• Gastroesophageal reflux (GER) frequently resolves most commonly by 1 year of age. However, gastroesophageal reflux disease (GERD) can become a chronic condition in some children.

• Regurgitation is the predominant symptom in infantile GERD. In older children, abdominal pain predominates. Both groups can present with extraesophageal symptoms (e.g., respiratory manifestations).

• GERD is optimally diagnosed by clinical suspicion and a response to therapy (i.e., most frequently acid suppression), but diagnostic testing such as upper endoscopy may be indicated to assess for GERD-related complications and/or its mimics (e.g., eosinophilic esophagitis).

• Conservative and lifestyle measures may be adequate to treat uncomplicated, mild GERD in infants, and should be employed in older children and adolescents with GERD, even in the face of pharmacological and/or surgical therapy.

Gastroesophageal reflux (GER) refers to the passage of gastric contents into the esophagus or oropharynx, with or without vomiting.1,2 GER can be a daily, normal physiological occurrence in infants, children, and adolescents. Most episodes of GER in healthy individuals last <3 minutes, occur in the postprandial period, and cause few or no troublesome symptoms. Regurgitation or “spitting up” is the most obviously visible symptom. It is characterized by effortless emesis and is seen particularly in a very young child, occurring daily in about 50% of infants <3 months of age. Regurgitation resolves spontaneously in most healthy infants by 12–14 months of age.3,4 Reflux episodes sometimes trigger vomiting: the forceful expulsion of gastric contents from the mouth. Vomiting associated with GER is thought to be the result of stimulation of pharyngeal sensory afferents by refluxed gastric contents. Rumination refers to the effortless regurgitation of recently ingested food into the mouth with subsequent mastication and re-swallowing. Rumination syndrome is a distinct clinical entity with regurgitation of ingested food within minutes following meals due to the voluntary contraction of the abdominal muscles.

Gastroesophageal reflux disease (GERD) refers to the symptoms and complications that may develop secondary to persistent GER.1,2 Differentiating GER from GERD is critical for the clinician in order to avoid unnecessary diagnostic testing and exposure to medications. Recently, there have been three critically important publications1,2,5 that offer the clinician a complete characterization of the evidence-based definitions of GER and GERD, particularly GERD-related complications as well as the diagnostic and therapeutic approach to the child with GERD. Complications of GERD in children include esophagitis, growth disturbance, and feeding aversion as well as extraesophageal disease such as respiratory disorders. The first of the two “definition” publications was the Montreal definition of GERD in adults published by Vakil et al. in 2006,5 and the second, using similar methodology for the establishment of the definitions, was the Global evidence-based consensus on the definition of GERD in children (Figures 12–1 and 12–2)1 Shortly thereafter, a joint committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and the European Society for Gastroenterology, Hepatology and Nutrition (ESPGHAN) published recommendations for the management of children with reflux.2

GERD in Adults versus Children

The committee that developed the Montreal definition of GERD in adults used a patient-centered, symptom-based definition of symptoms that have a measurable impact on the patient’s quality of life.5 For children, the Global Consensus Definition Committee incorporated both development criteria and reports of troublesome symptoms. In particular, the Global Consensus Committee operated under the assumption that child development and communicative abilities mandate an age group-specific approach to GER and GERD definitions. Thus, unlike adult GERD, the definition of when reflux-related symptoms become troublesome in children depends on age.1,5 Although the verbal child can communicate pain, descriptions of the intensity, location, and severity may be unreliable until at least 8 years old, and sometimes later.6,7 Also, younger children are generally more suggestible, so that queries from parents or clinicians regarding a specific symptom may be biased toward affirmative responses. Thus, self-reporting cannot reliably be used as a component of a GERD definition until the individual is more than approximately 8 years of age. In younger patients, reliance on a parent or caregiver is generally necessary, but reporting of reflux-related symptoms by these surrogates may decrease the validity of diagnosis. Validated symptom questionnaires are currently lacking.6,8

In adults5 and adolescents,5,9,10 heartburn and regurgitation are the characteristic symptoms of GERD. In infants, the issue is clearly more complicated. During the development of a GERD questionnaire, differences were identified in the prevalence of regurgitation, food refusal, and crying between a healthy cohort and infants with abnormal esophageal pH studies and/or esophatitis.11 However, these symptoms do not respond to proton pump inhibitor (PPI) therapy and improve with non-pharmacological therapy, raising questions about the causative role of acid reflux.12,13

Altered Motor Function

The patterns of normal physiological reflux change as a child ages, that is, in particular, the frequency and quantity of normal reflux are greater in the very young compared to older children, adolescents, and adults. The increase in normal physiological reflux in infants and young children is due primarily to a number of factors, namely: (1) higher frequency of feeds in infants (i.e., thus increased time over the 24-hour day that the stomach is full), (2) a shorter esophagus and wide angle between the esophagus and stomach in the ≤24-month-old population, thereby allowing reflux to occur more readily, and (3) the increased amount of time infants spend in the supine rather than upright position. Mechanisms for GERD in age groups have been carefully studied and characterized, and are similar across age groups, whether comparing infants, older children or adolescents, and adults (even those that are premature) with GERD to those subjects of similar age that have no GERD. Aerodigestive reflexes (oral, pharyngeal, and esophageal coordinated functions) are fully developed in most children before delivery, by an estimated 38 weeks of gestational age. If there is dysfunction of motility, troublesome GER-related symptoms can ensue. These mechanisms include:

