Gastro-oesophageal reflux in infancy

Gastro-oesophagealreflux in infancyVinod KolimaralaR Mark BeattieAkshay BatraAbstractGastro-oesophageal reflux is very common in infancy.It is important to differentiate benign physiological reflux from gastro-oesophageal reflux disease,which is associated with significant morbidity.This re-view summarises the approach to infants with symptoms and signs of reflux,differential diagnosis,investigations and management including non-pharmacological,pharmacological and surgical treatments.Most infants with physiological gastro-oesophageal reflux do not require any medical management if the infant is thriving.Severe cases require a careful diagnostic work,treatment of associated conditions and aggressive medical management of the reflux.Involvement of the multidisciplinary team is essential and in persistent refractory reflux surgical intervention may need to be considered.Keywords gastro-oesophageal reflux;infancy;oesophagitis;reflux; vomitingGastro-oesophageal refluxGastro-oesophageal reflux(GOR)is the involuntary passage of the gastric contents into the oesophagus.It is a normal physio-logical phenomenon,particularly common in infancy.Most epi-sodes,in healthy individuals,last less than3minutes,occur in the postprandial period,and cause few or no symptoms.It is a very common presentation;both in primary and secondary care setting and can affect nearly50%of infants less than three months old.Major factors include the high volume of milk ingested compared with older children/adults,posture and the functional immaturity of the lower oesophageal sphincter.The natural history of GOR is generally of improvement with age,with less than5%of children with vomiting or regurgitation in infancy continuing to have symptoms after the age of14 months.This is due to a combination of growth in length of the oesophagus,a more upright posture,increased tone of the lower oesophageal sphincter,and a more solid diet.Gastro-oesophageal reflux disease(GORD)Gastro-oesophageal reflux disease(GORD)is defined as‘gastro-oesophageal reflux associated with troublesome symptoms or complications’although the authors caution that this definition is complicated by unreliable reporting of symptoms in young chil-dren.Gastrointestinal sequelae include oesophagitis,haema-temesis,oesophageal stricture formation,and Barrett’s oesophagus.Extra-intestinal sequelae can include acute life-threatening events and apnoea,chronic otitis media,sinusitis, secondary anaemia,and chronic respiratory disease(chronic wheezing/coughing or aspiration),as well as failure to thrive.Oesophagitis can develop as a result of acid or non-acid reflux and presents with symptoms of crying and irritability in infants and can lead to food aversion.This is likely to be a significant factor in faltering growth seen in some children with GORD. EpidemiologyGORD is a significant problem for infants in the community and in hospital setting.Determination of the exact prevalence of GORD at any age is difficult because of a lack of specific symp-toms but approximately33%of infants seek medical attention for symptoms suggestive of reflux,of whom up to20%require diagnostic evaluation.The problem is more pronounced in certain groups like infants born prematurely,infants with neu-rodisability,with congenital malformations like repaired oeso-phageal atresia or congenital diaphragmatic hernia,and those with chronic lung disease.Over50%of children with neuro-disability have GORD,due to oesophageal dysmotility and a poorly functioning lower oesophageal sphincter.They have trouble expressing their symptoms,and may also have co-morbidities,which may impact on the ability to perform investigations.PathophysiologyThe physical barrier between the oesophagus and stomach is provided by the lower oesophageal sphincter(LOS)and the diaphragm.The LOS,or internal sphincter,is a specialised part of the circular smooth muscle of the distal oesophagus.Both com-ponents work together to stop refluxing of gastric contents into the oesophagus.The major mechanism of reflux is transient lower oesophageal sphincter relaxation(TLOSR).This is a normal phenomena.Relaxation of LOS occurs in response to swallowing but this is brief and lasts less than10seconds.In contrast,in infants with GORD,TLOSR is prolonged(more than 10secs)and accounts