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. 2014 Nov 24;2014(11):CD008550.
doi: 10.1002/14651858.CD008550.pub2.

Pharmacological treatment of children with gastro-oesophageal reflux

Mark Tighe  1 , Nadeem A Afzal, Amanda Bevan, Andrew Hayen, Alasdair Munro, R Mark Beattie
Affiliations

Pharmacological treatment of children with gastro-oesophageal reflux

Mark Tighe et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Gastro-oesophageal reflux (GOR) is a common disorder, characterised by regurgitation of gastric contents into the oesophagus. GOR is a very common presentation in infancy in both primary and secondary care settings. GOR can affect approximately 50% of infants younger than three months old (Nelson 1997). The natural history of GOR in infancy is generally that of a functional, self-limiting condition that improves with age; < 5% of children with vomiting or regurgitation continue to have symptoms after infancy (Martin 2002). Older children and children with co-existing medical conditions can have a more protracted course. The definition of gastro-oesophageal reflux disease (GORD) and its precise distinction from GOR are debated, but consensus guidelines from the North American Society of Gastroenterology, Hepatology and Nutrition (NASPGHAN-ESPGHAN guidelines 2009) define GORD as 'troublesome symptoms or complications of GOR.'

Objectives: This Cochrane review aims to provide a robust analysis of currently available pharmacological interventions used to treat children with GOR by assessing all outcomes indicating benefit or harm.

Search methods: We sought to identify relevant published trials by searching the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 5), MEDLINE and EMBASE (1966 to 2014), the Centralised Information Service for Complementary Medicine (CISCOM), the Institute for Scientific Information (ISI) Science Citation Index (on BIDS-UK General Science Index) and the ISI Web of Science. We also searched for ongoing trials in the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com).Reference lists from trials selected by electronic searching were handsearched for relevant paediatric studies on medical treatment of children with gastro-oesophageal reflux, as were published abstracts from conference proceedings (published in Gut and Gastroenterology) and reviews published over the past five years.No language restrictions were applied.

Selection criteria: Abstracts were reviewed by two review authors, and relevant RCTs on study participants (birth to 16 years) with GOR receiving a pharmacological treatment were selected. Subgroup analysis was considered for children up to 12 months of age, and for children 12 months to 16 years of age, and for those with neurological impairment.

Data collection and analysis: Trials were critically appraised and data collected by two review authors. Risk of bias was assessed. Meta-analysis data were independently extracted by two review authors, and suitable outcome data were analysed using RevMan.

Main results: A total of 24 studies (1201 participants) contributed data to the review. The review authors had several concerns regarding the studies. Pharmaceutical company support for manuscript preparation was a common feature; also, because common endpoints were lacking, study populations were heterogenous and variations in study design were noted, individual drug meta-analysis was not possible.Moderate-quality evidence from individual studies suggests that proton pump inhibitors (PPIs) can reduce GOR symptoms in children with confirmed erosive oesophagitis. It was not possible to demonstrate statistical superiority of one PPI agent over another.Some evidence indicates that H₂antagonists are effective in treating children with GORD. Methodological differences precluded performance of meta-analysis on individual agents or on these agents as a class, in comparison with placebo or head-to-head versus PPIs, and additional studies are required.RCT evidence is insufficient to permit assessment of the efficacy of prokinetics. Given the diversity of study designs and the heterogeneity of outcomes, it was not possible to perform a meta-analysis of the efficacy of domperidone.In younger children, the largest RCT of 80 children (one to 18 months of age) with GOR showed no evidence of improvement in symptoms and 24-hour pH probe, but improvement in symptoms and reflux index was noted in a subgroup treated with domperidone and co-magaldrox(Maalox(®) ). In another RCT of 17 children, after eight weeks of therapy. 33% of participants treated with domperidone noted an improvement in symptoms (P value was not significant). In neonates, the evidence is even weaker; one RCT of 26 neonates treated with domperidone over 24 hours showed that although reflux frequency was significantly increased, reflux duration was significantly improved.Diversity of RCT evidence was found regarding efficacy of compound alginate preparations(Gaviscon Infant(®) ) in infants, although as a result of these studies, Gaviscon Infant(®) was changed to become aluminium-free and has been assessed in its current form in only two studies since 1999. Given the diversity of study designs and the heterogeneity of outcomes, as well as the evolution in formulation, it was not possible to perform a meta-analysis on the efficacy of Gaviscon Infant(®) . Moderate evidence indicates that Gaviscon Infant(®) improves symptoms in infants, including those with functional reflux; the largest study of the current formulation showed improvement in symptom control but was limited by length of follow-up.No serious side effects were reported.No RCTs on pharmacological treatments for children with neurodisability were identified.

