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Gastroesophageal Reflux in Infants and Children

Lee Bass, MD
Clinical Practice Director and Director of Endoscopy, Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago; Assistant Professor of Pediatrics, Northwestern University Feinberg School of Medicine
Disclosure: Dr. Bass has no industry relationships to disclose and does not refer to products that are still investigational or not labeled for the use in discussion. Read Dr. Bass' profile
Dr. Mary Nevin, Course Director; Vita Lerman, Planning Committee Member; Dr. John X. Thomas, Senior Associate Dean for Medical Education; Genevieve Napier, CME Director, Tara Scavelli and Jennifer Banys, CME Project Specialist have nothing to disclose.

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Educational objectives

At the conclusion of this activity, participants will be able to:

  • Distinguish physiologic gastroesophageal reflux (GER) from gastroesophageal reflux disease (GERD)
  • Identify children at high risk for GERD and its complications
  • Select appropriate treatment approach

Estimated time to complete: 0.5 hours
CME Credit: 0.5

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Gastroesophageal reflux (GER) occurs in over two-thirds of otherwise healthy infants and is best managed with lifestyle changes. However, proton pump inhibitors (PPIs) are increasingly prescribed to treat uncomplicated GER in children. To avoid unnecessary diagnostic procedures or pharmacologic therapy, all practitioners who treat children with reflux-related disorders need to be able to distinguish patients with a simple presentation of physiologic gastroesophageal reflux (GER) from patients who exhibit symptoms of gastroesophageal reflux disease (GERD). To promote appropriate care for children with gastroesophageal reflux, this article will review recommendations from the recent clinical report from the American Academy of Pediatrics that highlights guidelines from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN)[1, 2]. 

Introduction 

Gastroesophageal reflux (GER) is a common occurrence in childhood and infancy. GER is defined as passage of gastric contents into the esophagus. More than two-thirds of healthy infants will experience GER and GER is discussed at a large proportion of routine infant visits. GER is a common reason for parents to seek medical care and is a frequent reason for referral to gastroenterology subspecialists.   

It is necessary to distinguish between GER and gastroesophageal reflux disease (GERD). GERD encompasses troublesome symptoms or complications associated with GER. It is imperative that clinicians who treat children be able to identify children with GERD, who may benefit from further evaluation and treatment.   

Physiology and natural history 

GER is considered a normal physiologic process that occurs several times a day in healthy infants, children and adults. Transient relaxation of the lower esophageal sphincter (LES) permits gastric contents to enter the esophagus. Regurgitation or spitting up is visible in most infants and reported to occur daily in 50% of all infants[3]. About half of infants 0-3 months and two-thirds of infants 4-6 months will spit up at least 1 time a day; 17% and 23%, respectively, will also spit up at least 4 times per day. By age 13-14 months, fewer than 5% of infants spit up most of their feedings. GER is not a significant problem in older children or adolescents.   

A number of natural barriers exist to prevent GER. These include the LES, the crural diaphragm and the phreno-esophageal ligament. These act in concert to keep refluxate in the stomach. In addition, the stomach forms an acute angle, known as the angle of HIS, in order to prevent refluxate in a normal individual. As the infant grows and matures, these natural defenses develop thus explaining the decrease in incidence of GER and GERD as infants approach 1 year of age. Thus, conservative recommendations are more appropriate in children with GER.   

There are many pathogenic factors that can lead to GERD. Primary mechanisms can be due to transient lower esophageal sphincter relaxation and impaired esophageal clearance. Secondary mechanisms include increased intra-abdominal pressure, decreased gastric compliance, delayed gastric emptying and reduced esophageal capacitance. The esophageal complications may be due to either defective tissue resistance or noxious composition of the refluxate. Mechanisms of airway complications (extra-esophageal manifestations) can be due to either increased vagal reflexes or impaired airway protection. 