for75e90%episodes of reflux in infants.Other causes for GORD include abnormal position of LOS as seen in hiatus hernia.This results in inability of diaphragm to contribute to lower oesophageal tone and contraction to prevent reflux.Delayed gastric emptying is felt to be a contributing factor in worsening of reflux and is especially seen in children with neurodisability.It exacerbates GOR by prolonging gastric distension and increasing the frequency of transient LOS relax-ation.There is an associated delay in clearance of reflux contentsVinod Kolimarala MBBS MRCPCH,Speciality Trainee,Paediatric Gastroenterology,Department of Paediatric Gastroenterology, University Hospital Southampton NHS Trust,Southampton,UK. Conflicts of interest:none declared.R Mark Beattie MBBS BSc(Hons)FRCPCH MRCP,Professor in Paediatric Gastroenterology and Nutrition,Department of Paediatric Gastroenterology,University Hospital Southampton NHS Trust, Southampton,UK.Conflicts of interest:none declared.Akshay Batra MBBS MD MRCPCH,Consultant,Paediatric Gastroenterology,Department of Paediatric Gastroenterology, University Hospital Southampton NHS Trust,Southampton,UK. Conflicts of interest:none declared.from oesophagus increasing oesophageal exposure to gastric contents,leading to oesophagitis.Symptoms,signs and historyGastro-oesophageal reflux disease can be oesophageal or extra-oesophageal depending on the presenting symptoms.The symptoms,signs and typical historical features of GORD are summarised in Tables1and2.Differential diagnosisGiven the frequency of gastro-oesophageal reflux it is easy to forget that other conditions can present with similar features. The commoner alternative diagnoses include:Infection,e.g.urinary tract infection,gastroenteritis,peptic ulcer diseaseIntestinal obstruction e.g.pyloric stenosis,malrotation,in-testinal atresia,Food allergy and intolerances e.g.cow’s milk allergy,soy allergy,coeliac diseaseEosinophilic oesophagitisMetabolic disorders e.g.diabetes,inborn errors of metabolismIntestinal dysmotilityDrug induced vomiting e.g.cytotoxic agentsPrimary respiratory disease e.g.asthma,cysticfibrosisFactitious induced illnessChild neglect or abuseIt is important to remain vigilant for other diagnoses. ManagementPhysiological reflux is common in infancy and is a clinical diagnosis.For most parents reassurance that the condition willresolve without treatment is all that is needed.It is important to carefully consider the differential diagnosis,particularly if symptoms persist or worsen.Full assessment of infants is essential including a full feeding history to explore possibility of overfeeding or difficulty with feeding.Careful attention needs to be paid to severity of symp-toms,faltering growth and relevant social factors,e.g.parental anxiety and stress.Severe cases need further assessments and investigation.These may include barium study,pH study, impedence study,gastro-oesophageal scintigraphy,gastroscopy and biopsy(described below).Difficult cases require assessment by multidisciplinary team including dietician,speech and language therapist,paediatric gastroenterologist and paediatric surgeon.InvestigationsOesophageal pH monitoringAcid reflux into the oesophagus occurs in all infants as a physi-ological phenomenon and is only significant when it occurs in excess.The pH probe is designed to measure acidity(i.e.acid reflux)in the lower oesophagus and monitors the frequency and duration of reflux into the oesophagus.It is a microelectrode passed through the nose and down the back of the throat to sit3 e5cms above the lower oesophageal sphincter and records for a set period,usually24hrs.A reflux episode is defined as the drop in oesophageal pH less mon parameters obtained from pH monitoring include the total number of reflux episodes, the number of reflux episodes lasting more than5minutes,the duration of the longest reflux episode,and the reflux index which is the percentage of time when pH was less than4.Specific indications for pH Study include diagnostic uncer-tainty in presence of extra oesophageal symptoms,poor response to medical treatment or to quantify the degree of reflux (Figure1).Interpretation of oesophageal pH studiesThe North American Society of Pediatric Gastroenterology, Hepatology and Nutrition(NASPGHAN)consensus recommen-dation is that a reflux index greater