Association of Pediatric Gastroesophageal Reflux Disease and Subglottic Stenosis: A Systematic Review and Meta-analysis

Abstract

Gastroesophageal reflux disease in children, which affects approximately 18% of infants, results from gastric contents flowing into the esophagus due to factors such as immature sphincter function. Regurgitation is normal and often resolves by age two; however, persistent gastroesophageal reflux disease can lead to otolaryngological lesions such as subglottic stenosis. PubMed, AIRE, Scholar, MEDLINE, Springer Nature Journal, and Scopus were searched from their inception to February 2024. Pediatric patients < 18 years diagnosed with subglottic stenosis and investigated for gastroesophageal reflux disease or related endoscopic findings were included. Studies not reporting relevant outcomes, duplicates, and non-English studies were excluded. Six studies conducted between 1990 and 2001 explored gastroesophageal reflux-associated otolaryngological issues among pediatrics. Among the 149 participants with subglottic stenosis, 53.47% had laryngopharyngeal reflux disease. Some studies used the Cotton–Myer classification to identify intubation and gastroesophageal reflux disease as primary causes. Younger age and difficulty with intubation were associated with subglottic stenosis severity. Early management of gastroesophageal reflux disease before surgical intervention improved outcomes and reduced endoscopic repair failure rates. A meta-analysis of risk ratios from three studies underscored the relationship's statistical significance, with an overall effect size of 0.03 (95%CI: 0.01 to 0.17) and a P-value < .0001. Heterogeneity analysis showed minimal variability across studies, supporting the observed association between gastroesophageal reflux disease and subglottic stenosis. The prevalence of gastroesophageal reflux disease in pediatric subglottic stenosis cases has been established, stressing the need for early diagnosis and treatment to minimize the necessity of surgery.

Introduction

Gastroesophageal reflux disease (GERD) in children is a common physiological condition characterized by the passage of gastric contents into the esophagus due to transient relaxation of the lower esophageal sphincter (LES) or inadequate adjustment of the sphincter tone to changes in abdominal pressure [1]. Studies have estimated an approximately 18% incidence of reflux in infants, with predisposing factors such as a shorter intra-abdominal esophagus and immature LES contributing to reflux in this population [2]. Although most infants experience regurgitation, which typically resolves by age two, persistent reflux can lead to respiratory and otolaryngological issues such as asthma, bronchitis, laryngomalacia, recurrent croup, and subglottic stenosis (SGS) [3]. A study by Alsaab et al. in 2008 suggested a link between reflux and otitis media, proposing that GERD contributes to its pathogenesis by refluxing gastric contents to the middle ear via the nasopharynx and Eustachian tube [4].

Multiple studies have associated SGS with GERD, with evidence indicating that GERD is a causative factor in its development, although the current evidence is primarily based on animal studies or uncontrolled human studies. The impact of gastric acid and pepsin on the subglottis has been demonstrated in animal experiments. Delahunty and Cherry conducted a classic experimental study in which gastric acid was intermittently applied to canine vocal cords, resulting in granulomas similar to those observed in early human laryngeal lesions [5]. In a separate canine model, the application of gastric contents to the subglottic mucosa every other day for 3–4 weeks led to a substantial ninefold increase in the development of SGS. In contrast, the control group experienced only a modest 1.5-fold increase [6].

Despite popular agreement that GERD plays a role in the development of SGS, the literature lacks a systematic review linking the two pediatric conditions for better comprehension and management. Therefore, this systematic review aims to provide a comprehensive overview of the association between GERD and pediatric SGS.

Methods

Overview

The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under ID: CRD42024512533. This review followed the updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines [7].

Eligibility Criteria

Pediatric patients aged < 18 years diagnosed with SGS and investigated for GERD or GERD-related endoscopic findings were included. Studies that did not report relevant outcomes, duplicate studies, and non-English studies were excluded.

Data Sources and Search Strategies

We developed a systematic review protocol with predefined aims and objectives. The search strategy, guided by the PICO question, focused on pediatric patients to determine the association between GERD diagnosis and SGS. This review also investigated whether anti-reflux medications improve SGS in this population. PubMed, AIRE, Scholar, MEDLINE, Springer Nature Journals, and Scopus were searched from their inception to February 2024 without timeframe restrictions. Medical search engines with Medical Subject Headings search terms, such as “subglottic stenosis” and “gastroesophageal reflux” were used, employing Boolean operators for comprehensive literature retrieval. Relevant articles were selected based on the predetermined criteria.

