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BMJ Clin Evid. 2008; 2008: 0310.
Published online 2008 October 1.
PMCID: PMC2907988

GORD in children

Dr Yadlapalli Kumar, MBBS DCH M Med Sc MRCP MRCPCH# and Dr Rajini Sarvananthan, Lecturer in Paediatrics#

Abstract

Introduction

Gastro-oesophageal regurgitation is considered a problem if it is frequent, persistent, and associated with other symptoms such as increased crying, discomfort with regurgitation, and frequent back arching. A cross-sectional survey of parents of 948 infants attending 19 primary care paediatric practices found that regurgitation of at least one episode a day was reported in 51% of infants aged 0 to 3 months.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatment for symptomatic gastro-oesophageal reflux? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 27 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review, we present information relating to the effectiveness and safety of the following interventions: domperidone, feed thickeners in infants, H2 antagonists, head elevated sleep positioning, left lateral or prone sleep positioning, metoclopramide, proton pump inhibitors, sodium alginate, surgery, soy formula with added fibre, and weight loss.

Key Points

Reflux of gastric contents into the oesophagus in children causes recurrent vomiting (usually before 6 weeks of age), epigastric and abdominal pain, feeding difficulties, failure to thrive, and irritability.

  • At least half of infants regurgitate feeds at least once a day, but this only causes other problems in about 20% of infants, and most cases resolve spontaneously by 12 to 18 months of age.
  • Risk factors include lower oesophageal sphincter disorders, hiatus hernia, gastric distension, raised intra-abdominal pressure, and neurodevelopmental problems.

Sleeping in the left lateral or prone position may improve oesophageal pH compared with sleeping supine or on the right side, but these positions may increase the risk of SIDS compared with supine sleeping, and their effect on clinically important outcomes is unknown.

Thickened feeds may reduce the severity and frequency of regurgitation in the short term.

Sodium alginate may reduce the frequency of regurgitation compared with placebo, although studies have given conflicting results.

  • The high sodium content of sodium alginate may make it unsuitable for use in preterm babies.

Metoclopramide may be effective, but studies have given conflicting results and it can cause adverse effects.

We don't know whether domperidone, H2 antagonists, proton pump inhibitors, or surgery reduce symptoms in babies with gastro-oesophageal reflux, and they may cause adverse effects.

Soy-based formula with added fibre may reduce the frequency of regurgitation in infants in the neonatal period compared with cow’s milk infant formulas.

About this condition

Definition

Gastro-oesophageal reflux disease (GORD) is the passive transfer of gastric contents into the oesophagus due to transient or chronic relaxation of the lower oesophageal sphincter. A survey of 69 children (median age 16 months) with GORD attending a tertiary referral centre found that presenting symptoms were recurrent vomiting (72%), epigastric and abdominal pain (36%), feeding difficulties (29%), failure to thrive (28%), and irritability (19%). However, results may not be generalisable to younger children or children presenting in primary care, who make up the most of the cases. Over 90% of children with GORD have vomiting before 6 weeks of age.

Incidence/ Prevalence

Gastro-oesophageal regurgitation is considered a problem if it is frequent, persistent, and associated with other symptoms such as increased crying, discomfort with regurgitation, and frequent back arching. A cross-sectional survey of parents of 948 infants attending 19 primary care paediatric practices found that regurgitation of at least one episode a day was reported in 51% of infants aged 0 to 3 months. “Problematic” regurgitation occurred in significantly fewer infants (14% with problematic regurgitation v 51% with regurgitation of at least 1 episode a day; P <0.001). Peak regurgitation reported as “problematic” was reported in 23% of infants aged 6 months. A prospective study of 2879 infants followed up from just after birth (from birth up to 2 weeks) to age 6 months by primary-care paediatricians found that regurgitation occurred in 23.1% of infants during the study period.

Aetiology/ Risk factors

Risk factors for GORD include immaturity of the lower oesophageal sphincter, chronic relaxation of the sphincter, increased abdominal pressure, gastric distension, hiatus hernia, and oesophageal dysmotility. Premature infants and children with severe neurodevelopmental problems or congenital oesophageal anomalies are particularly at risk.