than7%is abnormal.In general reflux index up to10%is mild,10e20%is moderate which is usually controlled by medical therapy and more than 30%is severe and may require surgical intervention.When interpreting studies it is important to consider the following: It is useful to correlate symptoms(e.g.,cough,chest pain) with acid reflux episodes and to select those infants and children with wheezing or respiratory symptoms in whom GOR is a causative/aggravating factor.The sensitivity,specificity and clinical utility of pH moni-toring for diagnosis and management of possible extra oesophageal complications of GOR are not wellestablished. Table1There are several limitations to pH studies.These include: pH studies are unable to detect anatomical abnormalities (e.g.stricture,hiatus hernia,malrotation)or aspiration. Non-acid reflux will not be detected.This should be borne in mind with non-acidic feeds such as infant formula and in particular when infants are continuously fed.The changes in environment,diet and behaviour as a result of investigation and admission to hospital may impact on the result.There is potential for technical difficulties and reproducibility is poor.pH studies provide no objective measures of inflammation,and thus are less useful than endoscopy and biopsies for the diagnosis and grading of oesophagitis.The severity of pathologic acid reflux does not correlate consistently with symptom severity or demonstrable bined multiple intraluminal impedance (MII)and pH monitoringSome of the limitations of the pH study in detecting nonacid reflux and proximal reflux can be overcome by combining it with intraluminal impedance monitoring.This measures changes in the electrical impedance (i.e.resistance)between multiple elec-trodes located along an oesophageal catheter.Oesophageal impedance tracings are then analyzed for the typical changes caused by liquid,solid,air or mixed bolus and can differentiate between antegrade and retrograde flow.MII reflux episodes can be categorized as acidic (pH less than 4lasting 4seconds or more),weakly acidic (pH4-7)or weakly alkaline (pH 7).Studies on the normal values in in-fants and children are lacking.Normal values are results of consensus agreements,data extrapolation and studies on symptomatic children.ESPGHAN EURO-PIG suggests up to 100reflux episodes in Infants aged less than 1and oesophageal acid exposure time up to 10%and up to 70episodes in children more than 1year and oesophageal exposure time less than 3%is regarded asnormal.Table2Figure 1An example of a pH study in an infant showing moderate re flux.The indications are the same as those for pH monitoring.MII-pH recording provides more information than simple pH mea-surement because it allows the study of non-acid reflux,extent of reflux and the temporal association between symptoms and reflux.MII still has the following limitations:high cost;limited contribution to medical therapeutic implications;and lack of evidence-based parameters for the assessment of GOR and especially symptom association in children (Figure 2).Radiological investigationsBarium swallow :assesses the patient over only short periods and may therefore miss pathological reflux or overdiagnose physiological reflux.It is therefore neither a sensitive or specific test.Its main role is in detecting anatomical abnormalities such as hiatus hernia,intestinal malrotation,oesophageal stricture or web,atypical pyloric stenosis,gastric web,duodenal web or volvulus.Gastro-oesophageal scintigraphy :uses continuous evaluation for up to an hour after radiolabelled meal.Food or milk labelled with 99Technetium is given to the infant and stomach and oesophagus are scanned.The standards for interpretation of this test are poorly established and it is not recommended for the routine evaluation of paediatric patients with suspected GORD.Its main role is in the assessment of gastric emptying times to identify the group of children with foregut dysmotility and delayed gastric emptying.It also has a limited role in diagnosis of pulmonary aspiration in patients with chronic and refractory respiratory symptoms.Delayed gastric emptying is especiallycommon in children with cerebral palsy in whom vomiting may reflect an overall gut dysmotility rather than GORD.Oesophageal manometry :measures the pressures and peristaltic contractions