Gastroesophageal Reflux: Management Guidance for the ... · Jenifer R. Lightdale, David A. Gremse...

DOI: 10.1542/peds.2013-0421; originally published online April 29, 2013; 2013;131;e1684Pediatrics

HEPATOLOGY, AND NUTRITIONJenifer R. Lightdale, David A. Gremse and SECTION ON GASTROENTEROLOGY,

Gastroesophageal Reflux: Management Guidance for the Pediatrician

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CLINICAL REPORT

Gastroesophageal Reflux: Management Guidance forthe Pediatrician

abstractRecent comprehensive guidelines developed by the North AmericanSociety for Pediatric Gastroenterology, Hepatology, and Nutrition definethe common entities of gastroesophageal reflux (GER) as the physio-logic passage of gastric contents into the esophagus and gastroesoph-ageal reflux disease (GERD) as reflux associated with troublesomesymptoms or complications. The ability to distinguish between GERand GERD is increasingly important to implement best practices inthe management of acid reflux in patients across all pediatric agegroups, as children with GERD may benefit from further evaluationand treatment, whereas conservative recommendations are the onlyindicated therapy in those with uncomplicated physiologic reflux. Thisclinical report endorses the rigorously developed, well-referencedNorth American Society for Pediatric Gastroenterology, Hepatology,and Nutrition guidelines and likewise emphasizes important conceptsfor the general pediatrician. A key issue is distinguishing between clin-ical manifestations of GER and GERD in term infants, children, and ado-lescents to identify patients who can be managed with conservativetreatment by the pediatrician and to refer patients who require con-sultation with the gastroenterologist. Accordingly, the evidence basispresented by the guidelines for diagnostic approaches as well as treat-ments is discussed. Lifestyle changes are emphasized as first-line ther-apy in both GER and GERD, whereas medications are explicitly indicatedonly for patients with GERD. Surgical therapies are reserved for chil-dren with intractable symptoms or who are at risk for life-threateningcomplications of GERD. Recent black box warnings from the US Foodand Drug Administration are discussed, and caution is underlinedwhen using promoters of gastric emptying and motility. Finally, atten-tion is paid to increasing evidence of inappropriate prescriptions forproton pump inhibitors in the pediatric population. Pediatrics2013;131:e1684–e1695

INTRODUCTION

Gastroesophageal reflux (GER) occurs in more than two-thirds ofotherwise healthy infants and is the topic of discussion with pedia-tricians at one-quarter of all routine 6-month infant visits.1,2 In additionto seeking guidance from their pediatricians, parents often requestevaluation by pediatric medical subspecialists.3 It is, therefore, notsurprising that strongly evidence-based guidelines incorporating

Jenifer R. Lightdale, MD, MPH, David A. Gremse, MD, andSECTION ON GASTROENTEROLOGY, HEPATOLOGY, ANDNUTRITION

KEY WORDSgastroesophageal reflux, gastroesophageal reflux disease,pediatrics, guidelines, review, global consensus, reflux-relateddisease, vomiting, regurgitation, rumination, extraesophagealsymptoms, Barrett esophagus, proton pump inhibitors,diagnostic imaging, impedance monitoring, gastrointestinalendoscopy, lifestyle changes

ABBREVIATIONSGER—gastroesophageal refluxGERD—gastroesophageal reflux diseaseGI—gastrointestinalH2RA—histamine-2 receptor antagonistMII—multiple intraluminal impedancePPI—proton pump inhibitor

This document is copyrighted and is property of the AmericanAcademy of Pediatrics and its Board of Directors. All authorshave filed conflict of interest statements with the AmericanAcademy of Pediatrics. Any conflicts have been resolved througha process approved by the Board of Directors. The AmericanAcademy of Pediatrics has neither solicited nor accepted anycommercial involvement in the development of the content ofthis publication.

The guidance in this report does not indicate an exclusivecourse of treatment or serve as a standard of medical care.Variations, taking into account individual circumstances, may beappropriate.

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PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

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Guidance for the Clinician inRendering Pediatric Care



state-of-the-art approaches to theevaluation and management of pedi-atric GER have been welcomed by bothgeneral pediatricians and pediatricmedical subspecialists and surgicalspecialists. GER, defined as the passageof gastric contents into the esophagus,is distinguished from gastroesophagealreflux disease (GERD), which includestroublesome symptoms or complica-tions associated with GER.4 Differen-tiating between GER and GERD lies atthe crux of the guidelines jointly de-veloped by the North American Soci-ety for Pediatric Gastroenterology,Hepatology, and Nutrition and theEuropean Society for Pediatric Gas-troenterology, Hepatology, and Nutri-tion.4 These definitions have furtherbeen recognized as representing aglobal consensus.5 Therefore, it isimportant that all practitioners whotreat children with reflux-related dis-orders are able to identify and dis-tinguish those children with GERD,who may benefit from further eval-uation and treatment, from thosewith simple GER, in whom conser-vative recommendations are moreappropriate.