Prognosis

Regurgitation is considered benign, and most cases resolve spontaneously by 12 to 18 months of age. In a cross-sectional survey of 948 parents, the peak age for reporting four or more episodes of regurgitation was at 5 months of age (23%), which decreased to 7% at 7 months (P <0.001). One cohort study found that infants with frequent spilling in the first 2 years of life (at least 90 days in the first 2 years) were more likely to have symptoms of gastro-oesophageal reflux at 9 years of age than those with no spilling (RR 2.3, 95% CI 1.3 to 4.0). The prevalence of “problematic” regurgitation also reduced from 23% in infants aged 6 months to 3.25% in infants aged 10 to 12 months. Rare complications of GORD include oesophagitis with haematemesis and anaemia, respiratory problems (such as cough, apnoea, and recurrent wheeze), and failure to thrive. A small comparative study (40 children) suggested that, when compared with healthy children, infants with GORD had slower development of feeding skills, and problems affecting behaviour, swallowing, food intake, and mother–child interaction.

Aims of intervention

To relieve symptoms, maintain normal growth, prevent complications such as oesophagitis, with minimal adverse effects of treatment.

Outcomes

Symptom severity: vomiting, regurgitation, and incidence of complications (e.g., oesophagitis). Reflux Index, a measure of the percentage of time with a low oesophageal pH (frequently <pH 4), is a surrogate outcome that is often used in RCTs. Clinical interpretation of Reflux Index measurements is problematic, as the correlation between these measurements and the symptoms of gastro-oesophageal reflux has not been well studied. We have only reported Reflux Index findings where data on clinical outcomes were unavailable.

Methods

Clinical Evidence search and appraisal August 2007. The following databases were used to identify studies for this review: Medline 1966 to 2007, Embase 1980 to July 2006, and The Cochrane Library, Issue 2, 2007. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), Agency for Healthcare Research & Quality (AHRQ), and NICE clinical guidelines. Abstracts of the studies retrieved were assessed independently by two information specialists using predetermined criteria to identify relevant studies. The authors also searched Cinahl for studies on incidence and prevalence. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 people, of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as “open”, “open label”, or not blinded unless the interventions could not be “blinded”. Studies did not often discuss whether breastfeeding was also undertaken or withdrawn in treatment groups. Presence or absence of concomitant breastfeeding may have confounded study results. We have included studies in pre-adolescent children (ages 012 years; also pre-term infants) with gastro-oesophageal reflux. Studies with mixed populations of adolescents and pre-adolescents were also included if they were of high quality. We have only included RCTs and systematic reviews of RCTs in the benefits sections. Systematic reviews of observational studies were included in harms where no adequate information was found in RCTs. Case series and case control studies providing information on harms were included in comments where such information was not available from RCTs. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are continually added to the review as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table
GRADE Evaluation of interventions for GORD in children.

Glossary

Choke-gag reflux
Regurgitation of food into the pharynx and upper oesophagus that causes choking and gagging as the person tries to protect the airway in an automatic reflex action.
Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Spilling
When liquid or substance in small particles falls or spills out of the mouth.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Dr Yadlapalli Kumar, Consultant Paediatrician, Royal Cornwall Hospital, Treliske, Truro, Cornwall, UK.

Dr Rajini Sarvananthan, Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia.

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2008; 2008: 0310.
Published online 2008 October 1.

Feed thickeners in infants

Summary

Thickened feeds may reduce the severity and frequency of regurgitation in the short term.

Benefits and harms

Feed thickeners versus non-thickened feeds:

We found one systematic review (search date 2003, 8 RCTs) and three subsequent RCTs. The RCTs included in the systematic review used cows' milk thickened with rice cereal/starch, or carob flour.

Symptom severity

Thickened formula feeds compared with non-thickened feeds Thickened formula feeds may be more effective in infants and children under 2 years at reducing regurgitation and vomiting at 4 weeks, and at reducing the percentage of feeds with choke–gag refluxes at 1 to 5 months (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Regurgitation

Systematic review
34 children (aged 1 month to 2 years) with GORD and who were developmentally normal
2 RCTs in this analysis
Regurgitation severity score
with thickened feeds
with no thickeners
Absolute results not reported

SMD –0.94
95% CI –1.35 to –0.52
See further information on studies for methodological issues
Effect size not calculatedthickened feeds

RCT
Crossover design
30 infants aged 3 to 5 months, with at least three episodes of regurgitation/day Median number of regurgitation episodes
1.6 with HL-450
3.5 with control milk

P = 0.0003
Effect size not calculatedthickened feed

RCT
Crossover design
30 infants aged 3 to 5 months, with at least three episodes of regurgitation/day Median number of regurgitation episodes
1.3 with HL-350
2.9 with control milk