• transient relaxation of the lower esophageal sphincter (LES);
  
• inhibition of esophageal body peristalsis;
  
• persistent decrease or absence of LES resting tone.14–18

Reflux episodes occur most often during transient LES relaxations unaccompanied by swallowing, which permit gastric contents to flow upward into the esophagus. A minor proportion of reflux episodes occur when the LES fails to increase pressure during a sudden increase in intra-abdominal pressure, or when LES resting pressure is chronically reduced.

Alterations in protective mechanisms allow physiological GER to become GERD. These include:

• insufficient clearance and buffering of refluxate;
  
• delayed gastric emptying;
  
• abnormalities in esophageal epithelial repair;
  
• decreased protective reflexes;
  
• hiatal hernia.

In hiatal hernia, the anti-reflux barriers at the LES (including the crural support, intra-abdominal segment, and angle of His) are compromised and transient LES relaxations also occur with greater frequency. Erosive esophagitis by itself may promote esophageal shortening and cause hiatal herniation. Hiatal hernia is prevalent in adults and children with severe reflux complications, and hernia size is a major determinant of GERD severity.

Genetic Factors

Significant clustering of reflux symptoms, hiatal hernia, erosive esophagitis, Barrett esophagus, and esophageal adenocarcinoma can occur in families, suggesting heritability of GERD and its complications. A large Swedish Twin Registry study found increased concordance for reflux in monozygotic, compared to dizygotic, twins. In another more recent study, collagen type III alpha I was determined to be a GERD susceptibility gene and a male risk factor for hiatus hernia in adults. Therefore, it is important for the clinician who is evaluating the child with suspected GERD to obtain a detailed family history. Several other pediatric patient populations appear to be at higher risk of GERD symptoms.

Other Risk Factors for GERD in Children

High-risk groups include individuals with neurologic impairment (NI) or developmental impairment, obesity, many genetic syndromes, esophageal atresia, chronic lung diseases, and those with a history of premature birth. Persistent GERD also occurs in children who have none of these risk factors.3,19,20 A significant proportion of adults with endoscopically proven GERD have a history of GERD-related symptoms in childhood, compared to adults without GERD.19 Once GERD is clinically or endoscopically evident in a child or adolescent, it continues as chronic lifelong condition in a substantial percentage of these patients.20,21 Although no population-based epidemiological studies have been performed, it is apparent that GERD is being increasingly recognized in children in both the United States and abroad.22 There also appears to be a rising prevalence of severe GERD-related outcomes such as erosive esophagitis and Barrett esophagus.

Vomiting

Normal regurgitation appears to peak at 2–4 months of age and resolves soon after 1 year of age (Figure 12–3). It is typically effortless, although it may appear more forceful in some infants.11,24,25 Regurgitation is distinguished from vomiting physiologically by the absence of the following factors: (1) a central nervous system emetic reflex, (2) retrograde upper intestinal contractions, (3) nausea, and (4) retching.11,25 It is also important to note that parents and even medical practitioners may confuse vomiting with regurgitation, or use other terms for regurgitation (i.e., “spitting up” or “spilling”).

Rumination refers to the effortless regurgitation of recently ingested food into the mouth with subsequent mastication and re-swallowing of food. Rumination syndrome has been more frequently recognized among older children, especially adolescent females, and is considered by some to lie within the spectrum of eating disorders.26 Features of rumination that distinguish it from GERD include onset of regurgitation early during the process of eating or drinking. In addition, rumination is associated with an absence of nocturnal symptoms, does not occur when lying down, fails to respond to prokinetics or acid suppression, and has a female preponderance.27,28 Infant rumination syndrome is a rare disorder that is characterized by voluntary, habitual regurgitation of stomach contents into the mouth for self-stimulation, and may be a sign of social deprivation or severe psycho-social dysfunction in the family.29 The Rome III criteria26,29 for rumination syndrome require that GERD be eliminated from the differential diagnosis.

Anatomic Lesions

Bilious vomiting or projectile vomiting are alarm signals that warrant further investigations to rule out anatomic abnormalities, such as intestinal malrotation, pyloric stenosis, or other causes of intestinal obstruction.

Heartburn, a cardinal symptom of GERD in adults, generally does not manifest until adolescence. Heartburn is defined as an uncomfortable burning sensation behind the sternum that can often reach a painful quality.5 Table 12–1 lists manifestations that should raise concern for GERD and alarm signals that could indicate other etiologies.