GER is considered a normal physio-logic process that occurs severaltimes a day in healthy infants, children,and adults. GER is generally associatedwith transient relaxations of the loweresophageal sphincter independent ofswallowing, which permits gastriccontents to enter the esophagus. Epi-sodes of GER in healthy adults tend tooccur after meals, last less than 3minutes, and cause few or no symp-toms.6 Less is known about the nor-mal physiology of GER in infants andchildren, but regurgitation or spittingup, as the most visible symptom, isreported to occur daily in 50% of allinfants.7,8

In both infants and children, reflux canalso be associated with vomiting, de-fined as a forceful expulsion of gastric

contents via a coordinated autonomicand voluntary motor response. Re-gurgitation and vomiting can be fur-ther differentiated from rumination, inwhich recently ingested food is ef-fortlessly regurgitated into the mouth,masticated, and reswallowed. Rumi-nation syndrome has been identifiedas a relatively rare clinical entity thatinvolves the voluntary contraction ofabdominal muscles.9 In contrast, bothregurgitation and vomiting can beconsidered common and often non-pathologic manifestations of GER.

Symptoms or conditions associatedwith GERD are classified by the prac-tice guidelines as being eitheresophageal or extraesophageal.4 Bothclassifications can be used to definethe disease, which can be furthercharacterized by findings of mucosalinjury on upper endoscopy. Esopha-geal conditions include vomiting, poorweight gain, dysphagia, abdominalor substernal/retrosternal pain, andesophagitis. Extraesophageal con-ditions have been subclassifiedaccording to both established andproposed associations; establishedextraesophageal manifestations of GERDcan include respiratory symptoms, in-cluding cough and laryngitis, as wellas wheezing in infancy.10,11 Althougholder studies from the 1990s sug-gested that GERD may aggravateasthma, recent publications havesuggested that the impact of GERD onasthma control is considerably lessthan previously thought.10,12–18 Otherextraesophageal manifestations in-clude dental erosions, and proposedassociations include pharyngitis, si-nusitis, and recurrent otitis media.Patients can be described clinically bytheir symptoms or by the endoscopicdescription of their esophageal mu-cosa. GERD-associated esophageal in-juries and complications found onendoscopy include reflux esophagitis,less commonly peptic stricture, and

rarely Barrett esophagus and adeno-carcinoma.

Although the reported prevalence ofGERD in patients of all ages world-wide is increasing,5 GERD is never-theless far less common than GER.Population-based studies suggestreflux disorders are not as commonin Eastern Asia, where the prevalenceis 8.5%,19 compared with WesternEurope and North America, where thecurrent prevalence of GERD is esti-mated to be 10% to 20%.20 New epi-demiologic and genetic evidencesuggests some heritability of GERDand its complications, including ero-sive esophagitis, Barrett esophagus,and esophageal adenocarcinoma.21–23

A few pediatric populations at highrisk of GERD have also been identi-fied, including children with neuro-logic impairment, certain geneticdisorders, and esophageal atresia24,25

(Table 1). The prevalence of severe,chronic GERD is much higher in pe-diatric patients with these “GERD-promoting” conditions. These patientsmay be more prone to experienc-ing complications of severe GERDthan patients who are otherwisehealthy.26

Population trends hypothesized tocontribute to a general increase inthe prevalence of GERD include glo-bal epidemics of both obesity andasthma. In some instances, GERD canbe implicated as either the underlyingetiology (ie, recurrent pneumonia in

TABLE 1 Pediatric Populations at High Riskfor GERD and Its Complications

Neurologic impairmentObeseHistory of esophageal atresia (repaired)Hiatal herniaAchalasiaChronic respiratory disordersBronchopulmonary dysplasiaIdiopathic interstitial fibrosisCystic fibrosis

History of lung transplantationPreterm infants

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the premature infant exacerbated byGERD) or a direct repercussion (ie,obesity leading to GERD) of suchconditions. In the great majority ofcases, however, GERD and comorbid-ities are known to occur simulta-neously in patients without a clearcausal relationship.

CLINICAL FEATURES OF GERD

Troublesome symptoms or complica-tions of pediatric GERD are associatedwith a number of typical clinical pre-sentations in infants and children,depending on patient age5 (Table 2).Reflux may occur commonly in pre-term newborn infants but is generallynonacidic and improves with matura-tion. A full discussion of reflux inneonates and preterm infants is be-yond the scope of this report.

