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. 2023 Aug 22;8(8):CD008550.
doi: 10.1002/14651858.CD008550.pub3.

Pharmacological treatment of gastro-oesophageal reflux in children

Mark P Tighe  1 , Edward Andrews  1 , Iona Liddicoat  1 , Nadeem A Afzal  2 , Andrew Hayen  3 , R Mark Beattie  4
Affiliations

Pharmacological treatment of gastro-oesophageal reflux in children

Mark P Tighe et al. Cochrane Database Syst Rev. .

Abstract

Background: Gastro-oesophageal reflux (GOR) is characterised by the regurgitation of gastric contents into the oesophagus. GOR is a common presentation in infancy, both in primary and secondary care, affecting approximately 50% of infants under three months old. The natural history of GOR in infancy is generally of a self-limiting condition that improves with age, but older children and children with co-existing medical conditions can have more protracted symptoms. The distinction between gastro-oesophageal reflux disease (GORD) and GOR is debated. Current National Institute of Health and Care Excellence (NICE) guidelines define GORD as GOR causing symptoms severe enough to merit treatment. This is an update of a review first published in 2014.

Objectives: To assess the effects of pharmacological treatments for GOR in infants and children.

Search methods: For this update, we searched CENTRAL, MEDLINE, Embase, and Web of Science up to 17 September 2022. We also searched for ongoing trials in clinical trials registries, contacted experts in the field, and searched the reference lists of trials and reviews for any additional trials.

Selection criteria: We included randomised controlled trials (RCTs) that compared any currently-available pharmacological treatment for GOR in children with placebo or another medication. We excluded studies assessing dietary management of GORD and studies of thickened feeds. We included studies in infants and children up to 16 years old.

Data collection and analysis: We used standard methodology expected by Cochrane.

Main results: We included 36 RCTs involving 2251 children and infants. We were able to extract summary data from 14 RCTs; the remaining trials had insufficient data for extraction. We were unable to pool results in a meta-analysis due to methodological differences in the included studies (including heterogeneous outcomes, study populations, and study design). We present the results in two groups by age: infants up to 12 months old, and children aged 12 months to 16 years old. Infants Omeprazole versus placebo: there is no clear effect on symptoms from omeprazole. One study (30 infants; very low-certainty evidence) showed cry/fuss time in infants aged three to 12 months had altered from 246 ± 105 minutes/day at baseline (mean +/- standard deviation (SD)) to 191 ± 120 minutes/day in the omeprazole group and from 287 ± 132 minutes/day to 201 ± 100 minutes/day in the placebo group (mean difference (MD) 10 minutes/day lower (95% confidence interval (CI) -89.1 to 69.1)). The reflux index changed in the omeprazole group from 9.9 ± 5.8% in 24 hours to 1.0 ± 1.3% and in the placebo group from 7.2 ± 6.0% to 5.3 ± 4.9% in 24 hours (MD 7% lower, 95% CI -4.7 to -9.3). Omeprazole versus ranitidine: one study (76 infants; very low-certainty evidence) showed omeprazole may or may not provide symptomatic benefit equivalent to ranitidine. Symptom scores in the omeprazole group changed from 51.9 ± 5.4 to 2.4 ± 1.2, and in the ranitidine group from 47 ± 5.6 to 2.5 ± 0.6 after two weeks: MD -4.97 (95% CI -7.33 to -2.61). Esomeprazole versus placebo: esomeprazole appeared to show no additional reduction in the number of GORD symptoms compared to placebo (1 study, 52 neonates; very low-certainty evidence): both the esomeprazole group (184.7 ± 78.5 to 156.7 ± 75.1) and placebo group (183.1 ± 77.5 to 158.3 ± 75.9) improved: MD -3.2 (95% CI -4.6 to -1.8). Children Proton pump inhibitors (PPIs) at different doses may provide little to no symptomatic and endoscopic benefit. Rabeprazole given at different doses (0.5 mg/kg and 1 mg/kg) may provide similar symptom improvement (127 children in total; very low-certainty evidence). In the lower-dose group (0.5 mg/kg), symptom scores improved in both a low-weight group of children (< 15 kg) (mean -10.6 ± SD 11.13) and a high-weight group of children (> 15 kg) (mean -13.6 ± 13.1). In the higher-dose groups (1 mg/kg), scores improved in the low-weight (-9 ± 11.2) and higher-weight groups (-8.3 ± 9.2). For the higher-weight group, symptom score mean difference between the two different dosing regimens was 2.3 (95% CI -2 to 6.6), and for the lower-weight group, symptom score MD was 4.6 (95% CI -2.9 to 12). Pantoprazole: pantoprazole may or may not improve symptom scores at 0.3 mg/kg, 0.6 mg/kg, and 1.2 mg/kg pantoprazole in children aged one to five years by week eight, with no difference between 0.3 mg/kg and 1.2 mg/kg dosing (0.3 mg/kg mean -2.4 ± 1.7; 1.2 mg/kg -1.7 ± 1.2: MD 0.7 (95% CI -0.4 to 1.8)) (one study, 60 children; very low-certainty evidence). There were insufficient summary data to assess other medications.