The natural history of GERD as it moves through childhood is well defined.  Infants who had frequent GER in the first 2 years life have an increased relative risk for GER in later childhood. Conversely, adults with GERD symptoms had increased rates of gastrointestinal complaints in childhood. As a result, moving forward, premature and small for gestational age infants, who are at high risk for GERD, may be at increased risk of esophageal cancer. There is an increase in GERD symptoms in adolescents starting at age 14.  

When to suspect GERD 

It is extremely important to distinguish GER from GERD. The typical patient with GER is well grown, typically feeds very well and spits up formula following feeding without any change of personality or discomfort. This is the example of the “happy spitter.” Noting appropriate weight gain over time in infants is a very reassuring sign that the patient has GER and that it is benign and self limited.  In infants, weight loss or poor weight gain is a crucial warning sign for GERD.  

GERD encompasses troublesome symptoms or complications associated with GER. Symptoms that maybe be associated with GERD in infants include irritability, weight loss or poor weight gain, difficulty feeding, recurrent regurgitation with/without vomiting, hematemesis, wheezing, stridor, cough or hoarseness.  

In infants, the frequency and severity of symptoms are not reliable to predict the presence or severity of esophagitis. Children with GERD aged 1-5 years have an increased incidence of cough, anorexia/feed refusal and regurgitation compared with adolescents, who have higher incidence of heartburn. Other possible symptoms may include unexplained crying, sleep disturbance and abdominal pain.   

Manifestations may not be limited to the esophagus. Children with GERD have increased risk of dental erosions. Sandifer syndrome is a specific manifestation of pediatric GERD and consists of abnormal posturing with head tilt, torticollis, and arching of the back. Sandifer syndrome must be differentiated from seizures, infantile spasms and dystonia. It may be a vagally mediated reflex response to esophageal acid exposure. The condition typically resolves with antacid therapy. Other signs and symptoms are included in TABLE 1. Older children who can communicate their symptoms with more accuracy will have more heartburn and dysphagia.   

Table 1: Signs & Symptoms Associated with GERD

 
Symptoms  Signs
Recurrent regurgitation/vomiting  Esophageal stricture
Weight loss/poor weight gain  Esophagitis
Irritability (infants)  Barrett’s esophagus
Ruminative behavior  Laryngopharyngeal inflammation
Heartburn or chest pain  Recurrent pneumonia
Hematemesis  Anemia
Dysphagia, odynophagia  Dental erosion
Wheezing  Feeding refusal
Stridor Dystonic posturing (Sandifer syndrome) 
Cough Apnea spells 
Hoarseness Apparent life-threatening events 

In patients with esophagitis, GERD may be a cause but physicians must also consider other causes. (See Table 2.)

  

Table 2: Esophagitis Causes

 
Eosinophilic esophagitis  
Infectious esophagitis due to either candida, herpes simplex virus, or cytomegalovirus 
Crohn’s disease 
Vomiting or bulimia 
Pill induced esophagitis 
Graft versus host disease 
Caustic ingestion 
Esophagitis due to sclerotherapy or banding of esophageal varices 
Radiation therapy 
Chemotherapy 
Bullous skin diseases 
Lymphoma 

Recurrent pneumonia may be a complication of reflux presumably as a result of failure of airway protective mechanisms. However, no test can determine if GERD is causative. Treatment may require nissen fundoplication, nasogastric or naso-jejunal feeding. However, elimination or reduction of reflux does not guarantee prevention of recurrent pneumonias. Additionally, a diagnosis of apparent life-threatening event (ALTE) warrants a consideration of causes other than GERD. 

Long term GERD related complications include erosive esophagitis, Barrett’s esophagus (BE), stricture, and adenocarcinoma. BE results from a metaplastic change in the esophagus where squamous epithelium is replaced by columnar epithelium. Esophageal mucosal injury from acid or bile reflux is critical to development of BE. BE may result in esophageal adenocarcinoma if there is progression. H. pylori testing is not recommended in patients with GERD. 

There are specific groups of patients who are at particular risk for severe GERD. Premature infants are a commonly seen population at particular risk. Patients with cystic fibrosis have significant GERD as a manifestation of their disease. Esophageal atresia, hiatal hernia, and obesity can have significant associated GERD symptoms. A family history of GERD and GERD related complications is associated with GERD in patients.   