Guidelines have distinguished betweenmanifestations of GERD in full-terminfants (younger than 1 year) fromthose in children older than 1 year andadolescents. Common symptoms ofGERD in infants include regurgitationor vomiting associated with irritability,anorexia or feeding refusal, poorweight gain, dysphagia, presumablypainful swallowing, and arching ofthe back during feedings. Relying ona symptom-based diagnosis of GERDcan be difficult in the first year of life,especially because symptoms of GERDin infants do not always resolve withacid-suppression therapy.5,27 GERD in

infants can also be associated withextraesophageal symptoms of cough-ing, choking, wheezing, or upper re-spiratory symptoms.7 The incidence ofGERD is reportedly lower in breastfedinfants than in formula-fed infants.27

In line with the natural history ofregurgitation, GERD in infants is con-sidered to have a peak incidence ofapproximately 50% at 4 months ofage and then to decline to affect only5% to 10% of infants at 12 months ofage.7,8

Common symptoms of GERD in chil-dren 1 to 5 years of age include re-gurgitation, vomiting, abdominal pain,anorexia, and feeding refusal.28 Gen-erally, GERD causes troublesomesymptoms without necessarily in-terfering with growth; however, chil-dren with clinically significant GERDor endoscopically diagnosed esoph-agitis may also develop an aversionto food, presumably because of astimulus-response association of eatingwith pain. This aversion, combined withfeeding difficulties associated with re-peated episodes of regurgitation, aswell as potential and substantial nu-trient losses resulting from emesis,may lead to poor weight gain or evenmalnutrition.

Older children and adolescents aremost likely to resemble adults in theirclinical presentation with GERD and tocomplain of heartburn, epigastricpain, chest pain, nocturnal pain, dys-phagia, and sour burps. When elicitinga history in school-aged children withsuspected GERD, it may be importantto directly ask patients themselvesabout their symptoms rather thanrelying strongly on parent report. In 1study, adolescents were significantlymore likely than their parents to re-port themselves to be experiencingsymptoms of sour burps or nausea.1

Extraesophageal symptoms in olderchildren and adolescents can includenocturnal cough, wheezing, recurrent

pneumonia, sore throat, hoarseness,chronic sinusitis, laryngitis, or dentalerosions. In a pediatric patient withGERD and dental erosions, the pro-gression of tooth structure loss maybe indicative that existing therapy forGERD is not effective. Conversely, sta-bility of dental erosions is 1 measureof adequacy of GERD management.

DIAGNOSTIC STUDIES

For most pediatric patients, a historyand physical examination in the ab-sence of warning signs are sufficientto reliably diagnose uncomplicatedGER and initiate treatment strategies.Generally speaking, diagnostic testingis not necessary. The reliability ofsymptoms to make the clinical di-agnosis of GERD is particularly high inadolescents, who often present withheartburn typical of adults.29–31 Nev-ertheless, dedicating at least part ofa clinical visit to obtaining a clinicalhistory and performing a physicalexamination are also essential to ex-clude more worrisome diagnoses thatcan present with reflux or vomiting(Table 3).

To date, no single symptom or clusterof symptoms can reliably be usedto diagnose esophagitis or othercomplications of GERD in children or topredict which patients are most likely

TABLE 2 Common Presenting Symptoms ofGERD in Pediatric Patients

Infant Older Child/Adolescent

Feeding refusal Abdominal pain/heartburn

Recurrentvomiting

Recurrent vomiting

Poor weightgain

Dysphagia

Irritability AsthmaSleepdisturbance

Recurrent pneumonia

Respiratorysymptoms

Upper airway symptoms(chronic cough,hoarse voice)

TABLE 3 Concerning Symptoms and Signs(“Warning Signs” in Figures) forPrimary Etiologies Presenting WithVomiting

Bilious vomitingGI tract bleedingHematemesisHematochezia

Consistently forceful vomitingFeverLethargyHepatosplenomegalyBulging fontanelleMacro/microcephalySeizuresAbdominal tenderness or distensionDocumented or suspected genetic/metabolicsyndrome

Associated chronic disease

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to respond to therapy.21 Nonetheless,a number of GERD symptom ques-tionnaires have been validated andmay be useful in the detection andsurveillance of GERD in affected chil-dren of all ages. Kleinman et al de-veloped a questionnaire for infantsthat was validated for documentationand monitoring of parent-reportedGERD symptoms.30 Another question-naire by Størdal et al32 for pediatricpatients 7 to 16 years of age com-pared favorably with results of pHmonitoring. As yet another example,the GERD Symptom Questionnaire de-veloped by Deal et al33 appears validfor differentiating children with GERDfrom healthy controls but has notbeen compared with objective stand-ards, such as pH monitoring or en-doscopic findings.

The strategy of using diagnostictesting to diagnose GERD may alsobe fraught with complexity, becausethere is no single test that can rule itin or out. Instead, diagnostic testsmust be used in a thoughtful and serialmanner to document the presenceof reflux of gastric contents in theesophagus, to detect complications, toestablish a causal relationship betweenreflux and symptoms, to evaluate theefficacy of therapies, and to excludeother conditions. The diagnostic meth-ods most commonly used to evaluatepediatric patients with GERD symptomsare upper gastrointestinal (GI) tractcontrast radiography, esophageal pHand/or impedance monitoring, and up-per endoscopy with esophageal biopsy.Upper GI tract series are useful todelineate anatomy and to occasion-ally document a motility disorder,whereas esophageal pH monitoringand intraluminal esophageal impedancerepresent tools to quantify GER. Up-per endoscopy with esophageal bi-opsy represents the primary method toinvestigate the esophageal mucosa toboth exclude other conditions that can