Crying and Sleep Disturbances

Infantile GERD can present with frequent regurgitation, vomiting, poor weight gain, feeding refusal, and irritability. Unfortunately, irritability is not very specific and often is a poor indicator of pathologic acid reflux. Crying is a normal feature of infancy, with an average daily duration that peaks in the second month of life at 2–2.5 hours/day.30,31 Distinguishing normal crying from crying as a disease-related symptom is complicated. Consequently, in infants, the combined presence of both normal regurgitation and normal crying may be mistaken for GERD.32,33 As with crying, sleeping patterns of normal infants show great individual and maturational variation as do parental expectations for sleep behavior.

The concept that irritability and sleep disturbances are manifestations of GER is largely extrapolated from descriptions of heartburn and sleep disturbances due to GERD in adult patients. Although one study in infants showed a correlation between infant grimacing and episodes of GER, multiple other studies have shown no relationship between crying and GERD, as determined by esophageal pH testing or the presence of esophagitis on endoscopy34,35. Recently, a study of colicky infants found abnormal pH test results only in those with excessive regurgitation or feeding difficulties.36 Taken these data together, the correlation between crying, night-time awakening, and GER as based on a “diagnostic” test remains unclear.

One way to sort this out is to look at the response to acid-blocker therapy. An early study showed a greater decrease in crying time in infants treated with a 1.0 mg/kg dose of famotidine than in infants given 0.5 mg/kg.37 The authors concluded that famotidine is effective in treating infant crying. However, this study had significant methodological shortcomings, including lack of a placebo control.37 A placebo-controlled study of infants with irritability and normal esophageal pH tests found that combined ranitidine and cisapride treatment was not superior to placebo or parent-directed counseling for persistent crying.38 A double-blind, placebo-controlled trial of a PPI (i.e., omeprazole) in irritable infants with proven GERD (esophagitis or abnormal pH probe study) found no difference in crying between treated and placebo groups.39 However, the study design was flawed in that the PPI dose was low, there was a brief wash-out period, and the parameters used to define abnormal esophageal acidification were actually normal.39 More recently, a larger, double-blind study of 162 infants randomized to 4 weeks of placebo or lansoprazole showed an identical response rate in each group (54%).13 Thus, it appears that acid blockers have a limited role in distinguishing crying caused by GERD.

Although they have limited efficacy in stopping fussiness, PPIs do have efficacy against acid reflux in infants. Another recent study sought to characterize the pharmacodynamics and clinical effects of esomeprazole in 26 preterm infants and term neonates with symptoms of GER and abnormal pH probe studies.40 Study patients received oral esomeprazole 0.5 mg/kg once daily for 7 days. As expected, acid reflux episodes were reduced on therapy. More importantly, in contrast to the previously mentioned study, the number of GER symptoms recorded over 24 hours was lower on therapy.40 It seems clear that research is critically needed to determine and validate both diagnosis and treatment outcomes in the infant with suspected GERD, and in particular, study designs that (1) include validated symptom-based diagnosis in infants and (2) appropriately defined case and placebo/control groups with sufficient sample size to achieve adequate power.

Beyond infancy, a variety of symptoms can be attributed to GERD, and many of these symptoms change with age. In one study of 1–17-year olds, cough, anorexia/food refusal, and regurgitation/vomiting were more common and more severe in children 1–5 years of age, compared with older children10 (in this study, toddlers and young children). In contrast, the predominant symptoms in older children (6–17 years) included epigastric pain or heartburn.10,41 These become increasing predominant with increasing age.9,10 In addition, per the Global Consensus definition, epigastric pain in older children and adolescents can be a major symptom of GERD.1 Overall, for 1–11-year olds, there are relatively few data on presenting symptoms, and no standardized definitions for reporting.10 For example, some studies allow reporting of abdominal pain, or epigastric pain, or both.10,41,42 In addition, the combination of arching of the back, torsion of the neck, and lifting of the chin suggests Sandifer syndrome.43–46 This GERD-associated condition has its peak occurrence at 18–36 months of age and is a specific manifestation of GERD in pediatric patients. Table 12–1 lists age-specific GERD signs and symptoms and warning/alarm signs that indicate other diseases.

Head and neck manifestations that have been associated with GERD include dental erosions, otitis media, pharyngitis, and vocal cord disorders such as laryngitis. However, the Global Consensus Definition Committee determined that, at present, there is insufficient evidence that GERD causes or exacerbates sinusitis, pulmonary fibrosis, pharyngitis, or serous otitis media in children.1 Placebo-controlled treatment trials in children with GERD and otolaryngologic manifestations (e.g., chronic otitis media), that are sufficiently powered (i.e., adequate cohort size), and include standard case definitions and clearly defined outcomes, are needed to support a cause-and-effect relationship.47,48

Lower respiratory manifestations that have been described include nocturnal cough or wheezing, reactive airway disease, asthma, and recurrent pneumonias.49–51 Per the Global Consensus definition, chronic cough, chronic laryngitis, hoarseness, and asthma may be associated with GERD.1 One study of 1037 children followed from birth to 26 years of age for respiratory symptoms and lung function found an association between symptoms of GERD (heartburn and regurgitation) and asthma, wheezing, and nocturnal cough. However, this association was only found in patients with late-onset asthma (teenage and adult), and not in childhood-onset asthma.52

Asthma

Proposed mechanisms by which GER might aggravate asthma have compelling supporting evidence. These mechanisms include the following: airway hyper-responsiveness triggered by aspiration of small amounts of acid, airway inflammation elicited by aspirated gastric contents, vagally mediated bronchial or laryngeal spasm, and neurally mediated inflammation.53,54 Interestingly, esophageal acidification in healthy adults has minimal effect on pulmonary function, but in asthmatic patients can produce airway hyper-responsiveness and airflow obstruction.