P = 0.021
Effect size not calculatedthickened feed

RCT
104 infants aged 14 to 120 days, with regurgitation at least five times/day % change in feeds that were followed by regurgitation 1 week
–34% with pre-thickened milk formula (Enfamil AR)
–22% with standard milk formula

P = 0.045
Effect size not calculatedthickened feed

RCT
104 infants aged 14 to 120 days, with regurgitation at least five times/day % change in feeds that were followed by regurgitation 5 weeks
–38% with pre-thickened milk formula (Enfamil AR)
–24% with standard milk formula

P = 0.036
Effect size not calculatedthickened feed

RCT
104 infants aged 14 to 120 days, with regurgitation at least five times/day % change in regurgitation volume 1 week
–4.5% with pre-thickened milk formula (Enfamil AR)
–3.4% with standard milk formula

P = 0.035
Effect size not calculatedthickened feed

RCT
104 infants aged 14 to 120 days, with regurgitation at least five times/day % change in regurgitation volume 5 weeks
–4.6% with pre-thickened milk formula (Enfamil AR)
–3.4% with standard milk formula

P = 0.05
Effect size not calculatedthickened feed

RCT
104 infants aged 14 to 120 days, with regurgitation at least five times/day % change in feeds with choke–gag reflux (decrease from baseline) 1 week
–27% with pre-thickened milk formula (Enfamil AR)
–15% with standard milk formula

P = 0.004
Effect size not calculatedthickened feed

RCT
104 infants aged 14 to 120 days, with regurgitation at least five times/day % change in feeds with choke–gag reflux (decrease from baseline) 5 weeks
with pre-thickened milk formula (Enfamil AR)
with standard milk formula
Absolute results not reported

P = 0.049
Effect size not calculatedthickened feed

RCT
96 formula-fed infants, mean age of 93 days, with more than five episodes of regurgitation and vomiting occurring a day and abnormal oesophageal pH Number of daily regurgitations 4 weeks
2.57 with corn starch-thickened casein-predominant formula
4.31 with standard milk formula

P = 0.0001
Effect size not calculatedthickened feed
Emesis

Systematic review
54 children (aged 1 month to 2 years) with GORD and who were developmentally normal
3 RCTs in this analysis
Frequency of emesis
with thickened feeds
with no thickeners
Absolute results not reported

SMD –0.91
95% CI –1.22 to –0.61
See further information on studies for methodological issues
Effect size not calculatedthickened feeds

RCT
96 formula-fed infants, mean age of 93 days, with more than five episodes of regurgitation and vomiting occurring a day and abnormal oesophageal pH Number of daily episodes of vomiting 4 weeks
1.45 with corn starch-thickened casein-predominant formula
2.74 with standard milk formula

P = 0.0011
Effect size not calculatedthickened feed
Weight gain

RCT
96 formula-fed infants, mean age of 93 days, with more than five episodes of regurgitation and vomiting occurring a day and abnormal oesophageal pH Mean weight gain 4 weeks
746 g with corn starch-thickened casein-predominant formula
642 g with standard milk formula

P = 0.06
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

Systematic review
90 infants
2 RCTs in this analysis
Coughing
with thickened feeds
with non-thickened feeds
Absolute results not reported

SMD in coughs/hour 0.38
95% CI 0.16 to 0.59
Effect size not calculatednon-thickened feeds

Systematic review
166 infants
Data from 1 RCT
Withdrawal because of diarrhoea
with thickened feeds
with non-thickened feeds
Absolute results not reported

RCT
Crossover design
30 infants aged 3 to 5 months, with at least three episodes of regurgitation/day Adverse effects
with thickened feeds
with control milk
Absolute results not reported

RCT
104 infants aged 14 to 120 days, with regurgitation at least five times/day Discontinuation rates
13% with pre-thickened milk formula (Enfamil AR)
20% with standard milk formula
Absolute numbers not reported

Reported as not significant
P value not reported
It is not clear what was substituted in those who stopped standard formula
Not significant

RCT
96 formula-fed infants, mean age of 93 days, with more than five episodes of regurgitation and vomiting occurring a day and abnormal oesophageal pH Change in number of stools passed daily 4 weeks
from 2.62 to 2.60 with corn starch-thickened casein-predominant formula
from 3.80 to 3.54 with standard milk formula

P = 0.08
Not significant

Further information on studies

RCTs identified by the review were generally small, and of short duration and low quality. Few RCTs provided data that could be included in meta-analyses. It was not clear if meta-analysis was based on intention-to-treat data. Many of the RCTs were crossover RCTs, and it was not clear from the review whether meta-analyses used data from before the crossover period.