There is increased frequency and severity of GERD among infants and children with neurological impairment (NI). This results due to muscle coordination problems, dysfunction of enteric nervous system impacting GE, and medications. These children are at increased risk of aspiration pneumonia, unexplained irritability, body posturing and arching, and overt or occult bleeding. The clinical diagnosis is frequently hampered due to difficult communication with the patient. Signs and symptoms to look for in this population may include vomiting, unexplained irritability, uncoordinated swallow or oral-pharyngeal dysfunction, coughing between meals, malnutrition, arching, feeding refusal, recurrent pneumonia, dental erosions or upper GI bleeding. Rumination is common in NI.   

High risk populations are summarized in Table 3.

  

Table 3: Populations at High Risk for GERD and its Complications

 
Cystic fibrosis 
Esophageal atresia 
Neurologic impairment 
Hiatal hernia 
Obesity 
Family history of GERD or GERD-related complications 
Premature infants 

 

Diagnosis 

GERD remains a clinical diagnosis and there are several aspects of medical history to consider in a patient with suspected GERD. While many infants and children with uncomplicated GERD will respond to initial treatment, the patient who is not responding to initial therapy becomes a diagnostic dilemma. A child who is demonstrating red flags of recurrent forceful vomiting, blood or bile in the vomit, weight loss or absolute refusal to feed should be referred to a pediatric gastroenterologist as soon as possible. (See Table 4.) These children may benefit from further evaluation.   

 

Table 4: Warning Signs Suggestive of a Non-GERD Diagnosis

 
Bilious vomiting 
Consistently forceful vomiting 
Hepatosplenomegaly 
GI bleeding 
Bulging fontanelle 
Fever 
Diarrhea 
Onset of vomiting after 6 months of life 
Suspected genetic or metabolic syndrome 
Macro/microcephaly 
FTT 

 

A feeding and dietary history detailing the amount and frequency of feeding may be helpful in the evaluation of overfeeding. Behavior during feedings, such as choking, gagging, cough, arching of back, discomfort or feeding refusal, may help the clinician direct therapy and diagnostic testing. The preparation of formula, changes in feeding type or feeding technique, burping history, and intolerance to types of formula or food are also useful to note.   

The pattern of vomiting may provide further clues as to the diagnosis. The clinician should inquire about the frequency and amount, and whether the vomiting is painful and forceful. The presence of blood or bile in the emesis may provide a warning sign as to non-GERD causes of vomiting. Other important aspects of the history include whether there is associated fever, lethargy or diarrhea, if the emesis includes digested vs. undigested food, sleep history and nocturnal symptoms. The differential diagnosis of vomiting in children is broad and can include metabolic/endocrine conditions, renal disease, neurologic disorders, GI obstruction, infections, toxic, cardiac, allergic, GI disorders among others. Pyloric stenosis, malrotation and achalasia are among conditions that may masquerade as GERD.   

Additional aspects of the history that may assist the clinician in making a diagnosis of GERD include prematurity, growth and development, past surgery/hospitalizations, newborn screen, recurrent illnesses (such as croup, pneumonia, asthma, otitis media, sinusitis), thyroid disease, cough, eczema, diarrhea, dental erosions. Clinicians should also ask about symptoms of hoarseness, fussiness or hiccups, celiac disease, and other chronic conditions.   

In checking family history, clinicians should inquire about pertinent history of esophageal dilatations, esophageal cancer, Barrett’s esophagus, food allergies including use of hypoallergenic formulas, esophageal surgeries, thyroid disease, celiac disease, or functional dyspepsia. The practitioner should also ask about medication use including over-the-counter antacids, H2 receptor antagonists (H2RA), proton pump inhibitors (PPI), and medications affecting motility (anticholinergics, opioids, antibiotics, cancer chemotherapy including vincristine). 