in the oesophagus.It is now increasingly used to help in the diagnosis of pathological reflux and has a role in identifying the position of lower oesophageal sphincter and assessing its morphology and function.The transient relaxation of the sphincter can be better defined with high resolution manometry and provocative tests with multiple swallows help assess severity.Its main role lies in looking for conditions,which can mimic GORD,e.g.achalasia or other motor disorders of the oesophagus such as diffuse oesophageal spasm,Chagas disease,isolated hypertensive lower oesophageal sphincter.Gastroscopy and biopsy:is used in children with suspected oesophagitis.Upper gastrointestinal endoscopy is a useful investigation and should be considered in all children with se-vere symptomatic reflux.Presence of active oesophagits either macroscopically or on histology is the most specific test for GORD though normal oesophageal histology does not exclude significant gastro-oesophageal reflux.The histological features include an increased eosinophil count,intrapapillary blood vessel dilatation,intraepithelial bleeding,basal cell hyperplasia,dilated intercellular spaces,and enhanced cellular proliferation.Endoscopic biopsy is important to identify or rule out other causes of oesophagitis and to diagnose and monitor Barrettoesophagus.Figure 2Combined MII and pH monitoring demonstrating acid re flux in an infant.The indications for endoscopy in GORD include:Gastrointestinal bleeding which can present as haemetem-esis or malenaFailure of resolution of symptoms beyond1year of age despite medical therapyFaltering growthFood aversionSuspected Sandifer’s syndromeManagementMost patients with physiological gastro-oesophageal reflux are managed in primary care by the health visitor and general practitioner and do not require any specific treatment.Non-pharmacological measures include:Review of feeding and feeding practice e checking for overfeeding,trial of smaller more frequent feeds,too small or too large a teat(both of which can cause air swallowing).Review of feeding posture e Infants have significantly less reflux when placed in the prone position than in a supine position.However,prone position is associated with a higher rate of sudden infants death syndrome(SIDS).In infants from birth to12months of age with reflux,the risk of SIDS generally outweighs the potential benefits of prone sleeping.In children more than1year it is likely that there is a benefit to right side positioning during sleep and elevation of the head of the bed.Use of feed thickeners and use of anti-regurgitation milks e these are useful in reducing the symptoms of GOR and should be considered in children with persistent symptom-atic reflux impacting on nutrient intake or through excessive vomiting on lifestyle.They should not be used for healthy children who regurgitate.Extensively hydrolysed or amino acid based formula e In-fants with persistent symptoms with associated redflags like blood in stools,history of eczema or atopy could have non IgE mediated cow’s milk protein intolerance and may benefit from a2e6week trial of elimination diet.This can be done by elimination of cow’s milk in maternal diet in breast fed infants.In bottle fed infants extensively hydrolysed formula should be used.Soya formulae should be avoided as there is significant cross reactivity between cow’s milk and soya protein and because of the presence of phytoestrogens in soya milk they are not recommended in infants less than6 months.Drug treatmentDrug treatment is indicated in children with severe symptomatic reflux or signs and symptoms suggestive of gastro-oesophageal reflux disease.The major pharmacological agents currently used for treating GORD in children are gastric acid e buffering agents,mucosal surface barriers,and gastric anti-secretory agents.Acid sup-pressant agents are the mainstay of treatment for all but the patient with occasional symptoms.The potential adverse effects of acid suppression,including increased risk of community-acquired pneumonias and GI infections,need to be balanced against the benefits of pound alginates:(e.g.Gaviscon Infant-Rickett Benckiser) are effective for symptomatic treatment for GOR.Infant gaviscon works by reacting with gastric acid to form a viscous gel.Infant Gaviscon comes in a dual sachet and each