The RCT reported no significant differences between the two concentrations of pre-thickened formulae. There were no differences in feeding volume between either formulae or control milk. At the end of the 2-week study, 81.3% of mothers who used HL-450 formula and 81.8% of those who used HL-350 formula wanted to continue with the pre-thickened formulae.

Comment

The clinical relevance of changes in regurgitation scores used in RCTs is unclear. Feeds are thickened with feed thickeners (rice, corn, or carob flour), some of these pre-thickened infant formulas thicken on contact with stomach acid.

Substantive changes

No new evidence

2008; 2008: 0310.
Published online 2008 October 1.

Sodium alginate

Summary

Sodium alginate may reduce the frequency of regurgitation compared with placebo, although studies have given conflicting results.

The high sodium content of sodium alginate may be inappropriate in preterm babies.

Benefits and harms

Sodium alginate versus placebo:

We found no systematic review, but found four RCTs.

Symptom severity

Sodium alginate compared with placebo Sodium alginate may be more effective in infants and children aged under 2 years of age at reducing the number of episodes of vomiting at 14 days, but we don't know whether it is more effective at reducing the number of regurgitation episodes (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Regurgitation

RCT
3-armed trial
30 children aged 4 months to 17 years Frequency of regurgitation episodes (episode defined as pH <4) over 24 hours
with sodium alginate
with placebo
Absolute results not reported

Difference among the three groups reported as not significant; between-group comparisons not reported
P value not reported
Not significant
Emesis

RCT
90 infants aged 0 to 12 months attending 25 general practices Median number of episodes of vomiting in previous 24 hours 14 days
3.0 with aluminium-free alginate
5.0 with placebo

P = 0.009
Effect size not calculatedaluminium-free alginate
General symptom improvement

RCT
90 infants aged 0 to 12 months attending 25 general practices Number of symptom-free days (at least 10% symptom-free days)
31% with aluminium-free alginate
11% with placebo
Absolute numbers not reported

P = 0.027
Effect size not calculatedaluminium-free alginate

RCT
20 children, mean age 28 months Total number of reflux episodes in 24 hours (as detected with pH monitoring; change in episodes from baseline)
from 131.6 to 65.0 with sodium alginate
from 87.0 to 91.0 with placebo

Significance not assessed

RCT
Crossover design
20 bottle-fed infants, mean age 163.5 days, with symptoms clinically suggestive of GORD Median number of reflux events an hour
1.58 with sodium plus magnesium alginate in milk
1.68 with placebo in milk

P = 0.78
Not significant

RCT
Crossover design
20 bottle-fed infants, mean age 163.5 days, with symptoms clinically suggestive of GORD Median number of acid reflux events an hour
0.25 with sodium plus magnesium alginate in milk
0.43 with placebo in milk

P = 0.94
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
90 infants aged 0 to 12 months attending 25 general practices Proportion of children experiencing one adverse effect 14 day
55% with aluminium-free alginate
59% with placebo
Absolute numbers not reported

P >0.2
Not significant

RCT
20 children, mean age 28 months Adverse effects
with sodium alginate
with placebo
Absolute results not reported

No data from the following reference on this outcome.

Further information on studies

None.

Comment

The high sodium content of sodium alginate may be inappropriate in preterm babies.

Substantive changes

No new evidence

2008; 2008: 0310.
Published online 2008 October 1.

Left lateral or prone sleep positioning

Summary

Sleeping in the left lateral or prone position may improve oesophageal pH compared with sleeping supine or on the right side. The effects of left lateral or prone sleeping on clinically important outcomes are unknown.

Both prone and side lateral positions may be associated with a higher risk of SIDS compared with supine positioning.

Benefits and harms

Prone or left lateral sleeping position versus other sleeping positions:

We found one systematic review (search date 2003, 4 RCTs), and one additional RCT. The review did not identify any RCTs assessing clinical outcomes, but found RCTs assessing the effect of posture on oesophageal pH variables such as Reflux Index.

