Proton Pump Inhibitor Use and Risk of Serious Infections in Young Children

DOI record: { "DOI": "10.1001/jamapediatrics.2023.2900", "ISSN": [ "2168-6203" ], "URL": "http://dx.doi.org/10.1001/jamapediatrics.2023.2900", "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 1 262 424 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).</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 pump inhibitors should not be used without a clear indication in this population.</jats:p></jats:sec>", "author": [ { "affiliation": [ { "name": "EPI-PHARE, Epidemiology of Health Products (French National Agency for the Safety of Medicines and Health Products [ANSM], and French National Health Insurance [CNAM]), Saint-Denis, France" } ], "family": "Lassalle", "given": "Marion", "sequence": "first" }, { "affiliation": [ { "name": "EPI-PHARE, Epidemiology of Health Products (French National Agency for the Safety of Medicines and Health Products [ANSM], and French National Health Insurance [CNAM]), Saint-Denis, France" }, { "name": "Versailles Saint-Quentin-en-Yvelines University, Versailles, France" } ], "family": "Zureik", "given": "Mahmoud", "sequence": "additional" }, { "affiliation": [ { "name": "EPI-PHARE, Epidemiology of Health Products (French National Agency for the Safety of Medicines and Health Products [ANSM], and French National Health Insurance [CNAM]), Saint-Denis, France" } ], "family": "Dray-Spira", "given": "Rosemary", "sequence": "additional" } ], "container-title": "JAMA Pediatrics", "container-title-short": "JAMA Pediatr", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2023, 8, 14 ] ], "date-time": "2023-08-14T15:01:13Z", "timestamp": 1692025273000 }, "deposited": { "date-parts": [ [ 2023, 10, 2 ] ], "date-time": "2023-10-02T15:02:59Z", "timestamp": 1696258979000 }, "indexed": { "date-parts": [ [ 2024, 9, 23 ] ], "date-time": "2024-09-23T06:43:38Z", "timestamp": 1727073818939 }, "is-referenced-by-count": 23, "issue": "10", "issued": { "date-parts": [ [ 2023, 10, 1 ] ] }, "journal-issue": { "issue": "10", "published-print": { "date-parts": [ [ 2023, 10, 1 ] ] } }, "language": "en", "link": [ { "URL": "https://jamanetwork.com/journals/jamapediatrics/articlepdf/2808367/jamapediatrics_lassalle_2023_oi_230045_1695847051.54709.pdf", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "10", "original-title": [], "page": "1028", "prefix": "10.1001", "published": { "date-parts": [ [ 2023, 10, 1 ] ] }, "published-print": { "date-parts": [ [ 2023, 10, 1 ] ] }, "publisher": "American Medical Association (AMA)", "reference": [ { "DOI": "10.1097/MPG.0000000000001889", "article-title": "Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.", "author": "Rosen", "doi-asserted-by": "publisher", "first-page": "516", "issue": "3", "journal-title": "J Pediatr Gastroenterol Nutr", "key": "poi230045r1", "volume": "66", "year": "2018" }, { "DOI": "10.1001/jamapediatrics.2013.2911", "article-title": "Gastroesophageal reflux in infants: more than just a pHenomenon.", "author": "Rosen", "doi-asserted-by": "publisher", "first-page": "83", "issue": "1", "journal-title": "JAMA Pediatr", "key": "poi230045r2", "volume": "168", "year": "2014" }, { "DOI": "10.7573/17404398", "article-title": "Gastroesophageal reflux in children: an updated review.", "author": "Leung", "doi-asserted-by": "publisher", "journal-title": "Drugs Context", "key": "poi230045r3", "volume": "8", "year": "2019" }, { "DOI": "10.1016/j.lanepe.2021.100129", "article-title": "Paediatric outpatient prescriptions in France between 2010 and 2019, a nationwide population-based study: paediatric outpatient prescriptions in France, 2010 to 2019.", "author": "Taine", "doi-asserted-by": "publisher", "journal-title": "Lancet Reg Health Eur", "key": "poi230045r4", "volume": "7", "year": "2021" }, { "DOI": "10.1097/MPG.0000000000001596", "article-title": "National study of off-label proton pump inhibitor use among New Zealand infants in the first year of life (2005-2012).", "author": "Blank", "doi-asserted-by": "publisher", "first-page": "179", "issue": "2", "journal-title": "J Pediatr Gastroenterol Nutr", "key": "poi230045r5", "volume": "65", "year": "2017" }, { "DOI": "10.1111/bcpt.2019.124.issue-6", "article-title": "Use of proton pump inhibitors among Danish children: a 16-year register-based nationwide