half is a dose.1dose for babies weighing less than4.5kg and2doses for those more than4.5kg given a maximum6times a day.Infant gaviscon can be added to formula feed or for breast fed infants dissolved in cooled boiled water and given by spoon after a feed.Chronic use of alginates is not recommended for GORD. Occasionally they can cause constipation and bloating.They should be used with caution in children with renal impairment as the product contains sodium and can cause hypernatraemia.An overdose can lead to a bezoar formation which may require surgical removal.Acid suppression agents:include H2-receptor blockers and proton pump inhibitors.H2receptor blockers are widely used in the management of reflux.They are safe and well tolerated and can be consid-ered before any further investigation in children who are thriving and in whom the diagnosis is robust.There are several studies that have suggested that H₂-antagonists are efficacious in children.Ranitidine is the most commonly used H2-receptor blocker.Ranitidine is well tolerated and has a low incidence of side-effects(common side-effects include fatigue,dizziness or diarrhoea).Oral ranitidine pro-vides symptomatic relief and endoscopic improvement of oesophagitis in children with GORD.Dosage for neonates is between2and3mg/kg TDS.Child1e5months1e3mg/kg TDS.Child6months-2years2e4mg/kg BD.Proton pump inhibitors(PPI)such as omeprazole and lan-soprazole are a group of drugs that irreversibly inactivate Hþ/KþATPase:the parietal cell membrane transporter.This increases the pH of gastric contents and decreases total volume of gastric secretion,thus facilitating emptying.Side effects reported with long term use include hypomagnese-mia,gastric fundal polyps and small increase in risk of osteoporotic fractures.Omeprazole is the most commonly used PPI and is shown to be effective in children with GORD resistant to ranitidine.For healing of erosive oesophagitis and relief of symptoms,PPIs are superior to H2-receptor blockers.Omeprazole is available as dispersible tablets or capsules given once daily.The tablet can be gently mixed or dispersed(not crushed)or the capsule broken for ease of administration in children.Dosage is0.7e1.4mg/kg per day although higher doses can be used,up to3mg/kg.When acid suppression is required,the smallest effective dose should be used.Most patients require only once-daily nsoprazole is the other commonly used PPI.Dosage0.5e1mg/kg OD a maximum dose of15mg OD can be used.Prokinetic drugs:can be helpful in some circumstances. Gastroesophageal reflux is primarily a motility disorder,and the use of pharmacologic agents that improve oesophageal and gastric motility are conceptually attractive as therapies.Unfor-tunately,the currently available prokinetic medications have only modest efficacy in relieving GORD symptoms,and the side effect profile makes them less useful clinical practice.Examples include metoclopramide,domperidone,and erythromycin.Domperidone is a dopamine-receptor(D2)blocker that has relatively fewer side effects but case reports of extrapyramidal side effects exist,as well as an effect on the QT interval(pro-longation).Domperidone acts to increase lower oesophageal sphincter pressure improve oesophageal clearance and promote gastric emptying.Domperidone is commonly used in clinical practice either as part of empirical medical therapy of gastro-oesophageal reflux disease or if delayed gastric emptying has been demonstrated on nuclear scintigraphy.In view of a small increased risk of cardiotoxicity,it is advisable to use domperidone in lower doses and only in cases with overt vomiting secondary to reflux.All infants should have an ECG to rule out prolonged QT interval before starting treat-ment and should be referred to a specialist if treatment is required for greater than3months.Buffering agents(magnesium hydroxide and aluminium hy-droxide)and sucralfate:are useful for occasional heart burn. Buffering agents carry significant risk of toxicity and are not recommended for long term use.Sucralfate binds to inflamed mucosa and forms a protective layer that resists further damage from gastric acid.Enteral feedingIn infants with faltering growth who are not responding to usual medical treatments a period of enteral tube feeding(ETF) should be considered.This ensures slow delivery of feeds and thus