Symptom severity

Prone or left lateral sleeping positions compared with supine and right lateral positions Prone or left lateral sleeping positions may be more effective at improving symptoms of GORD (number of episodes and reflux index) (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Episodes of reflux

RCT
Crossover design
24 infants, aged under 5 months with Reflux Index of >5%
In review
Mean number of episodes 48 hours
4.3 with prone sleeping position
5.8 with left lateral sleeping position
5.5 with right lateral sleeping position
7.1 with supine sleeping position

P = 0.007 in favour of prone over supine positioning
Effect size not calculatedprone positioning

RCT
Crossover design
15 infants, aged under 6 months
In review
Mean number of episodes
5.2 with prone sleeping position
19.6 with supine sleeping position

P <0.001
Effect size not calculatedprone position

RCT
Crossover design
18 infants, <37 weeks' gestation but >7 days old Mean number of reflux episodes 24 hours
with prone sleeping position
with left lateral sleeping position
with right lateral sleeping position
Absolute results not reported

P <0.001 for between-group comparisons of prone and left lateral positions versus right lateral position
Effect size not calculatedprone and left lateral positions
Reflux index

RCT
Crossover design
24 infants, aged <5 months with Reflux Index of >5%
In review
Mean reflux index 48 hours
6.7% with pronesleeping position
7.7% with left lateral sleeping position
12.0% with right lateral sleeping position
15.3% with supine sleeping position

P <0.001 in favour of prone or left lateral positioning
Effect size not calculatedprone or left lateral positioning

RCT
Crossover design
15 infants, aged <6 months
In review
Mean reflux index
7.9% with prone sleeping position
37.4% with supine sleeping position

P <0.001
Effect size not calculatedprone position

RCT
Crossover design
18 infants, <37 weeks' gestation but >7 days old Mean reflux index 24 hours
with prone sleeping position
with left lateral sleeping position
with right lateral sleeping position
Absolute results not reported

P <0.001 for between-group comparisons of prone and left lateral positions versus right lateral position
Effect size not calculatedprone and left lateral positions

Adverse effects

No data from the following reference on this outcome.

Further information on studies

None.

Comment

The RCTs identified by the systematic review measured the surrogate outcome of Reflux Index, and it is difficult to interpret the clinical importance of the observed changes. The review cited one case control study (244 SIDS cases and 868 controls matched for age and place of birth) that examined the combined effects of sleeping position and prenatal risk factors in SIDS. The study found that both prone (OR 13.9, 95% CI 8.2 to 24.0) and side (OR 3.5, 95% CI 2.1 to 5.7) sleeping positions significantly increased the risk of SIDS compared with supine positioning (also see prone positioning in review on SIDS). One large, prospective cohort study found that the left lateral sleeping position increased the risk of SIDS compared with the supine position (at 2 months: adjusted OR 6.6, 95% CI 1.7 to 25.2).

Substantive changes

No new evidence

2008; 2008: 0310.
Published online 2008 October 1.

Metoclopramide

Summary

Metoclopramide may be effective, but studies have given conflicting results.

Metoclopramide has been associated with adverse effects including irritability, dystonia, and tardive dyskinesia.

Benefits and harms

Metoclopramide versus placebo or no treatment:

We found two systematic reviews (search dates 2003 and not reported) comparing metoclopramide versus no treatment or placebo, and one additional RCT. Three of the RCTs reported in the second review are also included in the first review.

Symptom severity

Metoclopramide compared with placebo/no treatment We don't know whether metoclopramide is more effective at reducing gastro-oesophageal reflux symptoms (including regurgitation and reflux index) in infants and children (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Regurgitation

RCT
3-armed trial
30 children aged 4 months to 17 years Frequency of regurgitation episodes (episode defined as pH <4) over 24 hours
with metoclopramide
with sodium alginate
with placebo
Absolute results not reported

Difference among the three groups reported as not significant; between-group comparisons not reported
P value not reported
Not significant
General symptom improvement

Systematic review
101 infants
2 RCTs in this analysis
Mean number of daily symptoms
with metoclopramide
with placebo/no treatment
Absolute results not reported

SMD –0.73
95% CI –1.16 to –0.30
See further information on studies for more details about RCTs identified by review
Effect size not calculatedmetoclopramide

Systematic review
22 children (aged 12 months or less)
Data from 1 RCT
Gastric fractional emptying rates
with metoclopramide
with placebo/no treatment
Absolute results not reported