Testing 

No single symptom or cluster of symptoms can be reliably used to diagnose esophagitis or other complications of GERD in children or predict which patients are likely to respond to therapy. There are a number of GERD questionnaires[4] which show variable accuracy. No single test can rule in or rule out GERD. A thorough history and physical exam remains the best method for diagnosis of GERD. However, there are a number of diagnostic tests, which can provide objective information to the clinician to assist with decision-making and diagnostic dilemmas with GERD.     

Esophageal pH consists of a catheter with a pH sensor placed in the nose and positioned within the esophagus. A related, recently developed test known as BRAVO consists of a capsule with a pH sensor that is placed endoscopically within the esophagus and has a wireless recorder. This allows for a longer duration of time in the esophagus and the patient does not need an NG tube in place during the procedure. Esophageal pH monitoring detects acid reflux and provides a temporal association between acid GER and symptoms. This method may also be used to assess adequacy of treatment and dosage. Normal values exist for pediatrics. However, some weaknesses exist. The test cannot detect non-acid reflux, cannot differentiate swallowed from refluxed acidic material, is insensitive to weak acid events, and the severity of pathologic reflux does not correlate with symptom severity that requires medication to be stopped.  

Multi channel intra-luminal impedance is pH independent and measures change in resistance to electrical current flow between 2 sensors. There are 7 sensors on the probe measuring both movement throughout the esophagus and pH sensors as well. Impedance detects non-acidic GER episodes and is ideal for detection of post-prandial reflux, while differentiating reflux from swallow. Impedance is able to accurately assess full column reflux and the sensitivity is equal to pH probe in untreated patients and is superior to pH probe in treated patients. However, there are no normal values in pediatric age group, analysis is time consuming, and it is unclear how results change management.   

Esophagogastroduodenoscopy enables visualization and biopsy of esophageal and gastric epithelium. This allows the practitioner to determine the presence of esophagitis and/or GERD-related complications. It also discriminates between GERD-related, infectious and allergic esophagitis. Disadvantages of endoscopy include sedation and poor correlation between endoscopic appearance and histology. The relationship between esophagitis and extra-esophageal symptoms is not clear.    

An upper GI study is useful for detecting anatomic abnormalities such as malrotation, strictures and achalasia. Upper GI cannot discriminate between physiologic and non-physiologic GER episodes. According to the new guidelines, routine upper GI tract radiographic imaging to diagnose GER or GERD is not justified. 

Gastric scintigraphy detects gastroesophageal emptying and may demonstrate aspiration. While this test can assist with esophageal transit, it is not standardized and has a limited period of observation. It is not routinely recommended for evaluation of children with GERD. Biomarkers in bronchi and saliva that can be obtained by an otolaryngologist or pulmonologist during direct laryngoscopy and bronchoscopy include lipid-laden macrophages, pepsin and bile. The correlation between these markers and GERD is weak and these markers are not useful in clinical practice.   

Management 

There are multiple lifestyle modifications that we can recommend to children with GERD. These can include avoidance of caffeine, tomato, spicy or citrus containing foods, deep-fried or fatty foods, and chocolate, as all of these relax the LES or delay emptying of the stomach. Other recommendations may include weight loss, particularly in patients with a higher body mass index, positioning changes during sleep such as raising the head of the bed 30 degrees or sleeping in the left lateral decubitus position. Patients should avoid eating within 1 hour prior to sleep and avoid use of cigarette and tobacco products.   

There are several evidence-based treatment recommendations that have been endorsed by NASPGHAN. In the infant with recurrent regurgitation, a thorough history and physical examination with attention to warning signs is sufficient to allow the clinician to establish a diagnosis of GER. In infants with uncomplicated regurgitation, parental education, reassurance, and anticipatory guidance are recommended. Thickening of formula can be considered in addition to parental education, reassurance and anticipatory guidance. If symptoms worsen or do not resolve by 12-18 months of age, or warning signs develop, referral to a pediatric gastroenterologist is recommended.   