cause GERD-like symptoms and evaluatefor esophageal injury attributable toGERD.4

Upper GI Tract Series

Upper GI tract contrast radiographygenerally involves obtaining a series offluoroscopic images of swallowedbarium until the ligament of Treitz isvisualized. According to the newguidelines, the routine performance ofupper GI tract radiographic imaging todiagnose GER or GERD is not justified,4

because upper GI tract series are toobrief in duration to adequately ruleout the occurrence of pathologic re-flux, and the high frequency of non-pathologic reflux during the examinationcan encourage false-positive diagnoses.Additionally, observation of the refluxof a barium column into the esoph-agus during GI tract contrast studiesmay not correlate with the severityof GERD or the degree of esophagealmucosal inflammation in patients withreflux esophagitis. It is recognized thatupper GI tract series are useful in theevaluation of vomiting to screen forpossible anatomic abnormalities of theupper GI tract.4 For example, in infantswith bilious vomiting, an upper GI tractseries may be useful for evaluating forpossible malrotation or duodenal web.Persistent, forceful vomiting in the firstfew months of life should be evaluatedwith pyloric ultrasonography to evalu-ate for possible pyloric stenosis. Anupper GI tract series should be re-served if the results of the pyloric ul-trasound are equivocal.

Esophageal pH Monitoring

Continuous intraluminal esophagealpH monitoring can be used to quan-tify the frequency and duration ofesophageal acid exposure duringa study period. The conventionaldefinition of acid exposure in theesophagus is a pH <4.0, the pH mostassociated with a complaint of heart-

burn in adults. Esophageal pH metricsgenerally include an absolute numberof reflux episodes detected duringmonitoring, the duration of reflux epi-sodes detected, and the reflux index,which is calculated as the percentageof a study period during which esoph-ageal pH is <4.0. Although esophagealpH monitoring may be useful for asso-ciating a temporal relationship betweena symptom and acid reflux and toevaluate the efficacy of pharmacologictherapy on acid suppression, mountingevidence suggests poor reproducibilityof pH testing, as well as a clear con-tinuum between pH findings in physio-logic GER and pathologic GERD. In turn,esophageal pH monitoring is losingvalue as a primary modality for di-agnosing or managing pediatric GERD.34

Multichannel IntraluminalImpedance Monitoring

Multiple intraluminal impedance (MII)is an emerging technology for detect-ing the movement of both acidic andnonacidic fluids, solids, and air in theesophagus, thereby providing a moredetailed picture of esophageal eventsthan pH monitoring.34 MII can be usedto measure volume, speed, and physi-cal length of both anterograde andretrograde esophageal boluses. Com-bined pH/MII testing is evolving into thetest of choice to detect temporal rela-tionships between specific symptomsand the reflux of both acid and nonacidgastric contents. In particular, MII hasbeen used in recent years to investigatehow GER and GERD correlate with ap-nea, cough, and behavioral symptoms.35

According to the new guidelines, MII andpH electrodes can and should be com-bined on a single catheter.4

Gastroesophageal Scintigraphy

Gastroesophageal scintigraphy scansfor reflux of 99mTc-labeled solids orliquids into the esophagus or lungsafter administration of the test





material into the stomach. This nuclearscan evaluates postprandial reflux andcan also quantitate gastric emptying;however, the lack of standardized tech-niques and age-specific normal valueslimits the usefulness of this test.Therefore, gastroesophageal scintigra-phy is not recommended in the routineevaluation of pediatric patients withGER.4

Endoscopy and Esophageal Biopsy

It is certainly preferable to pursueconservative measures for treatingGERD in children before consideringthe use of more invasive testing. Inparticular, any diagnostic benefits ofpursuing upper endoscopy in pediatricpatients suspected of having GERDmust also be weighed against minimal,but not entirely negligible, proceduraland sedation risks.36 Nevertheless, theperformance of upper endoscopy al-lows direct visualization of the esoph-ageal mucosa to determine the presenceand severity of injury from the reflux ofgastric contents into the esophagus.26

Esophageal biopsies allow evaluationof the microscopic anatomy.24 Upperendoscopy with esophageal biopsy maybe useful to evaluate inflammation inthe esophageal mucosa attributable toGERD and to exclude other associatedconditions with symptoms that canmimic GERD, such as eosinophilicesophagitis. Recent data confirm thatapproximately 25% of infants youngerthan 1 year will have histologic evi-dence of esophageal inflammation.37

This test is indicated in patients withGERD who fail to respond to pharma-cologic therapy or as part of the ini-tial management if symptoms of poorweight gain, unexplained anemia orfecal occult blood, recurrent pneumo-nia, or hematemesis exist.

