Childhood gastroesophageal reflux disease: A comprehensive review of disease, diagnosis, and therapeutic management

Abstract

Gastroesophageal reflux disease (GERD) affects both adults and children, although the symptoms differ significantly between these groups. While adults typically experience heartburn and regurgitation, children may present with more subtle signs, such as failure to thrive, chronic cough, wheezing, and Sandifer syndrome. Diagnosing GERD in children necessitates a multifaceted approach due to the diverse symptomatology and challenges in communication. Clinical assessment serves as the cornerstone of diagnosis, supported by tools like pH monitoring, esophageal impedance testing, and upper gastrointestinal endoscopy. Imaging studies, such as barium swallow, can also provide valuable insights into anatomical abnormalities and the extent of reflux. Treatment strategies for pediatric GERD include lifestyle adjustments, pharmacotherapy, and, in severe cases, surgical interventions. Lifestyle adjustments may involve changes in feeding patterns, positional therapy, and weight management. Pharmacological options range from acid suppression with proton pump inhibitors or histamine-2 receptor antagonists to surgical procedures like fundoplication for refractory cases. Personalized management is essential, considering the child’s age, symptom severity, and the presence of complications. This article aims to offer a comprehensive understanding of pediatric GERD by utilizing current research to enhance clinical approaches and improve patient outcomes.

Key Words: Pediatric gastroesophageal reflux disease; Gastroesophageal reflux disease; Childhood reflux; Gastroesophageal reflux disease diagnosis; Gastroesophageal reflux disease management; Pediatric gastrointestinal disorders

Core Tip: This comprehensive review explores the unique presentation, diagnosis, and management of gastroesophageal reflux disease (GERD) in children, emphasizing the differences from adult GERD. It highlights diagnostic challenges, including the use of pH monitoring, impedance testing, and endoscopy, and offers a detailed analysis of treatment strategies. From lifestyle modifications and acid suppression therapy to surgical interventions, the review underscores the importance of individualized management approaches tailored to age, symptom severity, and complications. This article serves as a valuable resource for improving the clinical approach to pediatric GERD and enhancing patient outcomes.

INTRODUCTION

Gastroesophageal reflux disease (GERD) is a common gastrointestinal (GI) disorder characterized by the regurgitation of gastric contents into the esophagus. The cause of this can be attributed to intrinsic and/or structural abnormalities that lead to the disruption of the esophagogastric junction barrier[1]. Although it is a disease most commonly seen in adults, gastroesophageal reflux (GER) is also seen in the pediatric population. Its prevalence is 50% in infants younger than 2 months of age, 60%–70% in infants 3–4 months of age, and 5% of infants by 12 months of age[2,3]. However, the data on pediatric populations older than 12 months are limited, with a prevalence determined to be 0.84 per 1000 people[4].

Regarding the clinical presentation of GERD in the pediatric population, it is important to distinguish between physiological regurgitation (spitting) and pathologic GERD. Spitting peaks at 4 months of age, when gastric contents are regurgitated after feeding due to the immature and developing gastroesophageal junction[3]. In those with GERD, there is an array of possible additional symptoms, such as heartburn, epigastric pain, vomiting, inconsolable crying, hematemesis, feeding refusal, hoarseness, wheezing, disturbed sleep, and failure to thrive[5]. Sandifer syndrome is characterized by spasmodic torsional dystonia with arching of the back, torsion of the neck, and lifting of the chin, a specific finding in children with GERD[6]. In older children, halitosis and dental erosions may also be present[7].

