Acid suppression therapy, in the form of histamine H2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs), is a common treatment in pediatrics for management of gastroesophageal reflux (GER). Symptoms commonly associated with GER in younger children include frequent emesis, back arching, fussiness, and discomfort. GER symptoms are reported in 10.3% of all children, with symptoms even more commonly noted in individuals <2 years old.1 At 4 months of age, 67% of children have daily regurgitation. Parents report a perceived problem with GER in 23% of 6-month-old infants.2 This high rate of concern results in GER being a common complaint in outpatient and inpatient settings. Combined with the ready availability of acid suppression therapy, this has led to increased prescribing of both H2RAs and PPIs in both infants and older children.3,4 Acid suppression therapy has been previously viewed as benign; however, recent research has revealed that these medications may carry risk.

In this issue of Pediatrics, Malchodi et al5 assessed possible long-term adverse effects from use of acid suppression therapy. The authors created a database of children to evaluate both the frequency of acid suppressant use and the median age of first bone fracture. An extensive database of 851 631 military dependent children born during a 12-year period was developed by using the Military Healthcare System. Use of this database allowed the authors to identify children <1 year of age prescribed an acid suppressant and any subsequent fracture diagnosis. The authors excluded children with conditions that increased the risk of fractures. Of the studied population, 97 286 (11%) infants were given courses of acid suppression therapy, with 71 578 (73%) given H2RAs, 7998 (9%) given PPIs, and 17 710 (18%) given a combination of PPIs and H2RAs.

The authors found an increased childhood fracture hazard ratio (HR) of 23% with PPIs (HR 1.23; 95% confidence interval 1.14–1.31) and of 31% for combination PPIs and H2RAs (HR 1.31; 95% confidence interval 1.25–1.37) when used at <1 year of age. They discovered no significant increased fracture hazard with H2RA monotherapy. Furthermore, the study also revealed increased fracture hazard with longer duration of PPI and combination PPI and H2RA use as well as earlier onset of use of those medications. The fracture hazard was most elevated at 50% with combination PPI and H2RA use for >338 days.

The argument for pediatric acid suppression therapy has mainly been focused on symptomatic relief of GER disease. Several acid-suppressing drugs have received pediatric exclusivity and an extra 6 months of patent extension for their manufacturers by performing clinical trials in children.6 However, in infants, multiple studies have failed to show reduction in clinical symptoms of crying, coughing, and back arching with PPIs compared with placebos.7 Those studies also did not demonstrate improvement in regurgitation in infants with use of PPIs. Trials used to assess H2RAs have had similar results, with no significant reduction in symptoms of crying in infants when compared with placebos.7 

Possible complications associated with use of acid suppression therapy have recently been addressed in adult literature, with a focus on PPIs. Possible adverse effects of PPIs include increased risk of chronic kidney disease, bone fracture, dementia, small intestinal bacterial overgrowth, enteric infection, and micronutrient deficiency.8 Studies addressing specific complications for children are becoming available. In previous articles, pediatric acid suppression therapy has been linked with increased risk for necrotizing enterocolitis, bloodstream infection, pneumonia, and gastroenteritis.3 In a recent study, use of both H2RAs and PPIs in the first 2 years of life was linked to obesity in older children.9 

In their study, Malchodi et al5 forwarded the conversation on the risk of acid suppression by specifically investigating a link with fractures in children. A previous study by Freedberg et al10 revealed an association between use of PPIs in individuals <30 years old and increased fractures; however, the authors were unable to establish a PPI-fracture relationship in children. In their study, Malchodi et al5 furthered our understanding by assessing how acid suppression exposure in infancy, during a period of significant bone development, has an influence on risk.

Investigations revealing a clear link between use of acid suppression medications and adverse effects may necessitate changing of prescribing patterns for these medications in children. This is especially true in the setting of data showing limited clinical improvement with their use. As discussed in recent societal practice guidelines, providers need to collaborate with their patients’ families to better understand the risks and benefits of such medications and consider offering nonmedication therapies that may be more beneficial.7 Studies documenting risk provide an opportunity to reflect on other medications commonly used in pediatrics. Unfortunately, most medications lack robust data on potential harms in children. This deficiency supports national efforts to monitor longer-term adverse effects of new medications brought to the market that are not captured in short-term clinical trials.

Opinions expressed in these commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.

FUNDING: No external funding.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2018-2625.

     
  • GER

    gastroesophageal reflux

  •  
  • H2RA

    histamine H2-receptor antagonist

  •  
  • HR

    hazard ratio

  •  
  • PPI

    proton pump inhibitor

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.