Upper endoscopy may also be helpfulin the assessment of other causes ofabdominal pain and vomiting in pe-diatric patients, such as esophageal

or antral webs, Crohn esophagitis,peptic ulcer, Helicobacter pylori in-fection, and infectious esophagitis.Erosive esophagitis is reported lessoften in infants and children withGERD than in adults with GERD; how-ever, a normal endoscopic appear-ance of the esophageal mucosa inpediatric patients does not excludehistologic evidence of reflux esoph-agitis.5,8 Esophageal biopsy is beneficialin evaluating for conditions that maymimic symptoms of GERD, such as eo-sinophilic esophagitis, infectious esoph-agitis (Candida esophagitis or herpeticesophagitis), Crohn disease, or Barrettesophagus.24 Because endoscopic find-ings correlate poorly with histologictesting in infants and children, per-forming esophageal biopsies duringendoscopy is recommended for theevaluation of GERD in children.4

MANAGEMENT

The new guidelines describe severaltreatment options for treating childrenwith GER and GERD. In particular, life-style changes are emphasized, becausethey can effectively minimize symptomsof both in infants and children. Forpatients who require medication, op-tions include buffering agents, acidsecretion suppressants, and promotersof gastric emptying and motility. Finally,surgical approaches are reserved forchildren who have intractable symp-toms unresponsive to medical therapyor who are at risk for life-threateningcomplications of GERD.

LIFESTYLE CHANGES

Lifestyle Modifications for Infants

Lifestyle changes to treat GERD ininfants may involve a combinationof feeding changes and positioningtherapy. Modifying maternal diet if in-fants are breastfed, changing formulas,and reducing the feeding volume whileincreasing the frequency of feedings

may be effective strategies to addressGERD in many patients. In particular,the guidelines emphasize that milkprotein allergy can cause a clinicalpresentation that mimics GERD ininfants. Therefore, a 2- to 4-week trialof a maternal exclusion diet that re-stricts at least milk and egg is rec-ommended in breastfeeding infantswith GERD symptoms, whereas an ex-tensively hydrolyzed protein or aminoacid–based formula may be appro-priate in formula-fed infants.4,30 It isimportant to note that this recom-mendation applies to the subset ofinfants with complications of GER, andnot “happy spitters.”

In 1 study of formula-fed infants, GERDsymptoms resolved in 24% of infantsafter a 2-week trial of changing toa protein hydrolysate formula thick-ened with 1 tablespoon rice cereal perounce, avoiding overfeeding, avoidingseated and supine positions, and avoidingenvironmental tobacco smoke.3 Feedingchanges can also be recommendedin breastfed infants, because it iswell known that small amounts ofcow milk protein ingested by themother may be expressed in humanmilk. Indeed, several studies havefound that breastfed infants maybenefit from a maternal diet thatrestricts cow milk and eggs.38,39

The feeding management strategy thatinvolves the use of thickened feedings,either by adding up to 1 tablespoon ofdry rice cereal per 1 oz of formula30 orchanging to commercially thickened(added rice) formulas for full-terminfants who are not cow milk proteinintolerant, is recognized as a reason-able management strategy for other-wise healthy infants with both GER andGERD.4 On the other hand, all pediatricclinicians should be aware of a possibleassociation between thickened feedingsand necrotizing enterocolitis in preterminfants.40 The Food and Drug Adminis-tration issued a warning regarding a



common commercially available thick-ening agent in 2011, suggesting that“parents, caregivers and health careproviders not...feed ‘SimplyThick’ toinfants born before 37 weeks gestationwho are currently receiving hospitalcare or have been discharged from thehospital in the past 30 days.”

Thickened feedings appear to de-crease observed regurgitation ratherthan the actual number of reflux epi-sodes. Little is known about the effectof thickening formula on the naturalhistory of infantile reflux or the po-tential allergenicity of commercialthickening agents. Excessive energyintake may occur with long-term use offeedings thickened with rice cereal orcorn. To this point, it is important torealize that thickening a 20-kcal/ozinfant formula with 1 tablespoon ofrice cereal per ounce increases theenergy density to 34 kcal/oz. Com-mercially available antiregurgitantformulae contain processed rice, corn,or potato starch; guar gum; or locustbean gum and may present an optionthat does not involve excess energyintake by infants when consumed innormal volumes. To date, there hasbeen little investigation into any re-lationship between use of added ricecereal or antiregurgitant formulae andchildhood obesity.

Lifestyle changes that may also benefitinfants with GERD include keepingthem in the completely upright posi-tion or even placing them prone. In-deed, a number of recent studies thatused impedance and pH monitoringhave confirmed older studies that usedpH monitoring to demonstrate signif-icantly less GER in infants in the flatprone position compared with theflat supine position.41,42 However, theguidelines are unequivocal that therisk of sudden infant death syndromein sleeping infants outweighs thebenefits of prone positioning in themanagement of GERD and, therefore,

that prone positioning should beconsidered acceptable only if the in-fant is observed and awake.4 Pronepositioning is suggested to be benefi-cial in children older than 1 year witheither GER or GERD, because the riskof sudden infant death syndrome isgreatly decreased in older age groups.