Several risk factors, diseases, and abnormalities can contribute to GERD in infants. Congenital GI disorders, such as congenital diaphragmatic hernia, absence of diaphragmatic crura, omphalocele, gastroschisis, esophageal atresia, and intestinal malrotation, have been reported[8]. Obesity has been associated with increased transient relaxation of the lower esophageal sphincter and higher intragastric pressure[9]. GERD is more frequently seen in patients with cystic fibrosis and interstitial lung disease due to the mechanical impact on the diaphragm caused by hyperinflation[10]. Table 1 outlines symptoms, risk factors, and complications associated with pediatric GERD[5-13]. Complications in children with GERD vary widely. Malnutrition caused by regurgitation leads to failure to thrive and protein-losing enteropathy with digital clubbing[14]. The reflux of acid can cause peptic esophagitis, which contributes to hematemesis, melena, and iron-deficiency anemia[11]. It may also result in peptic esophagitis and esophageal mucosal dysplasia[15]. Reflux is a known trigger for chronic cough, bronchial asthma, bronchitis, pneumonia, laryngitis, and interstitial fibrosis[12,13].

Table 1 Symptoms, risk factors, and complications associated with pediatric gastroesophageal reflux disease.

Category	Details	Ref.
Symptoms	Vomiting, regurgitation, feeding refusal, failure to thrive, Sandifer syndrome	Gonzalez Ayerbe et al[5], Czinn and Blanchard[6]
Extraesophageal symptoms	Chronic cough, wheezing, dental erosions, halitosis	Baird et al[7]
Risk factors	Prematurity, obesity, neurologic impairments, congenital anomalies (e.g., esophageal atresia, hernia)	Marseglia et al[8], Pashankar et al[9], Dziekiewicz et al[10]
Complications	Esophagitis, anemia, aspiration pneumonia, chronic lung disease, Barrett’s esophagus	Leung and Chan[11], Gaude[12], Khoshoo et al[13]

DIAGNOSIS

Diagnosing GERD in children continues to be challenging. While diagnostic studies and imaging can assist in excluding other conditions, there is no definitive method for diagnosing pediatric GERD[5]. The diagnostic approach varies based on the child's age and reported symptoms.

Initially, the child's history and physical examination findings are evaluated to identify symptoms or warning signs associated with GERD. If GERD is suspected, lifestyle changes should be considered, such as thickened feedings, dietary modifications, postural adjustments, weight loss, and avoiding secondhand smoke, overfeeding, and eating before bedtime. Progress should be monitored, and if symptoms resolve by 12 months of age, no further workup is required[16]. Improvement should be reassessed, and if symptoms improve, the lifestyle changes should be continued. If symptoms do not improve, further evaluation is necessary to rule out other disorders. This evaluation may include an upper GI barium study, ultrasound, esophageal manometry, a trial of proton pump inhibitors (PPIs), scintigraphy, esophagogastroduodenoscopy, esophageal pH monitoring, and multichannel intraluminal impedance (MII)[16]. Table 2 summarizes the diagnostic tools used for evaluating pediatric GERD[5,16-23].

Table 2 Diagnostic tools for pediatric gastroesophageal reflux disease.

Diagnostic tool	Use	Advantages	Ref.
Clinical history and exam	Identifies symptoms and risk factors	Accessible, non-invasive	Gonzalez Ayerbe et al[5], Friedman et al[16]
PH monitoring	Detects acid reflux (pH < 4); assesses reflux index	Gold standard for acid reflux	Leung and Hon[17], Mousa et al[18]
Multichannel intraluminal impedance	Measures acid and non-acid reflux events	Evaluates atypical symptoms, non-acid reflux	Mousa et al[18]
Upper endoscopy	Detects complications (e.g., esophagitis, strictures)	Direct visualization, biopsy possible	Arasu et al[19], Mousa and Hassan[20], Rosen et al[21]
Barium swallow	Rules out structural abnormalities (e.g., atresia, malrotation)	Useful for anatomical evaluation	Winter[22], Michail[23]
Esophageal manometry	Rules out motility disorders	Identifies achalasia or rumination syndrome	Mousa and Hassan[20], Michail[23]