In addition, similar to GERD as a cause for asthma, biological plausibility for the converse relationship is also strong.55–58 Chronic hyperinflation caused by asthma can flatten the diaphragms, alter crural function, and displace the LES into the negative atmosphere of the chest, effectively reducing resting LES pressure and causing disappearance of the acute esophagogastric angle of His.57–59 Lung hyperinflation and airflow obstruction may produce increased negative intrathoracic pressure, promoting GER. Theophylline (now rarely used in clinical practice) and β-receptor agonists cause a reduction of resting LES pressure.60,61 However, to date, these drugs have not been associated with the development of GERD in treated asthmatics.

An association between asthma and measurements of GER by pH probe or pH probe plus multichannel intraluminal impedance (MII) has been recently demonstrated. These studies found that 60–80% of children with asthma have GER.48,62–64 A study of 77 children aged 3–14 years old with difficult-to-control asthma found that 66% had an abnormal reflux index on pH testing. In a study of 84 otherwise healthy infants with daily wheezing, 64% had abnormal 24-hour pH studies, and 44% of these had no overt symptoms of GERD. In addition, in clinical practice and descriptive reports, nocturnal wheezing appears particularly related to GERD.65,66 One study used combined esophageal pH and MII monitoring and demonstrated a tighter association between reflux episodes and respiratory symptoms than pH monitoring alone. Unfortunately, no studies to date demonstrate that pH/MII studies are useful in identifying those patients whose asthma might respond to anti-reflux therapy.

Apnea

A causal relationship between reflux and apnea has been postulated and instituted in clinical practice for many years, especially in newborns and young infants.67 However, the GERD–apnea association could simply be attributed to both conditions being common at this stage in life. In addition, a recent study demonstrated no association between abnormal esophageal pH monitoring and apnea.68–70 Moreover, the literature on the relationship between apnea, respiratory pauses, apparent life-threatening events (ALTEs), or sudden infant death syndrome (SIDS) and GER is quite conflicting. The confusion in the literature is due in part to the use of different criteria to define breath stoppage, varying methods used to measure GER and respiratory pauses, and the study of different populations.1,71 MII and pH monitoring studies have both been used to demonstrate a relationship between short episodes of physiological apnea and reflux in infants.72 Overall, GERD and apnea do not appear temporally related in “asymptomatic convalescent” preterm babies,73 despite strong physiological evidence that stimulation of laryngeal afferents elicits central apnea and laryngeal adduction.74 However, in a subpopulation of infants with neurodevelopmental impairment, there may be an increased incidence of both apnea and GER.75 Despite the controversy, and the difficulty in “doing nothing” in clinical practice, many centers still treat all infants presenting with apnea with anti-reflux therapies.

Acute life-threatening events (ALTEs) are characterized by a combination of apnea, color change (cyanosis, pallor, and plethora), abnormal muscle tone (limpness and stiffness), choking, and gagging that require intervention by the observer. As might be expected, GERD is a frequent diagnostic consideration in infants following an ALTE.76 Typically, these occur between 1 and 8 months of age. ALTEs may recur, and infants with an ALTE are felt to be at slightly increased risk for a subsequent sudden death. ALTEs may be associated with infection, child abuse, upper airway obstruction, and cardiac, respiratory, metabolic, and neurologic disorders. ALTEs associated with GERD may not be pathologic; some may be an exaggeration of normal protective reflexes that inhibit breathing while the infant retches or while the pharynx is filled with gastric contents. However, there are no compelling data available at present that reliably define the prevalence of GERD in ALTE. In fact, one study, reflux of gastric acid, appears to be related in <5% of infants with ALTE.77

A thorough history and physical examination can be the key to diagnosis of GERD, with specific attention to the child’s age, as well as the character and frequency of GERD-related symptoms. The original NASPGHAN clinical practice guidelines for GERD in children recommended that a trial of acid suppression should be considered, based on history and physical examination.78 This “PPI test” has been effective in adults, with resolution of symptoms being the diagnostic test for GERD.79–81

In the United States, a random sample of members of the American Academy of Pediatrics recently revealed that 82% of the respondents would initiate therapy solely based on clinical suspicion (i.e., history and physical exam).82

