Proton Pump Inhibitor Use and Risk of Serious Infections in Young Children
PharmD Marion Lassalle, PhD Mahmoud Zureik, MD, PhD Rosemary Dray-Spira
JAMA Pediatrics, doi:10.1001/jamapediatrics.2023.2900
IMPORTANCE Proton pump inhibitor (PPI) use may lead to infections through alteration of the microbiota or direct action on the immune system. However, only a few studies were conducted in children, with conflicting results. OBJECTIVE To assess the associations between PPI use and serious infections in children, overall and by infection site and pathogen.
DESIGN, SETTING, AND PARTICIPANTS This nationwide cohort study was based on the Mother-Child EPI-MERES Register built from the French Health Data System (SNDS). We included all children born between January 1, 2010, and December 31, 2018, who received a treatment for gastroesophageal reflux disease or other gastric acid-related disorders, namely PPIs, histamine 2 receptor antagonists, or antacids/alginate. The index date was defined as the first date any of these medications was dispensed. Children were followed up until admission to the hospital for serious infection, loss of follow-up, death, or December 31, 2019. EXPOSURE PPI exposure over time. MAIN OUTCOMES AND MEASURES Associations between serious infections and PPI use were estimated by adjusted hazard ratios (aHRs) and 95% CIs using Cox models. PPI use was introduced as time-varying. A 30-day lag was applied to minimize reverse causality. Models were adjusted for sociodemographic data, pregnancy characteristics, child comorbidities, and health care utilization.
RESULTS The study population comprised 1 262 424 children (median [IQR] follow-up, 3.8 [1.8-6.2] years), including 606 645 who received PPI (323 852 male [53.4%]; median [IQR] age at index date, 88 [44-282] days) and 655 779 who did not receive PPI (342 454 male [52.2%]; median [IQR] age, 82 [44-172] days). PPI exposure was associated with an increased risk of serious infections overall (aHR, 1.34; 95% CI, 1.32-1.36). Increased risks were also observed for infections in the digestive tract (aHR, 1.52; 95% CI, 1.48-1.55); ear, nose, and throat sphere (aHR, 1.47; 95% CI, 1.41-1.52); lower respiratory tract (aHR, 1.22; 95% CI, 1.19-1.25); kidneys or urinary tract (aHR, 1.20; 95% CI, 1.15-1.25); and nervous system (aHR, 1.31; 95% CI, 1.11-1.54) and for both bacterial (aHR, 1.56; 95% CI, 1.50-1.63) and viral infections (aHR, 1.30; 95% CI, 1.28-1.33).
CONCLUSIONS AND RELEVANCE In this study, PPI use was associated with increased risks of serious infections in young children. Proton pump inhibitors should not be used without a clear indication in this population.
Conflict of Interest Disclosures: None reported. Data Sharing Statement: See Supplement 2.
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'abstract': '<jats:sec id="ab-poi230045-4"><jats:title>Importance</jats:title><jats:p>Proton pump '
'inhibitor (PPI) use may lead to infections through alteration of the microbiota or direct '
'action on the immune system. However, only a few studies were conducted in children, with '
'conflicting results.</jats:p></jats:sec><jats:sec '
'id="ab-poi230045-5"><jats:title>Objective</jats:title><jats:p>To assess the associations '
'between PPI use and serious infections in children, overall and by infection site and '
'pathogen.</jats:p></jats:sec><jats:sec id="ab-poi230045-6"><jats:title>Design, Setting, and '
'Participants</jats:title><jats:p>This nationwide cohort study was based on the Mother-Child '
'EPI-MERES Register built from the French Health Data System (SNDS). We included all children '
'born between January 1, 2010, and December 31, 2018, who received a treatment for '
'gastroesophageal reflux disease or other gastric acid–related disorders, namely PPIs, '
'histamine 2 receptor antagonists, or antacids/alginate. The index date was defined as the '
'first date any of these medications was dispensed. Children were followed up until admission '
'to the hospital for serious infection, loss of follow-up, death, or December 31, '
'2019.</jats:p></jats:sec><jats:sec '
'id="ab-poi230045-7"><jats:title>Exposure</jats:title><jats:p>PPI exposure over '
'time.</jats:p></jats:sec><jats:sec id="ab-poi230045-8"><jats:title>Main Outcomes and '
'Measures</jats:title><jats:p>Associations between serious infections and PPI use were '
'estimated by adjusted hazard ratios (aHRs) and 95% CIs using Cox models. PPI use was '
'introduced as time-varying. A 30-day lag was applied to minimize reverse causality. Models '
'were adjusted for sociodemographic data, pregnancy characteristics, child comorbidities, and '
'health care utilization.</jats:p></jats:sec><jats:sec '
'id="ab-poi230045-9"><jats:title>Results</jats:title><jats:p>The study population comprised '
'1\u202f262\u202f424 children (median [IQR] follow-up, 3.8 [1.8-6.2] years), including '
'606\u202f645 who received PPI (323\u202f852 male [53.4%]; median [IQR] age at index date, 88 '
'[44-282] days) and 655\u202f779 who did not receive PPI (342\u202f454 male [52.2%]; median '
'[IQR] age, 82 [44-172] days). PPI exposure was associated with an increased risk of serious '
'infections overall (aHR, 1.34; 95% CI, 1.32-1.36). Increased risks were also observed for '
'infections in the digestive tract (aHR, 1.52; 95% CI, 1.48-1.55); ear, nose, and throat '
'sphere (aHR, 1.47; 95% CI, 1.41-1.52); lower respiratory tract (aHR, 1.22; 95% CI, '
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'infections (aHR, 1.30; 95% CI, 1.28-1.33).</jats:p></jats:sec><jats:sec '
'id="ab-poi230045-10"><jats:title>Conclusions and Relevance</jats:title><jats:p>In this study, '
'PPI use was associated with increased risks of serious infections in young children. Proton '
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