study.", "author": "Aznar-Lou", "doi-asserted-by": "publisher", "first-page": "704", "issue": "6", "journal-title": "Basic Clin Pharmacol Toxicol", "key": "poi230045r6", "volume": "124", "year": "2019" }, { "DOI": "10.1111/apa.v111.11", "article-title": "Proton pump inhibitors for infants in three Scandinavian countries increased from 2007 to 2020 despite international recommendations.", "author": "Lyamouri", "doi-asserted-by": "publisher", "first-page": "2222", "issue": "11", "journal-title": "Acta Paediatr", "key": "poi230045r7", "volume": "111", "year": "2022" }, { "DOI": "10.1001/jamapediatrics.2020.0007", "article-title": "Association between proton pump inhibitor use and risk of fracture in children.", "author": "Wang", "doi-asserted-by": "publisher", "first-page": "543", "issue": "6", "journal-title": "JAMA Pediatr", "key": "poi230045r8", "volume": "174", "year": "2020" }, { "DOI": "10.21037/atm", "article-title": "Proton pump inhibitors and the risk of hospital-acquired acute kidney injury in children.", "author": "Li", "doi-asserted-by": "publisher", "first-page": "1438", "issue": "21", "journal-title": "Ann Transl Med", "key": "poi230045r9", "volume": "8", "year": "2020" }, { "DOI": "10.1001/jamapediatrics.2022.5193", "article-title": "Prenatal and infant exposure to acid-suppressive medications and risk of allergic diseases in children.", "author": "Noh", "doi-asserted-by": "publisher", "first-page": "267", "issue": "3", "journal-title": "JAMA Pediatr", "key": "poi230045r10", "volume": "177", "year": "2023" }, { "DOI": "10.1001/jamapediatrics.2020.5710", "article-title": "Association between proton pump inhibitor use and risk of asthma in children.", "author": "Wang", "doi-asserted-by": "publisher", "first-page": "394", "issue": "4", "journal-title": "JAMA Pediatr", "key": "poi230045r11", "volume": "175", "year": "2021" }, { "DOI": "10.5863/1551-6776-24.6.489", "article-title": "Proton pump inhibitors, H2 blocker use, and risk of inflammatory bowel disease in children.", "author": "Schwartz", "doi-asserted-by": "publisher", "first-page": "489", "issue": "6", "journal-title": "J Pediatr Pharmacol Ther", "key": "poi230045r12", "volume": "24", "year": "2019" }, { "DOI": "10.1038/nrgastro.2017.117", "article-title": "Proton-pump inhibitors: understanding the complications and risks.", "author": "Malfertheiner", "doi-asserted-by": "publisher", "first-page": "697", "issue": "12", "journal-title": "Nat Rev Gastroenterol Hepatol", "key": "poi230045r13", "volume": "14", "year": "2017" }, { "DOI": "10.1007/s40261-017-0519-y", "article-title": "Acid-suppressive therapy and risk of infections: pros and cons.", "author": "Fisher", "doi-asserted-by": "publisher", "first-page": "587", "issue": "7", "journal-title": "Clin Drug Investig", "key": "poi230045r14", "volume": "37", "year": "2017" }, { "DOI": "10.1001/jamapediatrics.2015.4276", "article-title": "Global and national burden of diseases and injuries among children and adolescents between 1990 and 2013: findings from the Global Burden of Disease 2013 Study.", "author": "Kyu", "doi-asserted-by": "publisher", "first-page": "267", "issue": "3", "journal-title": "JAMA Pediatr", "key": "poi230045r15", "volume": "170", "year": "2016" }, { "DOI": "10.1016/j.cgh.2021.07.028", "article-title": "Serious infections in children born to mothers with inflammatory bowel disease with in utero exposure to thiopurines and anti-tumor necrosis factor.", "author": "Meyer", "doi-asserted-by": "publisher", "first-page": "1269", "issue": "6", "journal-title": "Clin Gastroenterol Hepatol", "key": "poi230045r16", "volume": "20", "year": "2022" }, { "DOI": "10.1111/apt.v52.9", "article-title": "Pregnancy in women with inflammatory bowel disease: a French nationwide study 2010-2018.", "author": "Meyer", "doi-asserted-by": "publisher", "first-page": "1480", "issue": "9", "journal-title": "Aliment Pharmacol Ther", "key": "poi230045r17", "volume": "52", "year": "2020" }, { "DOI": "10.5009/gnl15502", "article-title": "25 Years of proton pump inhibitors: a comprehensive review.", "author": "Strand", "doi-asserted-by": "publisher", "first-page": "27", "issue": "1", "journal-title": "Gut Liver", "key": "poi230045r18", "volume": "11", "year": "2017" }, { "DOI": "10.1136/bmj-2021-069211", "article-title": "Reduce unnecessary use of proton pump