The PPI Test: Empiric Trial of Acid Suppression

In adults, a trial of empiric treatment with acid suppression using a defined dose, defined duration of therapy, and clear endpoints has been called the PPI test. This has particularly been used to differentiate cardiac from non-cardiac chest pain.79,83 The PPI test has also been used for GERD-related complaints of heartburn, chronic cough, and dyspepsia.80,84–86 Empiric therapy has variable sensitivity and specificity as a diagnostic test for GERD, depending on the comparative gold standard used (endoscopy, pH monitoring, or symptom questionnaires).87 The appropriate duration of a diagnostic trial of acid suppression has not been determined. A meta-analysis evaluating pooled data from three large treatment trials among adults with non-erosive reflux disease showed that 85% of patients who had symptom resolution after 1 week of PPI treatment remained well for the entire 4 weeks of PPI treatment, thus “confirming” the diagnosis.88 However, 22% of patients who had no improvement after 1 week of treatment did improve by the fourth week of treatment. An uncontrolled trial of esomeprazole therapy in adolescents with heartburn, epigastric pain, and acid regurgitation showed complete resolution of symptoms in 30–43% by 1 week, but the responders increased to 65% following 8 weeks of treatment.89 Another uncontrolled treatment trial of pantoprazole in children aged 5–11 years reported greater symptom improvement at 1 week with a 40-mg dose compared to a 10- or 20-mg dose.90 Interestingly, all treatment groups improved after 8 weeks. Similar improvement in symptoms over time has been observed in adults with erosive esophagitis.91,92

The treatment period required to achieve uniform therapeutic responses with PPI therapy probably varies with disease severity, treatment dose, and specific symptoms or complications.93 A 2-week “PPI test” lacks adequate specificity and sensitivity for use in clinical practice, particularly in the pediatric patient. In an older child or adolescent with symptoms suggesting GERD, an empiric PPI trial is justified for up to 4 weeks. Nevertheless, improvement following treatment does not absolutely confirm a diagnosis of GERD, since symptoms may improve spontaneously or due to the placebo effect. Finally, data suggest there is no evidence to support an empiric trial of pharmacological treatment in infants ≤12 months of age with symptoms suggestive of GERD.

Barium Contrast Radiography

Although the above-mentioned American Academy of Pediatrics survey revealed that the upper gastrointestinal (GI) series is the preferred test of pediatricians for children with suspected GERD, this diagnostic approach is neither sensitive nor specific for diagnosing this condition.82 The upper GI series is useful to detect anatomic abnormalities such as esophageal stricture, hiatal hernia, achalasia, tracheoeospahgeal fistula, intestinal malrotation, or pyloric stenosis that may be considered in the differential diagnosis. The sensitivity, specificity, and positive predictive value of the upper GI series range from 29% to 86%, 21% to 83%, and 80% to 82%, respectively, when compared to esophageal pH monitoring.94–96 The brief duration of the upper GI series produces false-negative results, while the frequent occurrence of non-pathologic reflux during the examination produces false-positive results. Therefore, routine performance of upper GI series to diagnose GER and GERD is not justified.97

Scintigraphy

In gastroesophageal scintigraphy, food or formula labeled with 99technitium is introduced into the stomach, following which the stomach, esophagus, and lungs are continuously imaged for evidence of GER and aspiration. The nuclear scan evaluates postprandial reflux and demonstrates reflux independent of the gastric pH. Scintigraphy can also provide information about gastric emptying, which may be delayed in children with GERD.98 A lack of standardized techniques and the absence of age-specific norms limit the value of this test. Sensitivity and specificity of a 1-hour scintigraphy for the diagnosis of GERD are 15–59% and 83–100%, respectively, when compared to 24-hour esophageal pH monitoring.99 Late postprandial acid exposure detected by pH monitoring may be missed with scintigraphy.100 Comparisons of scintigraphy to MII, pH monitoring, and with symptom-based diagnosis are lacking. Gastroesophageal scintigraphy scanning can detect GER episodes and aspiration of gastric contents occurring during or shortly after meals, but its reported sensitivity for microaspiration is relatively low.101 Evidence of pulmonary aspiration may be detected during a 1-hour scintigraphic study or on images obtained up to 24 hours after administration of the radionuclide. A negative test does not exclude the possibility of infrequently occurring aspiration. One study of children with refractory respiratory symptoms found that half had scintigraphic evidence of pulmonary aspiration.101 However, aspiration of both gastric contents and saliva also occurs in healthy adults during deep sleep.102 At present, there is no role for nuclear scintigraphy in the diagnosis and management of GERD in pediatric patients.