Study Selection

After deduplication, 518 records underwent primary screening based on titles and abstracts. Twenty-seven articles were identified for potential inclusion after independent examinations by two authors (NFA and MAG). The full texts of the articles were obtained for further evaluation. Articles mentioning both SGS and GERD and their interrelationships were included, whereas case reports, review articles, studies without pediatric patients, articles not available in English, and articles without human participants were excluded. The retrieved articles were reviewed by two independent authors (NFA and MAG) and decisions were mediated and collected by another author (GA).

Data Extraction

Data extraction into a spreadsheet was independently conducted by (NFA and MAG). The extracted variables included study characteristics, study design, duration, sample size, setting, demographics, limitations, conclusions, and the presence of a control group. Factors related to SGS and GERD, such as stenosis grade, cause, diagnostic method, and endoscopic findings, were also recorded.

Risk of Bias Assessment

The methodological index for nonrandomized studies (MINORS) tool was used to assess the risk of bias at the study level.

Results

Study Selection

A total of 844 records were exported from the included databases. These records were screened for duplicates and investigated for inclusion or exclusion. A screening by abstract and title was done; 326 articles were duplicates, and 491 articles were excluded. The remaining 27 articles underwent full-text assessment. Twenty-two articles were excluded because they did not meet the inclusion criteria. Finally, six articles were included in the qualitative assessment [8, 13]. Further details are presented in Fig. 1.

Fig. 1.

The PRISMA flowchart showing the screening process of articles based on the study inclusion and exclusion criteria. PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analysis

Study Characteristics and Results

All the included studies were conducted between 1990 and 2001. The six studies examined gastroesophageal reflux-associated otolaryngological problems in pediatric patients. These studies were conducted in the USA and Canada. Regarding study design, four studies were prospective, one was a retrospective study, and one was a case series. This systematic review includes 149 participants diagnosed with SGS, and 66 (44.29%) participants were also diagnosed with GERD. Regarding the sex distribution, some studies did not report the sex distribution proportion, which made it difficult to determine the precise number. Overall, there were 52 males and 38 females, with ages ranging from 4 months to 5 years. Further details are shown in Table 1. Regarding the method of GERD diagnosis, three studies used either dual pH probe or single pH probe for patient diagnosis. Burton et al. used upper gastrointestinal series and pH probe testing [13]. Nicklaus et al. diagnosed GERD in patients based on the clinical history of prior diagnoses [9]. An esophageal biopsy was used in Yellon et al.’s study, which was consistent with esophagitis [8]. In two studies conducted by Walner et al. and Halstead et al., the Cotton–Myer classifications were reported. Walner et al. reported that 65 patients were classified as either grade II or III, and Halstead et al. reported that 11 patients were classified as grade I, 11 patients as grade II, and 3 patients as grade III [10, 11]. Among the six studies included in this review, only three reported the etiology of SGS to be due to intubation and GERD. The incidence of comorbidities was discussed in three studies. The most common comorbidities were premature birth (33.33%), bronchopulmonary dysplasia (15.97%), history of Nissen fundoplication (11.11%), and prolonged intubation (4.86%). Further details are shown in Tables 2, 3.

Table 1.

Characteristics of the included studies

Title	Study duration	Country	Study design	Sex		Total population	Age (mean)
				Male	Female
Yellon, 2000	3 years	USA	Prospective cohort	NR	NR	34	20 months
Nicklaus, 1990	3 years	Canada	Prospective cohort	3	4	7	NR
Walner, 1998	6 years	USA	Prospective cohort	43	31	74	60 months
Halstead, 1999	5 years	USA	Retrospective	NR	NR	25	9.84 months
Suskind, 2001	4 years	USA	Prospective cohort	3	2	5	4 months
Burton, 1992	NR	USA	Case series	3	1	4	7.25 months

NR Not reported

Table 2.

Causes of SGS, GERD diagnosis method, Cotton–Myer classification, and the incidence rate of GERD

Title	Cause of SGS	Method of diagnosing GERD	Cotton–Myer classification (N)	Outcome measure	Incidence rate of GERD among studies
Yellon, 2000	NR	Esophageal biopsy consistent with esophagitis	NR	% with GERD	68%
Nicklaus, 1990	Intubation	History	NR	% with GERD	14%
Walner, 1998	NR	24 h pH probe Upper and lower esophagus	Grade I: 3 Grade II:21 Grade III: 44 Grade IV:6	% with GERD	32.43%
Halstead, 1999	Intubation	Upper or lower pH probe	Grade I: 11 Grade II: 11 Grade III: 3	Resolution of stenosis after medical treatment	36%
Suskind, 2001	Intubation	pH probe	NR	Resolution of stenosis after anti-reflux surgery	100%
Burton, 1992	Intubation	UGI series and 24 h pH probe	NR	Resolution of stenosis after medical treatment	100%

GERD gastrointestinal reflux disease, NR not reported, SGS subglottic stenosis, UGI upper gastrointestinal

Table 3.