Perceived and actual benefits of seatedor semisupine positioning are alsoexplored in the new guidelines.Semisupine positioning, particularlyin an infant carrier or car seat, mayexacerbate GER and should beavoided when possible, especiallyafter feeding.43 More recent dataobtained with esophageal imped-ance–pH monitoring have confirmedthat postprandial reflux occurssimilarly when infants are in carseats as when they are supine butalso suggests that being in a carseat for 2 hours after a feedingreduces reflux-related respiratoryevents.44

Lifestyle Modifications for Childrenand Adolescents

Lifestyle changes that may benefitGERD in older children and adoles-cents are more akin to recommen-dations made for adult patients,including the importance of weightloss in overweight patients, cessationof smoking, and avoiding alcohol use.Recommendations for conservativelymanaging GERD in older children andadolescents, likewise, may involve di-etary modification and positioningchanges, although the effectiveness ofthe latter as a treatment of GERD inolder children has not been as wellstudied as in infants. In terms of di-etary changes, older children andadolescents are advised to avoid caf-feine, chocolate, alcohol, and spicyfoods as potential symptom triggers.The guidelines also point out that 3independent studies have demonstrateddecreased reflux episodes with

postprandial chewing of sugarlessgum.45–47

PHARMACOTHERAPEUTIC AGENTSFOR PEDIATRIC GERD

Several medications may be used totreat GERD in infants and children. The2 major classes of pharmacologicagents for treatment of GERD are acidsuppressants and prokinetic agents(Table 4). Growing evidence that de-monstrates the former to be moreeffective than the latter has led to anincreased use of acid suppressants tomanage suspected GERD in pediatricpatients4,39; however, there is also sig-nificant concern for the overprescriptionof acid suppressants, particularly protonpump inhibitors (PPIs), and it is im-portant to understand the new guide-lines for medication indications.

Acid Suppressants

The main classes of acid suppressantsare antacids, histamine-2 receptorantagonists (H2RAs), and PPIs. Theprinciples of using these medicationsin the treatment of pediatric GERD aresimilar to those in adults, other thanthe need to prescribe weight-adjusteddoses and the need to consider theform of the drug prescribed (ie, forease of ingestion in infants and chil-dren). Dosage ranges for drugs com-monly prescribed for pediatric patientswith GERD are listed in Table 4.

Antacids

Antacids are a class of medicationsthat can be used to directly buffergastric acid in the esophagus or stom-ach to reduce heartburn and ideallyallow mucosal healing of esophagitis.There is limited historical evidencethat on-demand use of antacids canlead to symptom relief in infants andchildren.48 Instead, although antacidsare generally seen as a relatively be-nign approach to treating pediatric





GERD, it is important to recognize thatthey are not entirely without risk. In-deed, several studies link aluminum-containing preparations with alumi-num toxicity and its complications inchildren.49–51 Similarly, milk-alkali syn-drome, a triad of hypercalcemia, al-kalosis, and renal failure, has beendescribed in children receiving calcium-containing preparations and adds toa note of caution. According to thenew guidelines, chronic antacid ther-apy is generally not recommended inpediatrics for the treatment of GERD.4

In addition, the safety and efficacy ofsurface protective agents, such asalginates or sucralfate, an aluminum-containing preparation, have not beenadequately studied in the pediatricpopulation. As such, no surface agentis currently recommended as indepen-dent treatment of severe symptomsof GERD or erosive esophagitis inchildren.4

H2RAs

H2RAs represent a major class ofmedications that has completely rev-olutionized the treatment of GERD inchildren. H2RAs decrease the secretionof acid by inhibiting the histamine-2receptor on the gastric parietal cell.Expert opinion suggests little clinical

difference between the various for-mulations of H2RAs. Randomized placebo-controlled pediatric clinical trials haveshown that cimetidine and nizatidineare superior to placebo for the treat-ment of erosive esophagitis in chil-dren.52,53 Pharmacokinetic studies inschool-aged children suggest thatgastric pH begins to increase within 30minutes of administration of an H2RAand reaches peak plasma concen-trations 2.5 hours after dosing. Theacid-inhibiting effects of H2RAs lastfor approximately 6 hours, so H2RAsare quite effective if administered 2or 3 times a day.

However, H2RAs inherently have somelimitations. In particular, a fairly rapidtachyphylaxis can develop within 6weeks of initiation of treatment, lim-iting its potential for long-term use. Inaddition, H2RAs have been shown to beless effective than PPIs in symptomrelief and healing rates of erosiveesophagitis. Although most of thesedownsides have been demonstratedmost clearly in adults, they are alsobelieved to affect children. It is alsoimportant to recognize that cimetidinehas specifically been linked to an in-creased risk of liver disease and gy-necomastia, and that these associationsmay be generalizable to other H2RAs.

PPIs

Most recently, PPIs have emerged asthe most potent class of acid sup-pressants by repeatedly demonstrat-ing superior efficacy compared withH2RAs. PPIs decrease acid secretion byinhibition of H+, K+-ATPase in the gas-tric parietal cell canaliculus. PPIs areuniquely able to inhibit meal-inducedacid secretion and have a capacity tomaintain gastric pH >4 for a longerperiod of time than H2RAs. Theseproperties contribute to higher andfaster healing rates for erosiveesophagitis with PPI therapy com-pared with H2RA therapy. Finally,unlike H2RAs, the acid suppressionability of PPIs has not been observedto diminish with chronic use.