ESOPHAGEAL PH MONITORING

Esophageal pH monitoring is a reliable and sensitive method for diagnosing GERD. Normally, the esophageal lumen's pH ranges between 3 and 7 in individuals without GERD. By continuously monitoring esophageal pH for 24 hours, GERD can be identified based on specific criteria: (1) The frequency of pH drops below 4; (2) The duration of these drops; and (3) The reflux index, which is the percentage of time that pH stays below 4 during the 24-hour period[17]. For infants, a reflux index above 11% is abnormal, while in older children, an index above 7% is considered abnormal[6]. However, 24-hour pH monitoring has limitations, particularly in young children or those receiving acid-lowering therapy, where it may underestimate reflux severity[18]. In such cases, MII-pH monitoring offers significant advantages by detecting acid, weakly acidic, and non-acid reflux events. MII-pH is particularly useful in establishing temporal associations between reflux and symptoms, making it the diagnostic modality of choice in pediatric GERD when available. This approach provides a more comprehensive evaluation of GERD, especially in cases with atypical or extraesophageal symptoms[18].

ENDOSCOPY

A normal upper GI endoscopy does not rule out GERD, as its negative predictive value is low[19]. The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition do not recommend upper GI endoscopy for diagnosing GERD in infants and children but suggest it in cases with significant clinical issues, such as recurrent vomiting, unexplained anemia, hematemesis, or for use in high-risk groups[19]. Endoscopy is useful for differentiating GERD from other conditions, such as eosinophilic esophagitis, which requires histopathology for diagnosis. It is also useful for assessing GERD complications, including esophagitis or stricture formation[20]. In children with extraesophageal symptoms, endoscopy can reveal microscopic esophagitis. Both societies recommend performing endoscopy with biopsy to evaluate GERD complications and suspected mucosal disease before escalating therapy[21].

BARIUM CONTRAST RADIOGRAPHY AND ESOPHAGEAL MANOMETRY

Barium swallow and upper GI studies are used to evaluate anatomical abnormalities, such as tracheoesophageal fistula, achalasia, and hiatus hernia[22]. While they can provide a rough assessment of esophageal and gastric transit time and help identify reflux episodes, they lack the sensitivity and specificity required for diagnosing GERD and do not correlate well with 24-hour pH study results[22]. An upper GI series is not recommended for diagnosing GERD in infants and children but can be useful for detecting anatomical abnormalities that cause vomiting, such as esophageal stricture and pyloric stenosis. However, the test relies heavily on the radiologist's interpretation and does not provide information on esophageal function[23]. Esophageal manometry can rule out motility disorders, including rumination syndrome and achalasia, which may mimic GERD symptoms, but there is insufficient evidence to support its use in diagnosing GERD[20].

ULTRASOUND

Ultrasound has a high sensitivity and positive predictive value for GERD as it can evaluate both the esophagus's anatomy and real-time reflux[24]. This non-invasive tool shows fair sensitivity (76%-100%) and specificity (50%-100%) compared to pH studies, according to evidence-based studies. One study observed that Thai children with GERD (n = 22, median age of 1.6 years) had shorter abdominal esophageal lengths, increased cervical and abdominal esophageal wall thickness, and variations in the diameter and angle of his compared to healthy children (n = 23), though these differences were not statistically significant[24]. The test's reliability also depends on the radiologist's experience[25].

MANAGEMENT

Non-pharmacological treatments are essential for managing GER and GERD in infants and children, focusing on conservative measures and dietary adjustments[26].

Postural therapy

Postural strategies after meals, such as maintaining a supine 40-degree anti-Trendelenburg position using specialized beds, are effective in reducing symptoms and acid reflux, although upright positioning may be preferable for daytime reflux episodes[27].