Significance not assessed in review
See further information on studies for more details about RCTs identified by review

Systematic review
30 infants (aged 1–9 months with gastro-oesophageal reflux diagnosed by pH probe)
Data from 1 RCT
Symptom scores and scintigraphy
with metoclopramide
with placebo/no treatment
Absolute results not reported

See further information on studies for more details about RCTs identified by review

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects not specified

Systematic review
120 infants
4 RCTs in this analysis
Adverse effects
11/71 (15%) with metoclopramide
1/49 (2%) with control

Risk difference +0.26
95% CI –0.02 to +0.53
Not significant

Systematic review
Adverse effects (any)
with metoclopramide
with control
Absolute results not reported

No data from the following reference on this outcome.

Further information on studies

The review identified seven RCTs in developmentally normal children between the ages of 1 month and 2 years with GORD. Few of the RCTs provided adequate data for meta-analysis. RCTs in the review used metoclopramide in doses ranging from 0.1 mg/kg four times daily to 0.3 mg/kg three times daily. RCTs included in the review were generally small. Meta-analyses tended to be based on data from a small number of infants in two studies.

The review identified 12 RCTs in infants (age range, preterm to 18 months) with GORD. Of the 12 studies included in the review only five were RCTs, and one of these RCTs included only 10 infants, and therefore does not meet the inclusion criteria for this review. There was no pooling of data owing to heterogeneity of trial populations, and variable dosing and outcome measures. The review reported that the quality of the included trials was poor, with only one of the RCTs reporting a power calculation. Two RCTs included in the review found similar pH measurements with metoclopramide and placebo (absolute numbers, CI, and P value not reported).

Drug safety alert

FDA highlights the risk of tardive dyskinesia associated with long-term or high-dose use of metoclopramide (26 February 2009).

The risk of tardive dyskinesia associated with long-term or high-dose use of metoclopramide has been highlighted by the FDA (http://www.fda.gov).

Comment

One observational study (42 infants) assessing the effect of metoclopramide 0.2 or 0.3 mg on pH parameters, found that metoclopramide was associated with dystonia in one infant and increased irritability in three infants.

Substantive changes

Metoclopramide One systematic review added comparing metoclopramide versus placebo. The review did not pool data owing to heterogeneity of trials. Individual trials found that metoclopramide improved gastric fractional emptying rates in term and postoperative infants compared with placebo, but found symptom scores and scintigraphy with metoclopramide and placebo. A subgroup analysis in one trial of infants aged less than 3 months found that metoclopramide improved weight gain compared with placebo. Two further RCTs included in the review found similar pH measurements with metoclopramide and placebo. Categorisation unchanged (Trade-off between benefits and harms).

2008; 2008: 0310.
Published online 2008 October 1.

Soy formula with added fibre

Summary

Soy-based formula with added fibre may reduce the frequency of regurgitation in infants in the neonatal period compared with cow’s milk infant formulas.

The long-term effects of phytoestrogens present in soy-based formulae on the health of children are unknown.

Benefits and harms

Soy formula with added fibre versus cows' milk-based formula:

We found one RCT comparing soy formula with added fibre versus cows' milk-based formula.

Symptom severity

Soy-based formula feeds with fibre compared with cow's milk Soy-based formula feeds with fibre are more effective at reducing the frequency of regurgitation at 7 to 28 days (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Regurgitation

RCT
179 young infants (aged 13–32 days) with more frequent than average regurgitation Daily rate of regurgitation 7 days
2.3 episodes with soy formula with fibre
3.4 episodes with cows' milk-based formula

P = 0.001
Effect size not calculatedsoy formula with fibre

RCT
179 young infants (aged 13–32 days) with more frequent than average regurgitation Rate of regurgitation (% of feedings regurgitated) 28 days
31% with soy formula with fibre
48% with cows' milk-based formula
Absolute numbers not reported

P = 0.001
Effect size not calculatedsoy formula with fibre

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
179 young infants (aged 13–32 days) with more frequent than average regurgitation Serious adverse effects
4/68 (6%) with soy formula with fibre
1/67 (1%) with cows' milk-based formula

Significance not assessed

RCT
179 young infants (aged 13–32 days) with more frequent than average regurgitation Excessive fussiness and crying
9/68 (13%) with soy formula with fibre
11/67 (16%) with cows' milk-based formula

Significance not assessed

RCT
179 young infants (aged 13–32 days) with more frequent than average regurgitation Constipation
9/68 (13%) with soy formula with fibre
4/67 (6%) with cows' milk-based formula

Significance not assessed

RCT
179 young infants (aged 13–32 days) with more frequent than average regurgitation Watery stools
3/68 (4%) with soy formula with fibre
8/67 (12%) with cows' milk-based formula

Significance not assessed

Further information on studies

None.