inhibitors.", "author": "Farrell", "doi-asserted-by": "publisher", "journal-title": "BMJ", "key": "poi230045r19", "volume": "379", "year": "2022" }, { "DOI": "10.1136/bmjopen-2022-060771", "article-title": "Association between proton pump inhibitor use and risk of pneumonia in children: nationwide self-controlled case series study in Sweden.", "author": "Wang", "doi-asserted-by": "publisher", "issue": "4", "journal-title": "BMJ Open", "key": "poi230045r20", "volume": "12", "year": "2022" }, { "DOI": "10.1016/j.jgyn.2015.08.009", "article-title": "Customized and non-customized French intrauterine growth curves: I - Methodology [in French].", "author": "Ego", "doi-asserted-by": "publisher", "first-page": "155", "issue": "2", "journal-title": "J Gynecol Obstet Biol Reprod (Paris)", "key": "poi230045r21", "volume": "45", "year": "2016" }, { "DOI": "10.1016/j.jpeds.2022.01.041", "article-title": "Pediatric prescriptions of proton pump inhibitors in France (2009-2019): a time-series analysis of trends and practice guidelines impact.", "author": "Yang", "doi-asserted-by": "publisher", "first-page": "158", "journal-title": "J Pediatr", "key": "poi230045r22", "volume": "245", "year": "2022" }, { "DOI": "10.1177/1756284819853790", "article-title": "Burden of drug use for gastrointestinal symptoms and functional gastrointestinal disorders in France: a national study using reimbursement data for 57 million inhabitants.", "author": "Tuppin", "doi-asserted-by": "publisher", "journal-title": "Therap Adv Gastroenterol", "key": "poi230045r23", "volume": "12", "year": "2019" }, { "DOI": "10.1001/jama.2018.21554", "article-title": "Using the E-value to assess the potential effect of unmeasured confounding in observational studies.", "author": "Haneuse", "doi-asserted-by": "publisher", "first-page": "602", "issue": "6", "journal-title": "JAMA", "key": "poi230045r24", "volume": "321", "year": "2019" }, { "DOI": "10.7326/M16-2607", "article-title": "Sensitivity analysis in observational research: introducing the E-value.", "author": "VanderWeele", "doi-asserted-by": "publisher", "first-page": "268", "issue": "4", "journal-title": "Ann Intern Med", "key": "poi230045r25", "volume": "167", "year": "2017" }, { "DOI": "10.1097/EDE.0b013e3181d61eeb", "article-title": "Negative controls: a tool for detecting confounding and bias in observational studies.", "author": "Lipsitch", "doi-asserted-by": "publisher", "first-page": "383", "issue": "3", "journal-title": "Epidemiology", "key": "poi230045r26", "volume": "21", "year": "2010" }, { "DOI": "10.1111/apa.v109.8", "article-title": "The effects of proton pump inhibitors on the microbiome in young children.", "author": "Levy", "doi-asserted-by": "publisher", "first-page": "1531", "issue": "8", "journal-title": "Acta Paediatr", "key": "poi230045r27", "volume": "109", "year": "2020" }, { "DOI": "10.1053/j.gastro.2020.08.065", "article-title": "Childhood development and the microbiome: the intestinal microbiota in maintenance of health and development of disease during childhood development.", "author": "Ronan", "doi-asserted-by": "publisher", "first-page": "495", "issue": "2", "journal-title": "Gastroenterology", "key": "poi230045r28", "volume": "160", "year": "2021" }, { "DOI": "10.1053/j.gastro.2017.01.031", "article-title": "The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association.", "author": "Freedberg", "doi-asserted-by": "publisher", "first-page": "706", "issue": "4", "journal-title": "Gastroenterology", "key": "poi230045r29", "volume": "152", "year": "2017" }, { "DOI": "10.1038/nrmicro.2016.142", "article-title": "Emerging pathogenic links between microbiota and the gut-lung axis.", "author": "Budden", "doi-asserted-by": "publisher", "first-page": "55", "issue": "1", "journal-title": "Nat Rev Microbiol", "key": "poi230045r30", "volume": "15", "year": "2017" }, { "DOI": "10.1017/ice.2019.23", "article-title": "Risk factors for Clostridium difficile infection in pediatric inpatients: a meta-analysis and systematic review.", "author": "Anjewierden", "doi-asserted-by": "publisher", "first-page": "420", "issue": "4", "journal-title": "Infect Control Hosp Epidemiol", "key": "poi230045r31", "volume": "40", "year": "2019" }, { "DOI": "10.1007/s00535-017-1369-3", "article-title": "Magnitude and direction of the association between Clostridium difficile infection and proton pump