The timing of dosing most PPIs isimportant for maximum efficacy.Both pediatricians and pediatricmedical subspecialists must be dili-gent at educating their patients toadminister PPIs, ideally, approxi-mately 30 minutes before meals.7

All clinicians should also recognizethat the metabolism of PPIs isknown to differ in children com-pared with adults, with a trendtoward a shorter half-life, necessi-tating a higher per-kilogram dose toachieve a peak serum concentration

TABLE 4 Pediatric Doses of Medications Prescribed for GERD

Medications Doses Formulations Ages Indicated by the Foodand Drug Administration

Cimetidine 30–40 mg/kg/d, divided in 4 doses Syrup ≥16 yRanitidine 5–10 mg/kg/d, divided in 2 to 3 doses Peppermint-flavored syrup; Effervescent tablet 1 mo–16 yFamotidine 1 mg/kg/d, divided in 2 doses Cherry-banana-mint–flavored oral suspension 1–16 yNizatidine 10 mg/kg/d, divided in 2 doses Bubble gum–flavored solution ≥12 yOmeprazole 0.7–3.3 mg/kg/d Sprinkle contents of capsule onto soft foods 2–16 yLansoprazole 0.7–3 mg/kg/d Sprinkle contents of capsule onto soft foods or select juices 1–17 y

Administer capsule contents in juice through nasogastric tubeStrawberry-flavored disintegrating tabletOrally disintegrating tablet via oral syringe or nasogastrictube (≥8 French)

Esomeprazole 0.7–3.3 mg/kg/d Sprinkle contents of capsule onto soft foods 1–17 yAdminister capsule contents in juice through nasogastric tube

Rabeprazole 20 mg daily Oral tablet 12–17 yDexlansoprazole 30–60 mg daily Oral tablet No pediatric indicationPantoprazole 40 mg daily (adult dose) Oral tablet No pediatric indication



and area under the curve similar tothose in adults.45 A fairly wide rangeof effective doses is evident in chil-dren. For example, an open-labelstudy of omeprazole in children re-vealed an effective dosage range of0.7 to 3.3 mg/kg daily, on the basis ofimprovement in clinical symptomsand the results of esophageal pHmonitoring.47 Lansoprazole, 0.7 to3.0 mg/kg daily, improved GERDsymptoms and healed all cases oferosive esophagitis in the treat-ment of 1- to 12-year-old childrenwith GERD.48 Other trials of PPItherapy support the efficacy of treat-ment of severe esophagitis and esoph-agitis refractory to H2RAs in children.4,45

As in adults, PPIs are considered safeand generally well tolerated with rel-atively few adverse effects. In terms oftheir long-term use, published studieshave reported PPI use for up to 11years in small numbers of children.16

The Food and Drug Administration hasapproved a number of PPIs for use inpediatric patients in recent years, in-cluding omeprazole, lansoprazole, andesomeprazole for people 1 year andolder and rabeprazole for people 12years and older. Nonetheless, the newguidelines strike a note of cautionwhen discussing the dramatic in-crease in past years in the number ofPPI prescriptions written for pediatricpatients, particularly infants, who maybe at increased risk of lower re-spiratory tract infections.54–56

Overuse or misuse of PPIs in infantswith reflux is a matter for greatconcern. Placebo-controlled trials ininfants have not demonstrated supe-riority of PPIs over placebo forreduction in irritability.57 Headaches,diarrhea, constipation, and nauseahave been described as occurring inup to 14% of older children andadults prescribed PPIs.25,58 Althoughconsidered a benign histologic change,enterochromaffin cell hyperplasia has

FIGURE 1Approach to the infant with recurrent regurgitation and vomiting.





recently been demonstrated in up to50% of children receiving PPIs for morethan 2.5 years.25 Finally, a growing bodyof evidence suggests that acid sup-pression, in general, with either H2RAsor PPIs, may be a risk factor for pedi-atric community-acquired pneumonia,gastroenteritis, candidemia, and necro-tizing enterocolitis in preterm infants.59,60

Prokinetic Agents

Desired pharmacologic effects ofprokinetic agents include improvingcontractility of the body of theesophagus, increasing lower esoph-ageal sphincter pressure, and in-creasing the rate of gastric emptying.To date, efforts to design a prokineticagent with benefits that outweighadverse effects has proven difficult.Even metoclopramide, the most com-mon prokinetic agent still available,recently received a black box warningregarding its adverse effects. Indeed,adverse effects have been reported in11% to 34% of patients treated withmetoclopramide, including drowsiness,restlessness, and extrapyramidal reac-tions. Although a meta-analysis of 7randomized controlled trials of meto-clopramide in patients younger than 2years with GERD confirmed a decreasein GERD symptoms, it was clearly at thecost of such significant adverse ef-fects.61 Other drugs in this categoryinclude bethanechol, cisapride (nolonger available commercially in theUnited States), baclofen, and eryth-romycin. Each works as a prokineticby using a different mechanism. Nev-ertheless, after careful review, guide-lines unequivocally state that there isinsufficient evidence to support theroutine use of any prokinetic agent forthe treatment of GERD in infants orolder children.4

