L , Powell D M , Short B L . Congenital diaphragmatic hernia. Outcome of preoperative extracorporeal membrane oxygenation . Clin Pediatr 1995 ; 34 : 471 – 4 . Google Scholar CrossRef Search ADS 24 Fasching G , Huber A , Uray E , Sorantin E , Lindbichler F , Mayr J . Gastroesophageal reflux and diaphragmatic motility after repair of congenital diaphragmatic hernia . Eur J Pediatr Surg 2000 ; 10 : 360 – 4 . Google Scholar CrossRef Search ADS PubMed 25 Kamiyama M , Kawahara H , Okuyama H et al. Gastroesophageal reflux after repair of congenital diaphragmatic hernia . J Pediatr Surg 2002 ; 37 : 1681 – 4 . Google Scholar CrossRef Search ADS PubMed 26 Cortes R A , Keller R L , Townsend T et al. Survival of severe congenital diaphragmatic hernia has morbid consequences . J Pediatr Surg 2005 ; 40 : 36-45-6 . Google Scholar CrossRef Search ADS 27 Su W , Berry M , Puligandla P S , Aspirot A , Flageole H , Laberge J-M . Predictors of gastroesophageal reflux in neonates with congenital diaphragmatic hernia . J Pediatr Surg 2007 ; 42 : 1639 – 43 . Google Scholar CrossRef Search ADS PubMed 28 Koivusalo A I , Pakarinen M P , Lindahl H G , Rintala R J . The cumulative incidence of significant gastroesophageal reflux in patients with congenital diaphragmatic hernia-a systematic clinical, pH-metric, and endoscopic follow-up study . J Pediatr Surg 2008 ; 43 : 279 – 82 . Google Scholar CrossRef Search ADS PubMed 29 Gischler S J , van der Cammen-van Zijp M H M , Mazer P et al. A prospective comparative evaluation of persistent respiratory morbidity in esophageal atresia and congenital diaphragmatic hernia survivors . J Pediatr Surg 2009 ; 44 : 1683 – 90 . Google Scholar CrossRef Search ADS PubMed 30 Kawahara H , Okuyama H , Nose K et al. Physiological and clinical characteristics of gastroesophageal reflux after congenital diaphragmatic hernia repair . J Pediatr Surg 2010 ; 45 : 2346 – 50 . Google Scholar CrossRef Search ADS PubMed 31 Peetsold M G , Kneepkens C M F , Heij H A , IJsselstijn H , Tibboel D , Gemke R J B J . Congenital diaphragmatic hernia: long-term risk of gastroesophageal reflux disease . J Pediatr Gastroenterol Nutr 2010 ; 51 : 448 – 53 . Google Scholar CrossRef Search ADS PubMed 32 Maier S , Zahn K , Wessel L M , Schaible T , Brade J , Reinshagen K . Preventive antireflux surgery in neonates with congenital diaphragmatic hernia: a single-blinded prospective study . J Pediatr Surg 2011 ; 46 : 1510 – 5 . Google Scholar CrossRef Search ADS PubMed 33 Valfrè L , Braguglia A , Conforti A et al. Long term follow-up in high-risk congenital diaphragmatic hernia survivors: patching the diaphragm affects the outcome . J Pediatr Surg 2011 ; 46 : 52 – 6 . Google Scholar CrossRef Search ADS PubMed 34 Caruso A M , Di Pace M R , Catalano P et al. Gastroesophageal reflux in patients treated for congenital diaphragmatic hernia: short- and long-term evaluation with multichannel intraluminal impedance . Pediatr Surg Int 2013 ; 29 : 553 – 9 . Google Scholar CrossRef Search ADS PubMed 35 Verbelen T , Lerut T , Coosemans W et al. Antireflux surgery after congenital diaphragmatic hernia repair: a plea for a tailored approach . Eur J Cardiothorac Surg 2013 ; 44 : 263 – 7 ; discussion 268 . Google Scholar CrossRef Search ADS PubMed 36 Yokota K , Uchida H , Kaneko K et al. Surgical complications, especially gastroesophageal reflux disease, intestinal adhesion obstruction, and diaphragmatic hernia recurrence, are major sequelae in survivors of congenital diaphragmatic hernia . Pediatr Surg Int 2014 ; 30 : 895 – 9 . Google Scholar CrossRef Search ADS PubMed 37 Terui K , Taguchi T , Goishi K et al. Prognostic factors of gastroesophageal reflux disease in congenital diaphragmatic hernia: a multicenter study . Pediatr Surg Int 2014 ; 30 : 1129 – 34 . Google Scholar CrossRef Search ADS PubMed 38 Delepoulle F , Martinot A , Leclerc F et al. Long-term outcome of congenital