Comment

Soy-based infant formulae are the only vegan infant formulae options available if babies are not exclusively breast fed.

Clinical guide:

In a position statement on the use of soy protein for infants in June 2003 (updated September 2003), The Paediatric Group of the British Dietetic Association recommended that the use of a soy-based infant formula as first-line treatment should be discouraged during the first six months of life. This was due to concern raised by two studies over the possible long-term effects of using soy formula in infancy in humans or animals. The first study showed an increase in prolonged (0.37 days) and painful menstruation in adult women who were fed soy formula as infants. The second study found changes in the number of Leydig cells in the testes and suppression of the testosterone rise in neonatal marmosets that were partially fed soy formula.

Substantive changes

Soy formula with added fibre New option for which we found one RCT comparing cows' milk formula versus soy formula with added fibre. Categorised as Trade-off between benefits and harms.

2008; 2008: 0310.
Published online 2008 October 1.

Domperidone

Summary

We don't know whether domperidone reduces symptoms in babies with gastro-oesophageal reflux.

We found no direct information from RCTs about domperidone in the treatment of children with GORD.

Benefits and harms

Domperidone:

We found no systematic review or RCTs about domperidone in the treatment of children with GORD.

Further information on studies

None.

Comment

None.

Substantive changes

No new evidence

2008; 2008: 0310.
Published online 2008 October 1.

H2 antagonists

Summary

We don't know whether H 2 antagonists reduce symptoms in babies with gastro-oesophageal reflux, and they may cause adverse effects.

Benefits and harms

H2 antagonists versus placebo:

We found no systematic review, but found two small RCTs. One of the RCTs (27 children, aged 3–14 years with GORD) identified compared different doses of cimetidine, but reported only physiological outcomes (gastric pH, gastric acid suppression) and is not discussed further. We found no RCTs of ranitidine in children with GORD.

Symptom severity

Cimetidine compared with placebo We don't know whether cimetidine is more effective at improving symptoms in children with GORD as clinical relevance of results is unclear (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Symptom improvement

RCT
37 children aged 1 month to 14 years with GORD complicated by oesophagitis, 32 analysed Proportion of children who improved 12 weeks
67% with cimetidine 30–40 mg/kg daily
30% with placebo
Absolute numbers not reported

P <0.01
The clinical score was developed for the study and the clinical importance of this result is unclear
Effect size not calculatedcimetidine

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects (any)

RCT
37 children aged 1 month to 14 years with GORD complicated by oesophagitis, 32 analysed Adverse effects
with cimetidine 30–40 mg/kg daily
with placebo
Absolute results not reported

Further information on studies

None.

Comment

Both identified RCTs were small and provided insufficient evidence about clinical effects. Cimetidine has been reported to cause bradycardia in a small subgroup of people. Uncontrolled studies of ranitidine have reported bronchospasm, acute dystonic reactions, sinus node dysfunction, bradycardia, and vasovagal reactions.

Substantive changes

No new evidence

2008; 2008: 0310.
Published online 2008 October 1.

Head elevated sleep positioning

Summary

We don't know whether sleeping in the prone elevated position reduces symptoms compared with the prone horizontal position reduces symptoms.

We found no clinically important results from RCTs on clinically relevant outcomes about head elevated supine positioning compared with flat supine positioning, or the prone horizontal positioning compared with prone elevated positioning in children under 6 months of age with GORD.

Benefits and harms

Head elevated sleep position versus prone horizontal sleep position:

We found one systematic (search date 2003, 3 RCTs) which did not identify any RCTs assessing clinical outcomes.