Diet

Dietary interventions include using extensively hydrolyzed protein or amino acid formulas for suspected GERD cases, with challenges in diagnosing cow’s milk protein allergy addressed by tools like the Cow Milk Symptom Score[28]. Thickened feedings, achieved by adding cereal to formula or breast milk, are beneficial, especially for premature infants, and have been shown to reduce regurgitation frequency effectively[29]. Lifestyle changes, such as promoting breastfeeding over formula feeding and avoiding overfeeding, smoking, alcohol, and certain foods (spicy, greasy, caffeinated, peppermint, chocolate), also play crucial roles in managing symptoms[30]. For infants not responding to initial interventions, a trial of hypoallergenic formulas or dietary modifications in breastfeeding mothers is recommended[31]. These non-pharmacological approaches are generally sufficient for managing mild or infrequent GER symptoms, with more intensive therapeutic options reserved for cases requiring careful consideration of symptom control and potential side effects[11].

PSYCHOLOGICAL INTERVENTIONS

Psychological interventions can significantly aid in managing GERD symptoms, particularly in children whose symptoms are exacerbated by stress or anxiety. Cognitive behavioral therapy has been shown to effectively alleviate stress-related symptoms by addressing psychological triggers[32,33]. Similarly, esophageal-directed hypnotherapy offers promise in reducing symptom burden by targeting esophageal hypersensitivity and hypervigilance, which often amplify discomfort[32]. Additionally, diaphragmatic breathing exercises help enhance diaphragmatic function and reduce transient lower esophageal sphincter relaxations (TLESRs), providing a non-invasive method to alleviate symptoms and improve quality of life[32,34]. These psychological approaches serve as valuable adjuncts to conventional GERD treatments, emphasizing a holistic approach to pediatric care. Table 3 outlines lifestyle and dietary modifications for managing pediatric GERD[27-31].

Table 3 Lifestyle and dietary modifications for pediatric gastroesophageal reflux disease.

Intervention	Details	Ref.
Thickened feeds	Adding cereal to formula or breast milk	Duncan et al[29], Forbes[30]
Positional therapy	Upright positioning after feeding	Vandenplas et al[27]
Dietary modifications	Hypoallergenic formula, avoiding overfeeding	Vandenplas et al[28], Lightdale et al[31]
Lifestyle modifications	Breastfeeding, avoiding secondhand smoke, weight management	Forbes[30], Lightdale et al[31]

Medical treatment

There are two primary categories of pharmacologic treatments for GERD: (1) Acid-suppressing agents; and (2) Prokinetic medications. The main types of acid suppressants include antacids, histamine-2 receptor antagonists (H2RAs), and PPIs. While the use of these medications in managing pediatric GERD is largely similar to their use in adults, it is important to adjust the dosage according to the child's weight and carefully select the appropriate drug formulation.

H2RAs work by reducing acid secretion through the inhibition of the histamine-2 receptors on gastric parietal cells. Clinical trials have demonstrated that cimetidine and nizatidine are more effective than placebo in treating erosive esophagitis in children[35,36]. Despite their effectiveness, H2RAs have certain limitations. One significant issue is the development of tachyphylaxis, which can occur as early as six weeks after starting treatment, thus reducing their suitability for long-term use. Additionally, cimetidine has been linked with an increased risk of liver disease and gynecomastia, and these risks may extend to other H2RAs as well[37].

PPIs represent the most powerful category of acid-suppressing medications. They reduce acid secretion by inhibiting the H⁺, K⁺-ATPase enzyme in the canaliculi of gastric parietal cells[38]. Unlike H2RAs, the effectiveness of PPIs does not appear to diminish with long-term use, and they are capable of maintaining a gastric pH above 4 for a longer duration. PPIs have been shown to be effective even in cases of esophagitis that do not respond to high-dose H2RA therapy, with numerous randomized controlled trials in adults demonstrating that PPIs outperform H2RAs in both symptom relief and esophagitis healing[37].

A long-term study in children revealed that extended PPI therapy is relatively safe, with few adverse effects. Common side effects of PPIs, reported in up to 14% of older children and adults, include headaches, diarrhea, constipation, and nausea[36]. Two different approaches to acid-reducing therapy exist: (1) Step-up; and (2) Step-down strategies. The step-up method begins with standard-dose H2RA therapy, followed by standard-dose PPI therapy, and, if needed, higher-dose PPI therapy to achieve symptom control. In contrast, the step-down method starts with a higher dose of PPI therapy to quickly manage symptoms, then transitions to a standard-dose PPI, and finally to H2RA therapy for ongoing management[39]. However, some studies have suggested that the use of acid-suppressing medications, such as H2RAs or PPIs, may increase the risk of pediatric community-acquired pneumonia, gastroenteritis, candidemia, and necrotizing enterocolitis in preterm infants[36].