Authors' conclusions: There is very low-certainty evidence about symptom improvements and changes in pH indices for infants. There are no summary data for endoscopic changes. Medications may or may not provide a benefit (based on very low-certainty evidence) for infants whose symptoms remain bothersome, despite nonmedical interventions or parental reassurance. If a medication is required, there is no clear evidence based on summary data for omeprazole, esomeprazole (in neonates), H₂antagonists, and alginates for symptom improvements (very low-certainty evidence). Further studies with longer follow-up are needed. In older children with GORD, in studies with summary data extracted, there is very low-certainty evidence that PPIs (rabeprazole and pantoprazole) may or may not improve GORD outcomes. No robust data exist for other medications. Further RCT evidence is required in all areas, including subgroups (preterm babies and children with neurodisabilities).

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Conflict of interest statement

There are no authors' conflicts of interest.

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

Figures

1
1
PRISMA study flow diagram
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
3
3
Risk of bias summary: review authors' judgements presented as percentages across all included studies
1.1
1.1. Analysis
Comparison 1: Omeprazole compared to placebo for infants with GORD, Outcome 1: Improvement in cry/fuss time
1.2
1.2. Analysis
Comparison 1: Omeprazole compared to placebo for infants with GORD, Outcome 2: Improvement in reflux index
2.1
2.1. Analysis
Comparison 2: Omeprazole compared to ranitidine for infants with GORD, Outcome 1: Improvement in symptom scores (WGSS)
3.1
3.1. Analysis
Comparison 3: Esomeprazole compared to placebo for infants with GORD, Outcome 1: Improvement in number of GORD‐related symptoms and signs
4.1
4.1. Analysis
Comparison 4: Rabeprazole at higher doses (1 mg/kg) compared to rabeprazole at lower doses (0.5 mg/kg) for GORD in children older than 1 year, Outcome 1: Improvement in symptom score ('Total GERD Symptoms and Severity' score)
4.2
4.2. Analysis
Comparison 4: Rabeprazole at higher doses (1 mg/kg) compared to rabeprazole at lower doses (0.5 mg/kg) for GORD in children older than 1 year, Outcome 2: Improvement in endoscopic scores (Hetzel Dent scores)
5.1
5.1. Analysis
Comparison 5: Pantoprazole in higher doses (1.2 mg/kg) compared to pantoprazole at lower doses (0.3 mg/kg) for GORD in children older than 1 year, Outcome 1: Improvement in symptom scores (WGSS)
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Treepongkaruna 2011 {published data only}
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References to studies awaiting assessment

Paknejad 2021 {published data only}
    1. Paknejad MS, Eftekhari K, Rahimi R, Vigeh M, Naghizadeh A, Karimi M. Myrtle (Myrtus communis L.) fruit syrup for gastroesophageal reflux disease in children: a double-blind randomized clinical trial. Phytotherapy Research 2021;35(11):6369-76. - PubMed
Shahmirzadi 2020 {published data only}
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References to other published versions of this review

Tighe 2014
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