Authors' conclusions: Moderate evidence was found to support the use of PPIs, along with some evidence to support the use of H₂ antagonists in older children with GORD, based on improvement in symptom scores, pH indices and endoscopic/histological appearances. However, lack of independent placebo-controlled and head-to-head trials makes conclusions as to relative efficacy difficult to determine. Further RCTs are recommended. No robust RCT evidence is available to support the use of domperidone, and further studies on prokinetics are recommended, including assessments of erythromycin.Pharmacological treatment of infants with reflux symptoms is problematic, as many infants have GOR, and little correlation has been noted between reported symptoms and endoscopic and pH findings. Better evidence has been found to support the use of PPIs in infants with GORD, but heterogeneity in outcomes and in study design impairs interpretation of placebo-controlled data regarding efficacy. Some evidence is available to support the use of Gaviscon Infant(®) , but further studies with longer follow-up times are recommended. Studies of omeprazole and lansoprazole in infants with functional GOR have demonstrated variable benefit, probably because of differences in inclusion criteria.No robust RCT evidence has been found regarding treatment of preterm babies with GOR/GORD or children with neurodisabilities. Initiation of RCTs with common endpoints is recommended, given the frequency of treatment and the use of multiple antireflux agents in these children.

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Conflict of interest statement

MT: none known.

NAA: none known.

AB has received support to attend unrelated educational activities from Abbvie and Forest inc.

AH: none known.

AM: none known.

RMB had previously received an educational research grant from GlaxoSmithKline in 2012/3, and speakers fees from Nestle, Nutricia and GlaxoSmithKline in 2011‐3. However, RMB’s participation in the development of this review was not sponsored by any of these companies.

A review of the medical treatment of gastro‐oesophageal reflux was completed for Paediatric Drugs (publishers: 'Adis') and was published in early 2009. However, that article is substantially different from the Cochrane review. The Paediatric Drugs article was not funded.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
See this image and copyright information in PMC

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References to studies awaiting assessment

Davidson 2013 {published data only}
    1. Davidson G, Wenzl TG, Thomson M, Omari T, Barker P, Lundborg P, et al. Efficacy and safety of once‐daily esomeprazole for the treatment of gastroesophageal reflux disease in neonatal patients. Journal of Pediatrics 2013;163(3):692‐8. - PubMed
Haddad 2013 {published data only}
    1. Haddad I, Kierkus J, Tron E, Ulmer A, Hu P, Sloan S, et al. Efficacy and safety of rabeprazole in children (1‐11 years) with gastroesophageal reflux disease. Journal of Pediatric Gastroenterology and Nutrition 2013;57(6):798‐807. - PubMed
Haddad 2014 {published data only}
    1. Haddad I, Kierkus J, Tron E, Ulmer A, Hu P, Sloan S, et al. Maintenance of efficacy and safety of rabeprazole in children with endoscopically proven GERD. Journal of Pediatric Gastroenterology and Nutrition 2014;58(4):510‐7. - PubMed
Hassall 2012b {published data only}
    1. Hassall E, Shepherd R, Koletzko S, Radke M, Henderson C, Lundborg P. Long‐term maintenance treatment with omeprazole in children with healed erosive oesophagitis: a prospective study. Alimentary Pharmacology and Therapeutics 2012;35(3):368‐79. - PubMed
Ummarino 2013 {published data only}
    1. Ummarino D, Sciorio E, Crocetto F, Miele E, Staiano, A. A prospective, comparative, randomized, controlled study on the efficacy of the treatment with magnesium (Mg‐) alginate in infants with gastroesophageal reflux. Digestive and Liver Disease 2013;45(Suppl 4):e299‐e300. [http://download.journals.elsevierhealth.com/pdfs/journals/1590‐8658/PIIS...