Incidence rate of comorbidities among patients

Comorbidities	Incidence rate
Brain injury	4.17%
Congenital SGS	4.17%
Developmental delay	4.86%
Patent ductus arteriosus ligation	6.94%
Reactive airway disease	6.94%
History of Nissen fundoplication	11.11%
Tracheomalacia	7.64%
Gastrostomy tube	9.03%
Bronchopulmonary dysplasia	15.97%
Prematurity	33.33%
Trisomy 21	0.69%
Prolonged intubation (more than 7 days)	4.86%
Intubation granulomas and stenosis	1.39%
Necrotizing enterocolitis	0.69%
Laryngomalacia	0.69%
Asthma	0.69%
Intubation	1.4%
Atopy	0.69%
Recurrent croup	0.69%
Nasopharyngeal mass antenatally	0.69%

SGS, subglottic stenosis

All studies revealed a significant association between GERD and SGS. Moreover, notable links were observed between histologic esophagitis and various symptoms, including asthma, recurrent croup, cough, apnea, sinusitis, stridor, laryngomalacia, posterior glottic erythema, and posterior glottic edema. Factors associated with SGS were younger age, smaller size, increased intubation attempts, difficult intubation, and non-Caucasians. Proactively addressing gastroesophageal reflux (GER) before surgical intervention in infants and children significantly enhanced clinical outcomes, notably reducing the failure rate of endoscopic repair. The conclusions and limitations of these studies are summarized in Table 4.

Table 4.

Studies’ conclusions and limitations

Title	Conclusion	Limitations
Yellon, 2000	Significant associations were found between the presence of histologic esophagitis and asthma, recurrent croup, cough, apnea, sinusitis, stridor, laryngomalacia, SGS, posterior glottic erythema, and posterior glottic edema	Causality between GERD and SGS could not be established
Nicklaus, 1990	The variables associated with SGS were younger age, smaller infants who had an increased number of intubation attempts, difficult intubation, and belonged to a non-white ethnic group	Small sample and single center
Walner, 1998	Gastroesophageal reflux is frequently present in patients with SGS. Gastric contents frequently reach the upper and lower esophagus in these patients. In addition, the high incidence of gastroesophageal reflux in these patients suggests that it may play a role in the development of SGS	Causality between GERD and SGS could not be established
Halstead, 1999	Aggressive treatment of GER in infants and children before surgical intervention significantly improved their clinical outcomes. The number of patients in whom endoscopic repair failed dropped dramatically	Follow-up after medical treatment was not discussed
Suskind, 2001	Gastroesophageal reflux has an important role in the cause of numerous otolaryngologic disorders. Although medical management should remain the mainstay of GER therapy, antireflux surgery provided definitive and successful treatment of potentially life-threatening manifestations of GERD	NR
Burton, 1992	Gastroesophageal reflux in the pediatric population has a variety of manifestations. Airway compromise may bring children with this disease to the attention of otolaryngologists. A high index of suspicion is required to accurately diagnose the disease and treat these patients	NR

NR not reported

Risk of Bias

The MINORS assessment tool was used in nonrandomized, non-comparative studies. A high score indicates a low risk of bias. Two studies achieved a score of 14, whereas two others scored 10. The MINORS tool was also used in nonrandomized and comparative studies [14]. A low risk of bias score was observed, with two studies scoring 19 and 18 (Tables 5, 6).

Table 5.

MINORS assessment tool for nonrandomized non-comparative studies (N = 4)

Item	Yellon,2000	Walner, 1998	Suskind, 2001	Burton, 1992
A clearly stated aim	2	2	2	2
Inclusion of consecutive patients	2	2	2	2
Prospective collection of data	2	2	0	0
Endpoints appropriate to the aim of the study	2	2	2	2
Unbiased assessment of the study endpoint	2	2	2	2
Follow-up period appropriate to the aim of the study	2	2	0	0
Loss to follow-up less than 5%	2	2	2	2
Prospective calculation of the study size	0	0	0	0
Total score	14	14	10	10

0: not reported, 1: reported but inadequate, 2: reported adequately

Total score: 11–16: low risk of bias; 6–10: moderate risk of bias; 0–5: high risk of bias

MINORS methodological index for nonrandomized studies

Table 6.