Symptom severity

Head elevated sleep position versus prone horizontal sleep position We don't know whether sleeping with head elevated is more effective than sleeping in the prone horizontal position at improving symptoms of GORD (reflux index and episodes of reflux) (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Reflux index

RCT
Crossover design
24 infants, aged <5 months with Reflux Index of >5%
In review
Mean reflux index
10.7% with horizontal positioning
10.1% with head elevation

Reported as not significant
P value not reported
Not significant

Systematic review
10 infants, aged 2 to 8 weeks, with excessive regurgitation
Data from 1 RCT
Median reflux index
18.3% with horizontal supine position
10.8% with head elevated supine position (10° elevation)

P = 0.003
Statistical analysis carried out by review using individual data
Results differ from those reported in original paper (mean reflux index: 19.1% with head elevated supine position v 10.6% with horizontal supine position; P = 0.08)
Effect size not calculatedhead elevated supine position

Systematic review
100 infants aged <6 months, 90 had GORD based on Reflux Index >10%
Data from 1 RCT
Median reflux index (subgroup of children with GORD)
28.8% with prone horizontal position
23.2% with prone plus head elevated

Reported as not significant
P value not reported
Not significant
Episodes of reflux

Systematic review
10 infants, aged 2 to 8 weeks, with excessive regurgitation
Data from 1 RCT
Mean number of episodes 24 hours
33.9 with horizontal supine position
32.3 with head elevated supine position (10° elevation)

P = 0.95
Not significant

Systematic review
100 infants aged <6 months, 90 had GORD based on Reflux Index >10%
Data from 1 RCT
Mean number of episodes
7.8 with prone horizontal position
5.7 with prone plus head elevated

Reported as not significant
P value not reported
Not significant

Adverse effects

No data from the following reference on this outcome.

Further information on studies

None.

Comment

The RCTs identified by the systematic review measured the surrogate outcome of Reflux Index, and it is difficult to interpret the clinical importance of the observed changes.

Substantive changes

No new evidence

2008; 2008: 0310.
Published online 2008 October 1.

Proton pump inhibitors

Summary

Proton pump inhibitors have been associated with hepatitis and omeprazole with chronically elevated serum gastrin.

Benefits and harms

Proton pump inhibitors versus placebo:

We found no systematic review, but found one RCT.

Symptom severity

Proton pump inhibitors compared with placebo Proton pump inhibitors may be more effective at improving symptoms (measured by change in reflux index) of GORD in children (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Reflux index

RCT
Crossover design
30 infants, aged 3 to 12 months with irritability and Reflux Index >5%, oesophagitis, or both Reduction in reflux index score
8.9% with omeprazole
1.9% with placebo

P <0.001
Effect size not calculatedproton pump inhibitor

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
Crossover design
30 infants, aged 3 to 12 months with irritability and Reflux Index >5%, oesophagitis, or both Adverse effects
with omeprazole
with placebo
Absolute results not reported

Further information on studies

None.

Comment

Proton pump inhibitors have been reported to cause hepatitis, and omeprazole chronically elevates serum gastrin. The RCT measured the surrogate outcome of Reflux Index, and it is difficult to interpret the clinical importance of the observed changes.

Substantive changes

No new evidence

2008; 2008: 0310.
Published online 2008 October 1.

Surgery

Summary

We don't know whether surgery reduces symptoms in babies with gastro-oesophageal reflux.

We found no clinically important results from RCTs about the effects of surgery compared with medical treatment in children with GORD.

Benefits and harms

Surgery versus postoperative medication:

We found one systematic review which compared fundoplication versus postoperative medication for GORD in children with neurological impairment undergoing gastrostomy. The review concluded that there were no trials that satisfied the inclusion criteria.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

Cohort study
106 children Failure rate
with
with
Absolute results not reported

Further information on studies

If only neurologically normal children were considered, the mortality was 2% in the immediate postoperative period and 3% on long-term follow-up (3 deaths in 62 children; all deaths were in children with congenital abnormalities).

Comment

We found a case series of 22 children who had anterior gastric fundoplication. Twenty children (91%) remained asymptomatic at 2 years. Complications of surgical treatment include dumping, retching, intestinal obstruction, “gas bloat”, and recurrence of GORD.

Substantive changes

Surgery One systematic review added comparing fundoplication versus postoperative medication for GORD in children with neurological impairment undergoing gastrostomy. The review found no RCTs. Categorised unchanged (Unknown effectiveness).

2008; 2008: 0310.
Published online 2008 October 1.

Weight loss

Summary

We don't know whether weight loss reduces symptoms.

We found no direct information from RCTs about weight loss in the treatment of children with GORD.

Benefits and harms

Weight loss:

We found no systematic review or RCTs for weight loss to treat GORD in children.

Further information on studies

None.

Comment

None.

Substantive changes

No new evidence


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