reduced distension of stomach and subsequent reflux. When tube feeding is started small oral stimulation in the form of small amount of oral feeds(milk or solids)should be continued.Post pyloric feeding,is reserved for severe cases not responding to other forms of management and associated with complications.As the stomach is bypassed there is no distension of stomach and there is reduction in reflux of gastric contents.This is particularly helpful in children with failure to thrive,severe oesophagitis and reflux related pul-monary aspiration.Continuous post pyloric feeding is most commonly used in children with neurodisability where the volume of feed is limited because of discomfort associated with feeding.SurgeryThe commonest operative intervention is fundoplication done laparoscopically or via open procedure.Children with co mor-bidities,particularly neurodisability who have the most severe GORD are at the highest risk for operative morbidity and post-operative failure.Before surgery it is essential to rule out non-GORD causes of symptoms and ensure that the diagnosis of chronic-relapsing GORD isfirmly established.Indications for surgery include:Failure of optimal medical therapyExtra oesophageal manifestation(asthma,cough,chest pain,recurrent pulmonary aspiration of refluxate) Complication of GORD(e.g.Barrett’s oesophagus or oeso-phageal stricture)It is important to provide families with appropriate education and a realistic understanding of the potential complications of surgery,which include recurrence of reflux(10%),retching, bloating,dumping and intestinal obstruction.Some children have a high risk of needing surgery.These include children with neurodisability,those with respiratory disease with intractable reflux(e.g.oesophageal atresia,bron-chopulmonary dysplasia),Children with complication of oeso-phagitis such as stricture or Barrett’s oesophagus and those who have had a tracheo-oesophagealfistula repair.Gastro-oesophageal reflux and neurodisabilityPaediatric neurodisability is an umbrella term for conditions associated with impairment of the nervous system,including conditions such as cerebral palsy,and epilepsy.Potential cau-ses of feeding difficulties include bulbar weakness,primary or secondary aspiration,reflux oesophagitis,widespread gut dys-motility,mobility and posture problems,poor nutritional state and constipation.These children require careful multidisci-plinary assessment by a feeding team including dietetics, speech and language therapy,occupational therapy and the neurodevelopmental paediatrician.Attention to nutrition is of key importance and many children with feeding difficulties benefit from a feeding gastrostomy.A fundoplication is required if reflux is severe although in some cases improved nutritional status will result in improvement of the reflux.The motility of the gut is a key factor in feed tolerance in children with cerebral palsy who may have delayed gastric emptying which impact significantly on the ability to feed particularly if nutrition is dependent upon nasogastric or gas-trostomy feeding.Therapeutic strategies include explanation and reassurance,trial of anti-reflux therapy,prokinetic agents such as domperidone and in some cases with marked dysmo-tility it may be necessary to give feeds by continuous infusion via gastrostomy or gastro-jejunal route.A milk free diet for a trial period of2e4weeks can be helpful.Hydrolysed protein formula feeds/MCT predominant feeds may be given as a milk substitute.Gastro-oesophageal reflux and respiratory disease Gastro-oesophageal reflux has been associated with significant respiratory symptoms in infants and children.There is a complex relationship between asthma and gastro-oesophageal reflux, manifested by a bidirectional cause and effect.One postulated mechanism for gastro-oesophageal reflux mediated airway disease involves micro-aspiration of gastric contents that leads to inflammation and bronchospasm. However,experimental evidence also supports the involve-ment of oesophageal acid e induced reflex bronchospasm,in the absence of frank aspiration.In such cases,gastro-oesophageal reflux therapy using either H2-blockers or pro-ton pump inhibitors has been shown to benefit patients with steroid-dependent asthma,nocturnal cough and reflux symp-toms.Similarly,intrinsic lung disease may