The rationale for using prokinetic therapy in the management of GERD is supported by evidence indicating that it improves esophageal peristalsis and accelerates gastric emptying. This approach may be particularly beneficial in treating GER in infants and children, especially in cases where acid suppressants alone are unlikely to be effective. While many children with GER find adequate symptom relief through acid suppression therapy, the addition of a prokinetic agent, such as erythromycin, may be considered when further treatment is required[40].

The limitations of current GERD treatments have led to increased exploration of alternative therapies. Baclofen, a gamma-aminobutyric acid(B) [GABA(B)] receptor agonist, has proven effective in reducing TLESRs and alleviating GERD symptoms in pediatric patients[41]. However, its widespread use is restricted by its association with central nervous system side effects. Emerging therapies for pediatric GERD offer promising alternatives for refractory cases. ADX10059, a metabotropic glutamate receptor 5 modulator, has shown potential in reducing acid reflux and improving symptoms by targeting TLESRs[42,43]. However, its use is limited by side effects like dizziness, highlighting the need for further research.

Additionally, GABA(B) receptor agonists, such as AZD3355 and AZD9343, show promise in reducing TLESRs and esophageal acid exposure with fewer central nervous system side effects compared to baclofen[42,44]. While preclinical studies are encouraging, their role in pediatric GERD is yet to be established through robust clinical trials. Table 1 provides an overview of pharmacologic treatments for pediatric GERD[5-13]. Table 4 summarizes the pharmacologic treatments for pediatric GERD, highlighting their uses, advantages, side effects[36-38,40,42-44].

Table 4 Summary of pharmacologic treatments for pediatric gastroesophageal reflux disease, including their uses, advantages, side effects, and relevant references.

Drug category	Examples	Uses	Advantages	Side effects	Ref.
H2RAs	Cimetidine, nizatidine	Treats erosive esophagitis, reduces acid secretion	Effective short-term relief, better than placebo	Tachyphylaxis after approximately 6 weeks, risk of liver disease, gynecomastia with cimetidine	Canani et al[36], Orenstein et al[37]
Proton pump inhibitors	Omeprazole, lansoprazole	Treats GERD, maintains gastric pH > 4, effective for esophagitis resistant to H2RAs	Long-term effectiveness, better symptom control	Headaches, diarrhea, nausea, increased risk of infections (e.g., pneumonia)	Canani et al[36], Illueca et al[38]
Prokinetic agents	Erythromycin	Improves esophageal peristalsis, accelerates gastric emptying	Helpful in cases where acid suppressants are insufficient	Potential gastrointestinal discomfort, antibiotic-related side effects	Chicella et al[40]
Gamma-aminobutyric acid(B) receptor agonists	Baclofen, AZD3355, AZD9343	Reduces TLESRs	Promising for refractory cases, fewer CNS effects with newer agents	Baclofen: CNS side effects; AZD3355 and AZD9343: Not yet validated in pediatrics	Lehmann[42], Kuo and Holloway[44]
Metabotropic glutamate receptor 5 modulators	ADX10059	Reduces acid reflux, targets TLESRs	Potential for symptom improvement in GERD	Dizziness, limited data, needs further research	Lehmann[42], Keywood et al[43]

CNS: Central nervous system; GERD: Gastroesophageal reflux disease; H2RAs: Histamine-2 receptor antagonists; TLESRs: Transient lower esophageal sphincter relaxations.