Surgery for Pediatric GERD

Several surgical procedures can beused to decrease GER disorders in

children. Fundoplication, whereby thegastric fundus is wrapped around thedistal esophagus, is most commonand can be performed to prevent refluxby increasing baseline pressure of thelower esophageal sphincter, decreasingthe number of transient lower esoph-ageal sphincter relaxations, and in-creasing the length of the esophagusthat is intra-abdominal to accentuatethe angle of His and reduce a hiatalhernia, if indicated.17,56,57 Total esoph-agogastric dissociation is another op-erative procedure that is rarely usedafter failed fundoplication. Both pro-cedures are associated with significant

morbidity and do not reduce the riskof direct aspiration of oral contents.Careful patient selection is one of thekeys to successful outcome.17 Childrenwho have failed pharmacologic treat-ment may be candidates for surgicaltherapy, as are children at severe riskof aspiration of their gastric contents.In most patients, if acid suppressionwith PPIs is ineffective, the accuracy ofthe diagnosis of GERD should be reas-sessed, because fundoplication maynot produce optimum clinical results.Clinical conditions, such as cyclicvomiting, rumination, gastroparesis,and eosinophilic esophagitis, should

FIGURE 2Approach to the infant with recurrent regurgitation and weight loss.



be carefully ruled out before surgery,because they are likely to still causesymptoms after surgery. If antirefluxsurgery is pursued, the new guide-lines also stress the importance ofproviding families with adequatecounseling and education before theprocedure so that they have a “re-alistic understanding of the potentialcomplications…including symptomrecurrence.”4

SUMMARY

The updated guidelines published in2009 are particularly rich with de-scriptions of typical presentations ofGERD across all pediatric age groups.4

With an emphasis on evidence-based,best practice, they present a numberof algorithms that can be of great useto both general pediatricians and pe-diatric medical subspecialists. Theguidelines discuss the evaluation andmanagement of recurrent regurgitationand vomiting in both infants and olderchildren and the importance of dis-tinguishing GERD from numerous otherdisorders. The figures shown demon-strate the recommended approachesfor commonly encountered presenta-tions of GERD in pediatric patients andare summarized here.

In the infant with uncomplicated re-current regurgitation, it may be im-portant to recognize physiologic GERthat is effortless, painless, and notaffecting growth (Fig 1). In this situa-tion, pediatricians should focus onminimal testing and conservativemanagement. Overuse of medicationsin the so-called “happy spitter” shouldbe avoided by all pediatric physicians.Instead, pediatricians are well servedto diagnose GER and provide signif-icant parental education, anticipa-tory guidance, and reassurance. Inturn, they will provide high-value,high-quality care without risk totheir patients or unnecessary directand indirect costs.

Pediatricians must also be able torecognize infants with recurrent re-gurgitation and troublesome symp-toms of GERD (Fig 2). The newguidelines emphasize weight loss asa crucial warning sign that shouldalter clinical management. Older chil-dren with heartburn may benefit fromempirical treatment with PPIs (Fig 3).In general, there is a paucity of stud-ies in pediatrics that demonstrate theeffectiveness of this approach. In-stead, it is essential to carefully followall patients empirically treated forGERD to ensure that they are improv-ing, because there are many clinicalconditions that may mimic its symp-toms. It cannot be overemphasizedthat pediatric best practice involvesboth identifying children at risk forcomplications of GERD and reassuringparents of patients with physiologic GER

who are not at risk for complicationsto avoid unnecessary diagnostic proce-dures or pharmacologic therapy.62–64

LEAD AUTHORSJenifer R. Lightdale, MD, MPHDavid A. Gremse, MD

SECTION ON GASTROENTEROLOGY,HEPATOLOGY, AND NUTRITIONEXECUTIVE COMMITTEE, 2011–2012Leo A. Heitlinger, MD, ChairpersonMichael Cabana, MDMark A. Gilger, MDRoberto Gugig, MDJenifer R. Lightdale, MD, MPHIvor D. Hill, MB, ChB, MD

FORMER EXECUTIVE COMMITTEEMEMBERSRobert D. Baker, MD, PhDDavid A. Gremse, MDMelvin B. Heyman, MD

STAFFDebra L. Burrowes, MHA

FIGURE 3Approach to the older child or adolescent with heartburn.





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DOI: 10.1542/peds.2013-0421; originally published online April 29, 2013; 2013;131;e1684Pediatrics

HEPATOLOGY, AND NUTRITIONJenifer R. Lightdale, David A. Gremse and SECTION ON GASTROENTEROLOGY,

Gastroesophageal Reflux: Management Guidance for the Pediatrician

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