inhibitors in adults and pediatric patients: a systematic review and meta-analysis.", "author": "Oshima", "doi-asserted-by": "publisher", "first-page": "84", "issue": "1", "journal-title": "J Gastroenterol", "key": "poi230045r32", "volume": "53", "year": "2018" }, { "DOI": "10.1183/13993003.03229-2020", "article-title": "The risk of community-acquired pneumonia in children using gastric acid suppressants.", "author": "van der Sande", "doi-asserted-by": "publisher", "issue": "4", "journal-title": "Eur Respir J", "key": "poi230045r33", "volume": "58", "year": "2021" }, { "DOI": "10.1097/MPG.0000000000001984", "article-title": "Proton pump inhibitors and infant pneumonia/other lower respiratory tract infections: national nested case-control study.", "author": "Blank", "doi-asserted-by": "publisher", "first-page": "335", "issue": "3", "journal-title": "J Pediatr Gastroenterol Nutr", "key": "poi230045r34", "volume": "67", "year": "2018" }, { "DOI": "10.3390/jcm7090252", "article-title": "Association between proton pump inhibitor use and CNS infection risk: a retrospective cohort study.", "author": "Hung", "doi-asserted-by": "publisher", "issue": "9", "journal-title": "J Clin Med", "key": "poi230045r35", "volume": "7", "year": "2018" }, { "DOI": "10.1007/s40266-019-00704-6", "article-title": "Proton pump inhibitors and infection-related hospitalizations among residents of long-term care facilities: a case-control study.", "author": "Wang", "doi-asserted-by": "publisher", "first-page": "1027", "issue": "11", "journal-title": "Drugs Aging", "key": "poi230045r36", "volume": "36", "year": "2019" }, { "DOI": "10.1007/s11606-012-2211-5", "article-title": "Confounding in the association of proton pump inhibitor use with risk of community-acquired pneumonia.", "author": "Jena", "doi-asserted-by": "publisher", "first-page": "223", "issue": "2", "journal-title": "J Gen Intern Med", "key": "poi230045r37", "volume": "28", "year": "2013" }, { "DOI": "10.1002/14651858.CD008550.pub2", "article-title": "Pharmacological treatment of children with gastro-oesophageal reflux.", "author": "Tighe", "doi-asserted-by": "publisher", "issue": "11", "journal-title": "Cochrane Database Syst Rev", "key": "poi230045r38", "volume": "2014", "year": "2014" }, { "DOI": "10.1002/pds.v25.7", "article-title": "Positive predictive values of selected hospital discharge diagnoses to identify infections responsible for hospitalization in the French national hospital database.", "author": "Sahli", "doi-asserted-by": "publisher", "first-page": "785", "issue": "7", "journal-title": "Pharmacoepidemiol Drug Saf", "key": "poi230045r39", "volume": "25", "year": "2016" }, { "DOI": "10.1001/jama.2011.822", "article-title": "Surveillance bias in outcomes reporting.", "author": "Haut", "doi-asserted-by": "publisher", "first-page": "2462", "issue": "23", "journal-title": "JAMA", "key": "poi230045r40", "volume": "305", "year": "2011" }, { "DOI": "10.1016/j.jpeds.2014.11.030", "article-title": "No effect of proton pump inhibitors on crying and irritability in infants: systematic review of randomized controlled trials.", "author": "Gieruszczak-Bialek", "doi-asserted-by": "publisher", "first-page": "767", "issue": "3", "journal-title": "J Pediatr", "key": "poi230045r41", "volume": "166", "year": "2015" }, { "DOI": "10.1371/journal.pmed.1003429", "article-title": "Mode of birth and risk of infection-related hospitalisation in childhood: a population cohort study of 7.17 million births from 4 high-income countries.", "author": "Miller", "doi-asserted-by": "publisher", "issue": "11", "journal-title": "PLoS Med", "key": "poi230045r42", "volume": "17", "year": "2020" }, { "DOI": "10.1007/s00228-019-02810-1", "article-title": "Use of proton pump inhibitors in adults in France: a nationwide drug utilization study.", "author": "Lassalle", "doi-asserted-by": "publisher", "first-page": "449", "issue": "3", "journal-title": "Eur J Clin Pharmacol", "key": "poi230045r43", "volume": "76", "year": "2020" } ], "reference-count": 43, "references-count": 43, "relation": {}, "resource": { "primary": { "URL": "https://jamanetwork.com/journals/jamapediatrics/fullarticle/2808367" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "Proton Pump Inhibitor Use and Risk of Serious Infections in Young Children", "type": "journal-article", "volume": "177" }