diaphragmatic hernia. A study of 17 patients . Arch Fr Pediatr 1991 ; 48 : 703 – 7 . Google Scholar PubMed 39 Jaillard S M , Pierrat V , Dubois A et al. Outcome at 2 years of infants with congenital diaphragmatic hernia: a population-based study . Ann Thorac Surg 2003 ; 75 : 250 – 6 . Google Scholar CrossRef Search ADS PubMed 40 Chiu P P L , Sauer C , Mihailovic A et al. The price of success in the management of congenital diaphragmatic hernia: is improved survival accompanied by an increase in long-term morbidity? J Pediatr Surg 2006 ; 41 : 888 – 92 . Google Scholar CrossRef Search ADS PubMed 41 Arena F , Romeo C , Baldari S et al. Gastrointestinal sequelae in survivors of congenital diaphragmatic hernia . Pediatr Int 2008 ; 50 : 76 – 80 . Google Scholar CrossRef Search ADS PubMed 42 Rocha G M , Bianchi R F , Severo M et al. Congenital Diaphragmatic Hernia. The Post-neonatal period. Part II . Eur J Pediatr Surg 2008 ; 18 : 307 – 12 . Google Scholar CrossRef Search ADS PubMed 43 Morandi A , Macchini F , Zanini A et al. Endoscopic surveillance for congenital diaphragmatic hernia: unexpected prevalence of silent esophagitis . Eur J Pediatr Surg 2016 ; 26 : 291 – 5 . Google Scholar CrossRef Search ADS PubMed 44 Krishnan U , Mousa H , Dall’Oglio L et al. ESPGHAN-NASPGHAN Guidelines for the Evaluation and Treatment of Gastrointestinal and Nutritional Complications in Children With Esophageal Atresia-Tracheoesophageal Fistula . J Pediatr Gastroenterol Nutr 2016 ; 63 : 550 – 70 . Google Scholar CrossRef Search ADS PubMed 45 Dariel A , Rozé J-C , Piloquet H , Podevin G French CDH Study Group . Impact of prophylactic fundoplication on survival without growth disorder in left congenital diaphragmatic hernia requiring a patch repair . J Pediatr 2010 ; 157 : 688 – 90 , 690.e1 . Google Scholar CrossRef Search ADS PubMed 46 Bagolan P , Morini F . Long-term follow up of infants with congenital diaphragmatic hernia . Semin Pediatr Surg 2007 ; 16 : 134 – 44 . Google Scholar CrossRef Search ADS PubMed 47 Putnam L R , Harting M T , Tsao K et al. Congenital diaphragmatic hernia defect size and infant morbidity at discharge . Pediatrics 2016 ; 138: e20162043. 48 Di Pace M R , Caruso A M , Catalano P , Casuccio A , De Grazia E . Evaluation of esophageal motility using multichannel intraluminal impedance in healthy children and children with gastroesophageal reflux . J Pediatr Gastroenterol Nutr 2011 ; 52 : 26 – 30 . Google Scholar CrossRef Search ADS PubMed 49 Di Pace M R , Caruso A M , Catalano P , Casuccio A , Cimador M , De Grazia E . Evaluation of esophageal motility and reflux in children treated for esophageal atresia with the use of combined multichannel intraluminal impedance and pH monitoring . J Pediatr Surg 2011 ; 46 : 443 – 51 . Google Scholar CrossRef Search ADS PubMed 50 Di Pace M R , Caruso A M , Farina F , Casuccio A , Cimador M , De Grazia E . Evaluation of esophageal motility and reflux in children treated for congenital diaphragmatic hernia with the use of combined multichannel intraluminal impedance and pH monitoring . J Pediatr Surg 2011 ; 46 : 1881 – 6 . Google Scholar CrossRef Search ADS PubMed 51 Fröhlich T , Otto S , Weber P et al. Combined esophageal multichannel intraluminal impedance and pH monitoring after repair of esophageal atresia . J Pediatr Gastroenterol Nutr 2008 ; 47 : 443 – 9 . Google Scholar CrossRef Search ADS PubMed 52 Pauker S G , Kassirer J P . Therapeutic decision making: a cost-benefit analysis . N Engl J Med 1975 ; 293 : 229 – 34 . Google Scholar CrossRef Search ADS PubMed 53 Pauker S G , Kassirer J P . The threshold approach to clinical decision making . N Engl J Med 1980 ; 302 : 1109 – 17 . Google Scholar CrossRef Search ADS PubMed © The Authors 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Diseases of the EsophagusOxford University Press

Published: Feb 9, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off