Additional references

Augood 2003
    1. Augood C, MacLennon S, Gilbert R, Logan S. Cisapride treatment for gastrooesophageal reflux in children. Cochrane Database of Systematic Reviews 2003, Issue 3. [DOI: 10.1002/14651858.CD002300] - DOI - PubMed
BNF for children 2013
    1. British Medical Association, Royal Pharmaceutical Society of Great Britain, Royal College of Paediatrics and Child Health, Neonatal and Paediatric Pharmacists Group. BNF for children. London: BMJ Group, Pharmaceutical Press, RCPCH Publications, 2013.
Campanozzi 2009
    1. Campanozzi A, Boccia G, Pensabene L, Panetta F, Marseglia A, Strisciuglio P, et al. Prevalence and natural history of gastroesophageal reflux: pediatric prospective survey. Pediatrics 2009;123(3):779‐83. - PubMed
Com Safety Med 2000
    1. Committee on Safety of Medicines and Medicines Control Agency. Cisapride (Prepulsid) withdrawn. Current Problems in Pharmacovigilance 2000;26:9‐14.
Craig 2007
    1. Craig WR, Hanlon‐Dearman A, Sinclair C, Taback S, Moffatt M. Metoclopramide, thickened feedings, and positioning for gastro‐oesophageal reflux in children under two years (Cochrane Review). Cochrane Database of Systematic Reviews 2004, Issue 3. [DOI: 10.1002/14651858.CD003502.pub3] - DOI - PubMed
Cucchiara 2000
    1. Cucchiara S, Franco MT, Terrin G, Spadaro R, Nardo G, Iula V. Role of drug therapy in the treatment of gastro‐oesophageal reflux disorder in children. Paediatric Drugs 2000 July‐August;2(4):263‐72. - PubMed
EMA 2013
    1. European Medicine Agency Committee on Medicinal Products for Human Use. European Medicines Agency recommends changes to the use of metoclopramide. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2... (accessed 21 May 2014).
EMA 2014
    1. European Medicines Agency. PRAC recommends restricting use of domperidone. European Medicines Agency 2012:EMA/129231/2014. [www.ema.europa.eu]
FDA 2009
    1. Food, Drug Administration (FDA). FDA requires boxed warning and risk mitigation strategy for metoclopramide‐containing drugs [press release]. Food and Drug Administration; Rockville, MD, February 26 , 2009.
Franckx 1984
    1. Franckx J, Noel P. Acute extrapyramidal dysfunction after domperidone administration. Report of a case. Helvetica Paediatrica Acta 1984;39(3):285‐8. - PubMed
Gaviscon Product Information 2008
    1. Reckitt Benckiser Healthcare (UK) Limited. Gaviscon Product Information. Reckitt Benckiser Healthcare (UK) Limited, Dansom Lane, Hull, HU8 7DS.
Hassall 2005
    1. Hassall E. Outcomes of fundoplication: causes for concern, newer options. Archives of Disease in Childhood 2005;90(10):1047‐52. - PMC - PubMed
Higgins 2008
    1. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.0.1 [updated September 2008]. The Cochrane Collaboration, 2008.
Hill 1999
    1. Hill DJ, Hosking CS, Heine RG. Clinical spectrum of food allergy in children in Australia and South‐East Asia: identification and targets for treatment. Annals of Medicine 1999;31(4):272‐81. - PubMed
Hyams 1988
    1. Hyams JS, Ricci A Jr, Leichtner AM. Clinical and laboratory correlates of esophagitis. Journal of Pediatric Gastroenterology and Nutrition 1988;7(1):52‐6. - PubMed
Hyman 1985
    1. Hyman PE, Abrams C, Garvey TO. Ranitidine tachyphylaxis. Gastroenterology 1985;88:1426.
Keady 2007
    1. Keady S. Update on drugs for gastro‐oesophageal reflux disease. Archives of Disease in Childhood 2007;92:ep114‐ep118. - PubMed
Mandel 2000
    1. Mandel KG, Daggy BP, Brodie DA, Jacoby HI. Review article: alginate‐raft formulations in the treatment of heartburn and acid reflux. Alimentary Pharmacology & Therapeutics 2000 Jun;14(6):669‐90. - PubMed
Martin 2002
    1. Martin AJ, Pratt N, Kennedy JD, Ryan P, Ruffin RE, Miles H, et al. Natural history and familial relationships of infant spilling to 9 years of age. Pediatrics 2002;109(6):1061‐7. - PubMed
MHRA 2012a
    1. Medicines Health Regulatory Authority. Proton pump inhibitors in long‐term use: reports of hypomagnesaemia. Drug Safety Update April 2012;5(9):http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON149774 (accessed 17 November 2014).
MHRA 2012b
    1. Medicines Health Regulatory Authority. Proton pump inhibitors in long‐term use: recent epidemiological evidence of increased risk of fracture. Drug Safety Update 2012;5(9):http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON149775 (accessed 17 November 2014).
NASPGHAN‐ESPGHAN guidelines 2009
    1. Vandenplas Y, Rudolph CD, Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). Journal of Pediatric Gastroenterology and Nutrition 2009;49(4):498‐547. [DOI: 10.1097/MPG.0b013e3181b7f563] - DOI - PubMed
Nelis 1994
    1. Nelis GF, Engelage AH, Samson G. Does long‐term inhibition of gastric acid secretion with omeprazole lead to small intestinal bacterial overgrowth?. Netherlands Journal of Medicine 1994;45(3):93‐100. - PubMed
Nelson 1997
    1. Nelson SP, Chen EH, Syniar GM, Christoffel K. Prevalence of symptoms of gastro‐oesophageal reflux during infancy: a paediatric practice‐based survey. Archives of Pediatrics and Adolescent Medicine 1997;151:569‐72. - PubMed
RevMan 2011 [Computer program]
    1. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011.
Shafrir 1985
    1. Shafrir Y, Levy Y, Ben‐Amitai D, Nitzan M, Steinherz R. Oculogyric crisis due to domperidone therapy. Helvetica Paediatrica Acta 1985;40(1):95. - PubMed
Sherman 2009
    1. Sherman PM, Hassall E, Fagundes‐Neto U, Gold BD, Kato S, Koletzko S, et al. A global, evidence‐based consensus on the definition of gastroesophageal reflux disease in the pediatric population. American Journal of Gastroenterology 2009;104(5):1278‐95. - PubMed
Vandenplas 1999
    1. Vandenplas Y. Diagnosis and treatment of gastroesophageal reflux disease in infants and children. World Journal of Gastroenterology 1999 Oct;5(5):375‐82. - PMC - PubMed

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