In infants, it has been demonstrated that children will have decreased acid reflux in prone position. This has fallen out of favor over the recent decades due to recommendations for supine sleeping as a lower risk for SIDS. However, if the infant is observed and awake, prone positioning may be useful following feeds. After age 1 year, the risk of SIDS is negligible and children can be encouraged to sleep on their stomachs. While lying in the left lateral decubitus position decreases reflux, side lying or any devices that provide side lying cannot be recommended.  

In otherwise normal infants without any symptoms associated with GERD but who present with unexplained crying, irritability or distressed behavior, there is no evidence that acid suppression will improve or resolve symptoms. Some children may manifest irritability as a result of milk protein allergy or milk protein intolerance. A trial of hypoallergenic formula, or, in breastfed infants, a trial of 2-4 week milk and soy elimination by the mother may be useful and help with resolution of these symptoms. Adequate burping technique should also be taught to the caregivers.   

Pharmacologic management 

There are several classes of drugs that we utilize in the treatment of GERD. Histamine 2 receptor antagonists (H2RAs) such as ranitidine, nizatidine, cimetidine and famotidine, have been demonstrated to increase healing of esophagitis when compared to placebo. H2RAs are associated with healing rates of esophagitis of approximately 60%-70%[5, 6], while proton pump inhibitors (PPIs) are associated with healing rates of 90%-100%[2, 7]. 

The most commonly used PPIs are omeprazole, esomeprazole, lansoprazole and pantoprazole. These medications inactivate the H+/K_+ ATPase pump in the stomach. Omeprazole demonstrated significant decrease in gastric pH, esophageal pH, number of acid reflux episodes and duration of acid reflux episodes over placebo. Esomeprazole improves GERD symptoms in children 1-11 years of age[8]. Pantoprazole provides resolution of GERD in children 5-11 years of age[9]. Esomeprazole improves GERD symptoms in adolescents 12-17 years of age[10].   

It is worthwhile to note that for the solely fussy infant, there is no difference between pantoprazole and placebo in symptom change in infants 1-11 months of age. In fact, many studies have shown that PPIs do not improve symptoms in infants. Omeprazole shows no improvement in cry-fuss time. Lansoprazole shows no improvement in crying, back arching, wheezing or regurgitation compared to placebo. Esomeprazole produces no change in bolus reflux despite significant acid suppression[11-13]. 

If a PPI is selected, consider using the smallest, most effective dose. Long term PPI use is safe and well tolerated. However, children on PPI are at higher risk for C. difficile infections and the use of PPI or H2RA can be associated with increased risk of community and hospital acquired pneumonia. Furthermore, small bowel bacterial overgrowth occurs more frequently among long-term PPI users. 

In patients with esophagitis, management requires PPI therapy for at least 3 months. The physician may consider increasing the dose at 4 weeks if symptom control is inadequate. The efficacy of treatment can be monitored by symptoms. Most patients require a once daily PPI to relieve symptoms and heal esophagitis.  Endoscopic monitoring is useful in patients with atypical signs or symptoms, persistent symptoms on therapy, or higher grades of damage at the time of diagnosis. A trial dose reduction or withdrawal after 3-6 months on treatment is recommended. The PPI may need to be tapered and not stopped abruptly.  Recurrence after repeated trials of PPI indicates chronic/relapsing GERD that requires long-term PPI therapy or anti-reflux surgery. 

Another class of drugs enhances gastric emptying. Erythromycin at a low dose is a motilin receptor agonist, which improves antral contractility and gastric emptying. Adult studies show benefit in improving GERD. Neonatal randomized controlled studies demonstrate that low dose erythromycin did not improve reflux burden but may improve time to full feeds. Metoclopramide is a 5-hydroxytryptamine (5HT4) agonist and dopamine antagonist, which increases esophageal, fundic and antral contractions. However, FDA implemented a Black Box warning in 2009 regarding long term and high dose use. In many cases, the risks of metoclopramide outweigh the benefits. Baclofen reduces transient LES relaxations and acid reflux. There is insufficient support to justify the routine use of metoclopramide, erythromycin, bethanechol, or domperidone for GERD. 

