Pharmacological treatment of children with gastro‐oesophageal reflux
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. 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. 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 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).
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.
PICOs
Plain language summary
Medicines for children with gastro‐oesophageal reflux
Review question
Most babies grow out of their symptoms of reflux as they eat more solid food and spend more time upright, and as the length of the oesophagus grows, but do medicines help to make them more comfortable while this is happening? Older children can have heartburn, just like adults. Which treatment works best for them?
Background
Gastro‐oesophageal reflux happens when stomach contents come back up into the food pipe (oesophagus). This can be a normal event ('functional reflux'), but in some children, and in many babies, it can happen a lot, or it can cause symptoms such as pain, weight loss or other problems (e.g. ear infection, cough, even pauses in breathing). If this happens, the condition can be labelled as gastro‐oesophageal reflux disease (GORD). Sometimes the oesophagus becomes inflamed—a condition known as 'oesophagitis.'
Current medicines (e.g. Gaviscon Infant®) aim to thicken stomach contents, neutralise stomach acid (ranitidine, omeprazole, lansoprazole) or help the stomach to empty faster (domperidone). We looked at all available studies to try to find out whether any of the medicines currently used for reflux can help babies and children. We wanted to know whether these medicines make babies and children feel better, or whether test results (such as healing of the lining of the oesophagus, assessed through endoscopy (a small camera passed down the food pipe), or lowering of the amount of acidity in the oesophagus, assessed using a pH probe over 24 hours) get better when these medicines are given.
Study characteristics
We included all studies (randomised controlled trials) comparing one type of medicine against another, or against an inactive medicine (placebo). We carefully looked at study results and tried to assess those that would be important to doctors, nurses and parents. We found a lot of differences between studies, and the small numbers of children included in the studies, the short follow‐up provided and differing outcomes made combining the data (meta‐analysis) in a meaningful way difficult.
Key results
Overall as a result of the small numbers of children recruited to these studies, we could not be certain whether medicines improve symptoms. We found little evidence to suggest that medicines for babies younger than one year work, especially for functional reflux; mixed evidence has been found on whether Gaviscon Infant® helps, and for infants with reflux disease (changes on pH studies or on endoscopy), medicines like omeprazole and lansoprazole are likely to help. In older children, proton pump inhibitors and histamine antagonists work better to improve symptoms, endoscopy appearances and pH probe findings, but we were unable to perform a meta‐analysis, or to assess further whether one medicine was superior to another.
Quality of the evidence
Overall available evidence was of moderate to low quality, depending on the medicine in question. We have made suggestions as to how future studies could be designed to provide better answers regarding which treatments are best for babies and children with reflux or reflux disease.
