Early Acid Suppression Therapy Exposure and Fracture in Young Children

Pediatrics. 2019 Jul;144(1):e20182625. doi: 10.1542/peds.2018-2625. Epub 2019 Jun 7.


Background: Acid suppression therapy (AST), including proton pump inhibitors (PPIs) and histamine H2-receptor antagonists (H2RAs), is frequently prescribed to treat symptomatic gastroesophageal reflux in otherwise healthy infants. PPI use has been associated with increased fracture risk in older adults; 2 preliminary studies in children have conflicting results.

Methods: A retrospective cohort of children born 2001 to 2013 who were followed for ≥2 years was formed. Those with osteogenesis imperfecta, cholestasis, or child maltreatment were excluded. Prescription data were used to identify AST prescription before age 1 year. International Classification of Diseases, Ninth Revision, Clinical Modification codes identified fractures after age 1 year. A Cox proportional hazard analysis assessed fracture hazard and was adjusted for sex, prematurity, low birth weight, previous fracture, anti-epileptics, and overweight or obesity.

Results: Of 851 631 included children, 97 286 (11%) were prescribed AST in the first year of life; 7998 (0.9%) children were prescribed PPI, 71 578 (8%) were prescribed H2RA, and 17 710 (2%) were prescribed both a PPI and H2RA. Infants prescribed AST had an earlier median first fracture age (3.9 vs 4.5 years). After adjustment, increased fracture hazard was associated with PPI use (21%) and PPI and H2RA use (30%), but not H2RA use alone. Longer duration of AST treatment and earlier age of first AST use was associated with increased fracture hazard.

Conclusions: Infant PPI use alone and together with H2RAs is associated with an increased childhood fracture hazard, which appears amplified by days of use and earlier initiation of ASTs. Use of AST in infants should be weighed carefully against possible fracture.

MeSH terms

  • Age Factors
  • Child
  • Child, Preschool
  • Drug Therapy, Combination
  • Female
  • Fractures, Bone / epidemiology*
  • Fractures, Bone / etiology
  • Gastroesophageal Reflux / drug therapy*
  • Histamine H2 Antagonists / adverse effects
  • Histamine H2 Antagonists / therapeutic use*
  • Humans
  • Incidence
  • Infant
  • Male
  • Proton Pump Inhibitors / adverse effects
  • Proton Pump Inhibitors / therapeutic use*
  • Retrospective Studies
  • Risk Factors
  • Time Factors
  • United States / epidemiology


  • Histamine H2 Antagonists
  • Proton Pump Inhibitors