Ultrasonography

Ultrasonography is a relatively new technique for diagnosing gastroesophageal disease in adults. At present, although there is potential for utility as the technology and methodology become more refined,103 ultrasound is not recommended as a test for pediatric GERD. Ultrasonography of the GE junction can detect fluid movements over short periods of time and thereby can detect non-acid reflux events. Ultrasound can also detect hiatal hernia, measure the length and position of the LES relative to the diaphragm, and demonstrate the gastroesophageal angle of His. When compared to the results of 24-hour esophageal pH testing as a diagnostic test for GERD, the sensitivity of color Doppler ultrasound performed for 15 minutes postprandially is about 95% with a specificity of only 11%, and there is no correlation between reflux frequency detected by ultrasound and reflux index detected by pH monitoring.104

Esophageal pH Monitoring

Intraluminal esophageal pH monitoring measures the frequency and duration of acid esophageal reflux episodes reaching the distal esophagus.105–109 Most commercially available systems include a catheter for nasal insertion with one or more pH electrodes (antimony, glass, or ion-sensitive field effect) arrayed along its length and a system for data capture, analysis, and reporting. Slow electrode response times (antimony being the slowest) do not substantially alter the assessment of total reflux time, but may affect the accuracy of correlation between symptoms and reflux episodes.110–112 Recently, wireless sensors that can be clipped to the esophageal mucosa during endoscopy (i.e., Bravo™ capsule) have allowed pH monitoring without a nasal cannula for up to 48 hours of monitoring.113,114 Placement of wireless electrodes requires upper endoscopy, and the accompanying sedation or anesthesia, and comfort has been an issue in some studies.113,114 The size of current wireless electrodes precludes their use in small infants. Benefits, risks, and indications for wireless electrode monitoring have also not been fully defined in children.

By convention, a drop in intraesophageal pH below 4.0 for >5 seconds is considered an acid reflux episode. This cut-off was initially chosen because heartburn induced by acid perfusion of the esophagus in adults generally occurs at pH <4.0. However, the duration of esophageal acidification necessary to cause symptoms or induce mucosal injury has not been clearly established, particularly in the pediatric patient population. Although interpretation of pH monitoring data is simplified by computerized analysis, visual inspection of the tracing is required to detect artifacts and evaluate clinical correlations.115,116 Common parameters obtained from pH monitoring include the total number of reflux episodes, the number of reflux episodes lasting >5 minutes, the duration of the longest reflux episode, and the reflux index or RI (percentage of the entire record that esophageal pH <4.0)23. The RI is the most commonly used summary score.

More recently, the value of esophageal pH-metry for diagnosis and management of pediatric GERD has been questioned as having a lack of utility overall.69,117,118 Esophageal pH-metry is insensitive to weakly acid and non-acid reflux events, and the response times of the most widely used electrodes are slow. These barriers are overcome by multichannel intraluminal impedance (MII) monitoring and/or by the use of ion-sensitive field-effect electrodes. Esophageal pH monitoring can correlate poorly with symptom severity and with response to therapy in pediatric patients.70 In infants with suspected GERD, an abnormal pH study (RI > 10%) was associated only with pneumonia, apnea with fussing, defecation less than once a day, and constipation.70 An abnormal RI is more frequently observed in adults with erosive esophagitis than in normals or those with non-erosive reflux disease, but there is substantial overlap among groups.119 In pediatric patients, the calculated area under the pH 4.0 curve has been associated with erosive esophagitis (Gold et al., unpublished data). Esophageal pH monitoring may be abnormal in patients with other disorders, including gastric outlet obstruction, motility disorders, and esophagitis due to other disorders, including eosinophilic esopahgitis.77,120,121

Esophageal pH monitoring may be useful for evaluating the efficacy of anti-secretory therapy. In children with esophagitis, normal esophageal pH monitoring suggests a diagnosis other than GERD.122,123

Multichannel Intraluminal Esophageal Impedance

MII is a procedure for measuring the movement of fluids, solids, and air in the esophagus.124–126 It is a relatively new technology that, in comparison to pH monitoring, provides a more detailed description of substances within the esophageal lumen and correlation with symptoms.125,127–131 MII measures changes in the electrical impedance (i.e., resistance) between multiple electrodes located along an esophageal catheter.132 Esophageal impedance tracings are analyzed for the typical changes in impedance caused by the passage of liquid, solid, gas, or mixed boluses.124 If the impedance changes of a liquid bolus appear first in the distal channels and proceed sequentially to the proximal channels, they indicate retrograde bolus movement, that is, GER.132 The direction and velocity of a bolus can be calculated using the defined distance between electrodes and the time between alterations in the impedance pattern of sequential electrode pairs. The upward extent of the bolus and the physical length of the bolus can also be evaluated.124–126 MII can detect very small bolus volumes.133

For improved performance, MII and pH electrodes can be combined on a single catheter. The combined measurement of pH and impedance (pH/MII) provides additional information as to whether a refluxed material is acid, weakly acidic, or non-acidic.124,127,134 Recent studies have found variable reproducibility of MII studies in pediatric patients. However, more recently, evaluation of MII recordings is aided by automated analysis tools135,136 that may improve accuracy. Until the currently available automatic analysis software has been validated, a visual reading of the data is still required. Normal values for all age groups have not yet been established.

The combination of pH/MII with simultaneous monitoring of other parameters using video polysomnography or manometry has proven useful for the evaluation of correlations between reflux episodes and apnea, cough, other respiratory symptoms, and behavioral symptoms.18,137,138 The technology is especially useful, compared to the pH-only study, when gastric contents are non-acidic, as in the postprandial period or when patients are taking acid blockers. Whether this new technology will provide measurements that vary directly with disease severity, prognosis, and response to therapy has yet to be determined.