Transpyloric feeds have comparable success to anti-reflux surgery in preventing aspiration pneumonias and may be beneficial in the neonatal population to prevent apnea and bradycardia. With these feedings, the reflux burden is reduced but not eliminated. 

Other considerations 

Barrett’s esophagus (BE), a common serious complication of GERD, is defined as displacement of the squamocolumnar junction proximal to the gastroesophageal junction with histological evidence of specialized intestinal metaplasia on biopsy. Endoscopically suspected BE is rare in children and adolescents but older age and the presence of hiatal hernia are possible risk factors for development of BE. The presence of dysplasia is managed in accordance with adult guidelines. If dysplasia is absent a follow-up endoscopy every 3-5 years is recommended. However, symptoms are a poor guide to treatment adequacy. Standard management includes treatment with long-term PPI or anti-reflux surgery. Long-term, it is unclear whether progression of dysplasia is slowed by acid control. 

Neurologically impaired children with GERD are often resistant to medical treatment and may need thickened feeds, acid suppression and G or GJ feeds. Surgical options of fundoplication in these patients are associated with high risk of complications. 

Anti-reflux surgery should be considered only in children with GERD and failure of optimized medical therapy, or long-term dependence on medical therapy where compliance or patient preference preclude ongoing use, or life-threatening complications. This is generally in a child who fails medical therapy, is dependent on aggressive or prolonged medical therapy, is significantly non-adherent with medical therapy, has persistent asthma or recurrent pneumonia, or has life threatening complications of GERD. 

Summary  

The clinician must be sure to differentiate between GER and GERD in infants and children. A careful history and physical exam may help determine which children might respond to a trial of H2 receptor antagonists or possibly PPI therapy. Children who are not responding to therapy, children at high risk for GERD or children who are demonstrating warning signs associated with GERD or a non-GERD diagnosis should be referred to a pediatric gastroenterologist for further evaluation.   

References  

[1.] Lightdale JR, Gremse DA. Gastroesophageal reflux: management guidance for the pediatrician. Pediatrics 2013;131(5):e1684-1695. 

[2.] Vandenplas Y., 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(4):498-547. 

[3.] Nelson SP, et al. Prevalence of symptoms of gastroesophageal reflux during childhood: a pediatric practice-based survey. Pediatric Practice Research Group. Arch Pediatr Adolesc Med 2000;154(2):150-154. 

[4.] Kleinman L, et al. The infant gastroesophageal reflux questionnaire revised: development and validation as an evaluative instrument. Clin Gastroenterol Hepatol 2006;4(5)588-596. 

[5.] Cucchiara S, et al. Cimetidine treatment of reflux esophagitis in children: an Italian multicentric study. J Pediatr Gastroenterol Nutr 1989;8(2)150-156. 

[6.] Simeone D, et al. Treatment of childhood peptic esophagitis: a double-blind placebo-controlled trial of nizatidine. J Pediatr Gastroenterol Nutr 1997;25(1):51-55. 

[7.] Boccia G, et al. Maintenance therapy for erosive esophagitis in children after healing by omeprazole: is it advisable? Am J Gastroenterol 2007;102(6):1291-1297. 

[8.] Gilger MA, et al. Safety and tolerability of esomeprazole in children with gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2008;46(5):524-533. 

[9.] Tolia V, et al. Multicenter, randomized, double-blind study comparing 10, 20 and 40 mg pantoprazole in children (5-11 years) with symptomatic gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2006;42(4):384-391. 

[10.] Gold BD, et al. Safety and symptom improvement with esomeprazole in adolescents with gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2007;45(5):520-529. 

[11.] Moore DJ, et al. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. J Pediatr 2003;143(2):219-223. 

[12.] Omari T, et al. Pharmacodynamics and systemic exposure of esomeprazole in preterm infants and term neonates with gastroesophageal reflux disease. J Pediatr 2009;155(2):222-228. 

[13.] Orenstein SR, et al. Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J Pediatr 2009;154(4):514-520.e4.

 


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