Surgical

Antireflux surgery is often considered for children who have not responded to medical management, particularly those with neurologic impairments, where GERD can significantly impact their quality of life[45]. Laparoscopic approaches have largely replaced open surgeries, with the Nissen fundoplication being the preferred method due to its effectiveness in controlling reflux symptoms and preventing complications[46,47]. In some cases, children with delayed gastric emptying may benefit from a pyloroplasty performed concurrently with fundoplication, although this is still debated due to the potential for increased short-term complications[48]. Additionally, surgical options such as gastrojejunostomy and total esophagogastric dissociation may be considered in complex cases where fundoplication is not feasible or has failed[49,50].

In addition to traditional surgical options, emerging techniques such as magnetic sphincter augmentation (MSA) and transoral incisionless fundoplication (TIF) offer promising alternatives for select pediatric GERD patients[32,51]. MSA involves placing a magnetic ring around the lower esophageal sphincter to augment its function, making it a viable option for patients with regurgitation refractory to PPIs. TIF, an endoscopic approach, creates a valve at the gastroesophageal junction and is particularly suitable for patients without large hiatal hernias[18,32,51]. These techniques provide less invasive options while addressing specific clinical needs, though their long-term efficacy in children requires further investigation.

LIMITATIONS

While this review provides a comprehensive overview of pediatric GERD, some limitations must be acknowledged. A significant limitation is the scarcity of robust clinical trial data specific to pediatric populations for many emerging therapies. Most evidence for newer pharmacological agents is derived from adult studies or preliminary trials, underscoring the urgent need for pediatric-specific research. Additionally, the long-term outcomes of both pharmacological and surgical interventions remain insufficiently documented, raising concerns about potential complications and their impact over time. Furthermore, non-pharmacological interventions, such as psychological therapies and dietary modifications, though promising, are underexplored in the current literature. These gaps highlight the need for further research to refine and personalize diagnostic and therapeutic approaches for pediatric GERD.

CONCLUSION

Childhood GERD requires a nuanced approach due to the diverse range of symptoms and the challenges associated with diagnosis in younger patients. Effective management hinges on a thorough clinical assessment, supported by appropriate diagnostic tools like MII-pH monitoring and endoscopy, to accurately identify and evaluate the condition. Emerging diagnostic modalities offer significant promise in improving the precision and reliability of GERD evaluation, particularly in distinguishing it from other conditions with overlapping symptoms.

Treatment strategies should be personalized, with lifestyle modifications and pharmacologic interventions forming the cornerstone of therapy. For refractory cases or when complications arise, surgical interventions such as fundoplication or emerging techniques like MSA provide viable options. Psychological therapies and dietary interventions also warrant greater incorporation into management protocols, particularly for children with complex or stress-exacerbated symptoms. Figure 1 illustrates the diagnostic and management algorithm for pediatric GERD. The ongoing advancement in understanding pediatric GERD will continue to inform and refine treatment protocols, ensuring better outcomes and improved quality of life for affected children. Future efforts should focus on developing standardized diagnostic and management algorithms for pediatric GERD to guide clinicians in both routine and challenging cases. Long-term studies are crucial to evaluate the outcomes of pharmacologic, surgical, and non-pharmacologic interventions to address the current gaps in knowledge. Continued research and adaptation of clinical practices are essential to meet the evolving needs of this patient population.

Figure 1  Flowchart illustrating the diagnostic and management algorithm for pediatric gastroesophageal reflux disease. The flowchart outlines step-by-step guidance, starting from symptom evaluation and diagnosis to the implementation of lifestyle modifications, pharmacologic interventions (e.g., histamine-2 receptor antagonists, proton pump inhibitors), and surgical options if necessary. The algorithm emphasizes a structured approach tailored to the severity of symptoms and the response to initial treatment. GERD: Gastroesophageal reflux disease; GI: Gastrointestinal; H2RAs: Histamine-2 receptor antagonists; PPIs: Proton pump inhibitors.

ACKNOWLEDGEMENTS

I extend my gratitude to the Department of Internal Medicine at LSU Health Shreveport for providing the academic resources essential for this project.