Invasive Diagnostic Approaches to GERD and Extraesophageal GERD

There are a number of invasive approaches to support the diagnosis of clinically suspected GERD in the pediatric patient. Clinicians employ laryngoscopy, bronchoscopy and alveolar lavage, endoscopy, esophageal and laryngeal biopsies, pH monitoring in the hypopharynx, and MII monitoring to diagnose GERD in pediatric patients presenting with extraesophageal symptoms.47,139–142 However, none of these tools independently establishes the diagnosis of GERD with extraesophageal symptoms.143–145 Hypopharyngeal pH-metry has been evaluated in children with symptoms suggestive of extraesophageal manifestation of GERD.144 In a prospective study of 222 children (1 day to 16 years old) divided into subgroups by symptoms (laryngeal, pulmonary, recurrent emesis, and non-respiratory), 78 had pharyngeal acid reflux in spite of normal distal esophageal pH tracings.145 Children with emesis, pulmonary symptoms, and laryngeal symptoms had more pharyngeal reflux episodes, compared with children with GI-related symptoms. The same method was applied in another prospective study of 105 children with symptoms suggestive of GERD, aged 4 months to 12 years, but in this instance hypopharynx-pH-metry did not differentiate between children with and without abnormal esophageal pH tracings, irrespective of presenting clinical symptoms.144

A blinded comparison of videomacrolaryngoscopy, laryngeal and esophageal biopsies, and dual pH-metry (of distal esophagus and hypopharynx) was performed in 39 consecutive children operated on for airway reconstruction.143 The upper probe pH did not correlate with any of the other assessed parameters.143 The definition of pathologic hypopharyngeal reflux is uncertain, because pharyngeal reflux also occurs in healthy controls.146–149 It is also unknown how much acid reflux is needed to cause pathology of the larynx. The same issues probably also apply for MII. So far, normative data from different pediatric age groups are not available.150 Therefore, additional carefully controlled studies are needed to define which diagnostic tool will best diagnose extraesophageal GERD.

When hematemesis or occult bleeding occurs in the face of GERD symptoms, esophagogastroduodenoscopy (EGD) or upper GI endoscopy may be indicated to assess for the presence and severity of GERD. EGD can also detect erosive (macroscopic) or histologic (microscopic) esophagitis, strictures, Barrett’s esophagus, and eosinophilic esophagitis (EoE), a potential GERD masquerader.120,151,152 EGD allows the pediatric gastroenterologist to have direct visual assessment of the esophageal mucosa, giving the clinician a macroscopic perspective. Random or targeted biopsies enable evaluation of the microscopic anatomy.153 Macroscopic abnormalities associated with GERD include esophagitis, erosions, ulcers, strictures, hiatal hernia, areas of possible suspected esophageal metaplasia, and polyps (Table 12–2). While endoscopy can detect strictures, subtle degrees of narrowing are better shown on barium contrast study. Unfortunately, anatomic abnormalities such as malrotation and achalasia cannot be diagnosed by endoscopy. These and other anatomic and motility disorders of the esophagus are better evaluated by barium radiology or motility studies.

Recent Global Consensus guidelines define reflux esophagitis as the presence of endoscopically visible breaks in the esophageal mucosa at or immediately above the GE junction.1,5,154 Evidence from adult studies indicates that visible breaks in the esophageal mucosa are the endoscopic sign of greatest interobserver reliability.155 Mucosal erythema or an irregular Z-line is not a reliable sign of reflux esophagitis. Grading the severity of esophagitis, using a recognized endoscopic classification system, is useful for evaluation of the severity of esophagitis and response to treatment. The Hetzel–Dent classification has been used in several pediatric studies,156,157 and more recently, the Los Angeles classification,154 which was generally used for adults, is also quite suitable for use in children. However, it is important to note that the presence of endoscopically normal esophageal mucosa does not exclude a diagnosis of non-erosive reflux disease or esophagitis of other etiologies.158,159

The diagnostic yield of endoscopy is generally greater if multiple samples of good size and orientation are obtained from esophageal mucosal biopsy sites that are identified relative to major anatomic features.153,160,161 Several variables impact on the validity of histology as a diagnostic tool for reflux-associated esophagitis, and/or the ability to rule out other etiologies of esophageal disease (e.g., EoE), including: (1) sampling errors due to the patchy distribution of inflammatory changes, (2) a lack in standardization of biopsy location, (3) variable methodologies for tissue processing, and (4) variable interpretation of morphometric parameters.159,162 Histology may be normal even in some patients with erosive reflux esophagitis; conversely, it may be abnormal in non-erosive reflux disease. Moreover, symptom severity has not been shown to correlate with either macroscopic or endoscopic findings in the child who has undergone diagnostic upper endoscopy.