through excessive coughing result in reflux.The association between gastro-oesophageal reflux and apparent life-threatening events is somewhat controversial and probably only relevant if the infant vomits,chokes or goes blue during or immediately after feeds.Barrett’s oesophagusThis refers to the presence of metaplastic columnar epithelium in the lower oesophagus thought to be a consequence of long-standing gastro-oesophageal reflux disease.There is an increased risk of adenocarcinoma of the oesophagus.It is rare in childhood and requires aggressive medical treat-ment,of the gastro-oesophageal reflux and regular endoscopic surveillance.Surgery(fundoplication)is often considered. Case study1A7week old baby formula fed baby presented with history of vomiting after most feeds and excessive crying.Vomiting was variable quantity,non-projectile and non-bilious.The child was thriving very well.There was no abnormality seen on examina-tion.A careful feed history revealed he was having nearly 200mlg/kg of formula feed.Parents were reassured and the volume of feeds was reduced.Symptoms resolved in3weeks.He continued to thrive and was discharged from follow-up.Over feeding is frequently seen in formula fed infants and a careful feeding history allows for an accurate diagnosis and helps in avoiding unnecessary treatments.Case study2An11month old with cerebral palsy and seizure disorder pre-sented with history of poor weight gain,recurrent vomiting and episodic crying.She was born at25weeks of gestation and had periventricular leukomalacia.She was particularly distressed at meal times as if she was in pain.Further investigations revealed significant reflux(reflux index14%and endoscopicfindings of oesophagitis).She was treated with proton pump inhibitors with improvement in her symptoms.Her symptoms were secondary of acid reflux in her oesophagus in response to gastric acid secretion associated with meal times.Her feeding improved with treatment of the reflux.Case study3A4month old presented with feed refusal,retching,constipation and eczema.Her symptoms failed to improve with anti-reflux therapy and her weight was static.She was referred to specialist clinic and was started on extensively hydrolysed for-mula.At6months she was started on a dairy free diet.Symp-toms improved and she showed good catch up growth.Cow’s milk was gradually introduced in her diet from the age of12 months.Cow’s milk allergy is the commonest food allergy in infancy and usually resolves by2years of life and almost always by5years of age.Gastro-oesophageal reflux can co-exist but poor a response to anti-reflux therapy should prompt consider-ation of cow’s milk allergy.AFURTHER READINGBeattie RM,Dhawan A,Puntis JWL,Batra A,Kyrana E.Oxford specialist handbook in paediatric gastroenterology,hepatology and nutrition.Oxford University Press,2018.Mutalib M,Rawat D,Lindley K,et al.BSPGHAN Motility working Group position statement:paediatric multichannel intraluminal pH impedance monitoring e indications,methods and interpretation.Front Gastroenterol2017;8:156e62.Nelson SP,Chen EH,Syniar GM,Christoffel KK.Prevalence of symptoms of gastroesophageal reflux during infancy.A pediatric practice-based survey.Pediatric Practice Research Group.Arch Pediatr Adolesc Med1997Jun;151:569e72.Rosen R,Vandenplas Y.Paediatric gastroesophageal reflux clinical practice guidelines:joint recommendations of the North American society for paediatric Gastroenterology,Hepatology,and nutrition and the European society for pediatric gastroenterology,hepatol-ogy,and nutrition.J Pediatr Gastroenterol Nutr2018;66:516e54. Rudolph CD,Vandenplas Y.Paediatric gastro-oesophageal reflux clinical practice guidelines:joint recommendation of NASPGHAN and ESPGHAN e J Pediatr Gastroenterol Nutr49;498-547. Sherman PM,Hassall E,Fagundes-Neto U.A global,evidence-based consensus on the definition of gastro-oesophageal reflux disease in the pediatric population.Am J Gastroenterol,2009;https://doi.org/10.1038/ajg.2009.129.Tighe M,Afzal NA,Bevan A,Hayen A,Munro A,Beattie RM.Phar-macological treatment of children with gastro-oesophageal reflux.Cochrane Database Syst Rev2014Nov24;11.Tighe MP,Beattie RM.Managing gastro-oesophageal reflux in in-fancy.Arch Dis Child2010;95:243e4.Tighe MP,Cullen M,Beattie RM.How to use:a pH study.Arch Dis Child Educ Pract Ed2009;94:18e23.。