Are medications for gastroesophageal reflux disease (GERD) safe and effective in children?
Among infants younger than 12 months diagnosed with GERD, weak evidence supports the use of proton pump inhibitors (PPIs) and histamine H2 antagonists. Among children 12 months and older, studies have shown moderate benefit from PPIs and weak benefit from H2 antagonists for providing symptomatic relief and/or improving histologic or pH indices of disease. No serious adverse effects were noted in the studies reviewed for any of the treatments. (Strength of Recommendation: B, based on inconsistent randomized controlled trials [RCTs].)
Gastroesophageal reflux is a benign, self-limited process caused by transient, intermittent relaxations of the lower esophageal sphincter. Gastroesophageal reflux often occurs postprandially and lasts less than three minutes with minimal symptoms. Most children with gastroesophageal reflux have normal weight gain, minimal irritability, and no respiratory symptoms.1 GERD occurs when reflux symptoms are more severe or when complications arise.2 The classic picture of infantile GERD is an irritable baby with poor weight gain and arching of the back during feeding, but symptoms may also include wheezing or coughing.1,2
The authors of this Cochrane review evaluated 24 RCTs examining pharmacologic management of GERD in children younger than 16 years. A subgroup analysis focused on infants younger than 12 months. Studies were small, often industry sponsored, varied in outcomes measured (symptom scores, pH levels, endoscopic appearance), and lacked head-to-head comparisons. Infants born prematurely, with neurologic impairments, or with anatomic malformations were not addressed in this review.
The PPIs reviewed included omeprazole (Prilosec), lansoprazole (Prevacid), pantoprazole (Protonix), and esomeprazole (Nexium). The H2 antagonists reviewed included ranitidine (Zantac), cimetidine (Tagamet), and nizatidine (Axid). Other agents in this review included the prokinetic agent domperidone (not available in the United States), the compound alginate agent Gaviscon Infant, and baclofen (Lioresal), an antispasmodic agent. Currently, ranitidine is the only antacid approved by the U.S. Food and Drug Administration for infants younger than 12 months.1
The authors concluded that there is weak evidence to support the use of PPIs and H2 antagonists in infants younger than 12 months. Several studies demonstrated that infants given PPIs had improvement in symptom scores, but these improvements were not significantly different than in infants given placebo. Weaknesses of the evidence included the small size of the trials, and the fact that trials in infants are based on parent or physician interpretation of cry/fuss time, and that many of these patients did not have GERD but merely functional reflux. The only agent that showed consistent benefit in two RCTs was domperidone. However, domperidone could not be evaluated for effectiveness by meta-analysis given differences in study design and outcomes.
Gaviscon Infant is a preparation of sodium and magnesium alginate that reportedly acts as a thickener to mitigate gastric acid. Because of toxicity concerns, it was reformulated in 1999 as an aluminum-free compound. Although individual trials were somewhat positive, showing improvement in vomiting as well as parent perceptions of symptoms, Gaviscon Infant was most effective when prescribed in combination with a PPI, and meta-analysis could not be performed. It is not widely available in the United States.
Among children 12 months and older, there was moderate-quality evidence that PPIs can improve reflux symptoms in those with erosive esophagitis. Analysis could not demonstrate the superiority of one PPI over another. Of the three H2 antagonists studied, only nizatidine showed improvement in objective indices in a single study of 26 patients. Ranitidine and cimetidine were each studied in an individual trial; neither revealed superiority to placebo or control. There was also inconclusive evidence to support the use of baclofen. In the single RCT that involved baclofen, the drug was compared with placebo in 30 children with a mean age of 10 years. The study demonstrated improvement in reflux symptoms and manometry but took place over only two hours.
Despite case reports and theoretic concerns of PPIs contributing to pneumonia and gastroenteritis, adverse effects reported in these trials were relatively benign, but included headache and diarrhea. Although 2009 specialty guidelines allow for a two-week trial of antisecretory therapy if conservative measures have failed, a 2013 Centers for Medicare and Medicaid Services publication stated that PPIs were not indicated for use in infants because of the possibility of Clostridium difficile–associated diarrhea.2,3 Guidelines in the United Kingdom support a four-week trial of H2 antagonists or PPIs for infants with feeding difficulties and poor growth.4