Histologic findings of eosinophilia, elongation of papillae (rete pegs), basal cell hyperplasia, and dilated intercellular spaces (DIS, or spongiosis) are neither sensitive nor specific for reflux esophagitis.70,122,158,162,163 These are non-specific reactive changes that may be found in esophagitis of other causes. Recent studies have shown considerable overlap between the histology of reflux esophagitis and EoE.120,121,158,164 Many histologic parameters are influenced by drugs used to treat esophagitis or other disorders.

GERD is likely the most common cause of esophagitis in children, but other disorders such as EoE, Crohn’s disease, and infections also cause esophagitis.158 EoE and GERD have very similar symptoms and signs, and can be best distinguished by endoscopy with biopsy. A key difference endoscopically is that EoE is not generally an erosive disease, but has its own typical endoscopic features such as speckled exudates, trachealization of the esophagus, or linear furrowing. In up to 30% of cases, however, the esophageal mucosal appearance is normal.165,166 When EoE is considered as part of the differential diagnosis, it is advisable to take esophageal biopsies from the proximal, mid, and distal esophagus.165 Mucosal eosinophilia may be present in the esophageal mucosa in asymptomatic infants <1 year of age167 and in symptomatic infants eosinophilic infiltrate may be due to milk protein allergy.166

Thus, at present, although hotly debated by pediatric gastroenterologists, there is insufficient evidence to support the use of histology to diagnose or exclude GERD. Clearly, more multicenter studies need to be done, particularly those that utilize a standard approach to anatomic landmarks, biopsy collection, and histologic characterization in order to address this issue. Currently, the primary role for esophageal histology is to rule out other conditions in the differential diagnosis, such as EoE, Crohn’s disease, Barrett esophagus, infection, and others.

The primary goals of treatment are to resolve symptoms, improve overall quality of life, and resolve and prevent complications of GERD. In “uncomplicated” infantile GER, conservative measures such as thickening the formula, giving smaller feeds more frequently, and upright positioning for at least 30 minutes after feeds may be sufficient to decrease regurgitation. In addition, thickening can increase the caloric density of the formula, which may benefit infants who have weight gain issues as a result of GER (one tablespoon of rice cereal per 2 ounces of formula increases the caloric density to 27 kcal/ounce). Prone positioning may decrease regurgitation but is not recommended due to the increased risk for SIDS. If milk protein intolerance or allergy is suspected, a 2–4-week trial of protein (partial whey or casein) hydrolysate formula should be considered (Figure 12–4).

Feeding Changes in Infants

About 50% of normal 3–4-month-old infants regurgitate at least once a day and up to 20% of caregivers in the United States seek medical help for this normal behavior.3,4 Breast-fed and formula-fed infants have a similar frequency of physiological GER, although the duration of reflux episodes measured by pH probe may be shorter in breast-fed infants.168–170

A subset of infants with allergy to cow’s milk protein experiences regurgitation and vomiting indistinguishable from that associated with GER.77,171–173 In these infants, vomiting frequency decreases significantly (usually within 2 weeks) after the elimination of cow’s milk protein from the diet, and re-introduction causes recurrence of symptoms.174,175 Studies support a trial of up to 4 weeks of extensively hydrolyzed or amino acid formula in formula-fed infants with bothersome emesis.12 Cow’s milk protein passes into human breast milk in small quantities. Breast-fed infants with regurgitation and vomiting may therefore benefit from a trial of withdrawal of cow’s milk and eggs from the maternal diet.176 The symptoms of infant GER are almost never so severe that breast-feeding should be discontinued. There are no studies specifically evaluating soy protein allergy in infants with regurgitation and vomiting, or the role of soy protein-based formula in the treatment of infants with regurgitation.

One small study in infants showed that large-volume feedings promote regurgitation, probably by increasing the frequency of transient LES relaxations, and reduced feeding volume decreased reflux frequency.177 Severe reduction in feeding volume over an extended period may deprive the infant of needed calories and adversely affect weight gain. Infants with inadequate weight gain due to losses by regurgitation may benefit from increasing the caloric density of formula when volume or frequency of feedings is decreased as part of therapy.

Adding thickening agents such as rice cereal to formula or milk does not decrease the time with pH <4 (reflux index) measured by esophageal pH studies, but does decrease the frequency of overt regurgitation.177,178 Studies with combined pH/MII show that the height of reflux in the esophagus is decreased with thickened formula.179 One study reported an improvement in esophageal pH parameters with cornstarch-thickened formula.180 Another study showed no change in esophageal impedance parameters of premature infants receiving cornstarch-thickened human milk.181

In the United States, rice cereal is the most commonly used thickening agent for formula.178 Rice cereal-thickened formula decreases the volume of regurgitation but may increase coughing during feedings.182 Formula with added rice cereal usually requires using a nipple with an enlarged hole to allow adequate flow. Excessive calorie intake is a potential problem with long-term use of feedings thickened with rice cereal or cornstarch.183 Thickening a 20 kcal/oz infant formula with one tablespoon of rice cereal per ounce increases the caloric density to 34 kcal/oz. Thickening with one tablespoon per 2 ounces of formula increases the caloric density to 27 kcal/oz.