MINORS assessment tool for nonrandomized comparative studies (N = 2)

Item	Nicklaus, 1990	Halstead, 1999
A clearly stated aim	2	2
Inclusion of consecutive patients	2	2
Prospective collection of data	2	0
Endpoints appropriate to the aim of the study	2	2
Unbiased assessment of the study endpoint	2	2
Follow-up period appropriate to the aim of the study	2	2
Loss to follow-up less than 5%	2	2
Prospective calculation of the study size	0	0
An adequate control group	1	2
Contemporary groups	0	0
Baseline equivalence of groups	2	2
Adequate statistical analyses	2	2
Total score	19	18

0: not reported, 1: reported but inadequate, 2: reported adequately

Total score of 16–22: low risk of bias; 8–15: moderate risk of bias; 0–7: high risk of bias

MINORS: methodological index for nonrandomized studies

Meta-Analysis Results

A meta-analysis of risk ratios from three prospective studies [8–10] indicated an overall effect size of 0.03 (95% CI: 0.01 to 0.17). The associated P-value was > ,0.0001which underscores the statistical significance of the observed relationship. Notably, heterogeneity analysis revealed an I² value of 0%, indicating minimal variability across the included studies. Further details can be found in the forest plot shown in Fig. 2.

Fig. 2.

Forest plot of risk ratios for the association between SGS and GER

Discussion

GER is common in infants and young children. Otolaryngologists are particularly concerned with the direct mucosal damage caused by stomach acid in the upper airway, as GERD is often associated with airway disease symptoms.

Researchers are increasingly recognizing GER as a contributing factor to various pediatric airway disorders such as croup, recurrent pneumonia, asthma, reactive airway disease, and SGS] 13, 15[. Some studies have suggested that up to 30% of children with airway diseases may experience GER-related problems [16]. Early observations by Bain et al. in 1983 suggested a potential link between GERD and SGS [17]., prompting further investigation by Little et al., who used a canine model to demonstrate the effects of acid exposure on tracheal lesions at the histological level [6[.

In 1998, Walner et al. examined 74 pediatric patients with SGS to assess the presence of GERD. Among these patients, 55 (74%) underwent dual-probe testing (upper and lower), whereas 19 (26%) underwent only lower-probe testing. The results of the upper probe testing indicated that none or very few of the 55 patients showed any risk of pathological airway symptoms associated with reflux. Conversely, lower probe testing revealed that 73 (98.65%) patients were at a marginal risk of experiencing such symptoms, with 24 (32.43%) classified as being at high risk for reflux-associated pathologic symptoms [10[. Yellon et al. examined the histological evidence of esophagitis through esophageal biopsy in 34 patients diagnosed with SGS. Their findings revealed that 68% of patients with SGS had a positive biopsy result indicating GERD [8[. Halstead et al. emphasized the importance of early and aggressive diagnosis and treatment of GERD before contemplating surgery. By adopting proactive management strategies, they observed a notable reduction in the failure rate of endoscopic repair from 1 in 5.7 patients to 1 in 25 patients. Additionally, surgery was avoided in 35% (9 of 26) of the patients by effectively controlling gastric acid levels and promoting the resolution of inflammation through medical interventions to the fullest extent possible [11[.

To our knowledge, this is the first systematic review to evaluate the association between GERD and SGS in pediatric patients, including 149 patients diagnosed with SGS. However, some limitations must be addressed for a careful interpretation of our results. In this systematic review, our findings relied on the accuracy and completeness of previously published articles. In addition, in our database search, we retrieved published literature and, therefore, could not correct biases that may have arisen during the publication process, such as publication bias favoring positive results, showing a link between reflux and SGS.

Conclusion

This systematic review provides valuable insights into the association between GERD and SGS. Understanding this association is essential for optimizing patient outcomes by accurately diagnosing the disease and treating patients with a high index of suspicion.

Authors’ Contribution

NFA contributed to the work as a first author, conceptualized the idea, designed the study protocol, edited the PROSPERO proposal, assembled the research team, created the tables, and reviewed, edited, and proofread the final manuscript. MAG performed the literature review, extracted the data, finalized the tables, drafted the manuscript, and edited and finalized the manuscript. GS resolved conflicts and reviewed and proofread the final manuscript. MHH reviewed and proofread the final manuscript. FS supervised, reviewed, and proofread the final manuscript. All the authors have read and approved the final manuscript.

Data Availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Declarations

Conflicts of interest

The authors declare no conflicts of interest.