{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T23:45:49Z","timestamp":1793835949479,"version":"4.6.1"},"reference-count":35,"publisher":"BMJ","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ"],"accepted":{"date-parts":[[2025,11,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To help to clarify whether long term use of proton pump inhibitors is associated with an increased risk of gastric adenocarcinoma by designing a study that considered the existing literature\u2019s methodological weaknesses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Population based case-control study using prospectively collected data from multiple complete nationwide registries in five Nordic nations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Setting<\/jats:title>\n                    <jats:p>All healthcare in five Nordic countries\u2014Denmark, Finland, Iceland, Norway, and Sweden\u2014between 1994 and 2020.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Participants<\/jats:title>\n                    <jats:p>Case patients with gastric adenocarcinoma, each matched for age, sex, calendar year, and country with 10 control participants randomly identified from each country\u2019s entire population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Exposure<\/jats:title>\n                    <jats:p>The exposure was long term (&gt;1 year) proton pump inhibitor use, excluding the 12 months before the diagnosis date (cases) or inclusion date (controls). Long term (&gt;1 year) use of histamine-2-receptor antagonists was analysed to assess the validity and specificity of the findings for proton pump inhibitor use<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main outcomes measures<\/jats:title>\n                    <jats:p>\n                      The outcome was gastric non-cardia adenocarcinoma. Gastric cardia adenocarcinoma was excluded to avoid confounding by indication (that is, gastro-oesophageal reflux). As well as controlling for the matching variables, multivariable logistic regression provided odds ratios with 95% confidence intervals, adjusted for country,\n                      <jats:italic>Helicobacter pylori<\/jats:italic>\n                      treatment, peptic ulcer disease, smoking related diseases, alcohol related diseases, obesity or type 2 diabetes, and drug treatment with metformin, non-steroidal anti-inflammatory drugs, and statins.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The study included 17\u2009232 cases of gastric (non-cardia) adenocarcinoma and 172\u2009297 controls. Long term proton pump inhibitor use occurred in 1766 (10.2%) cases and 16\u2009312 (9.5%) controls. No association was found between long term proton pump inhibitor use and gastric adenocarcinoma (adjusted odds 1.01, 95% confidence interval 0.96 to 1.07). The risk was similar for histamine-2-receptor antagonist use (adjusted odds ratio 1.03, 0.86 to 1.23). Multiple sources of error that led to a false positive association were identified\u2014inclusion of proton pump inhibitor use shortly before the gastric adenocarcinoma diagnosis, short term use of proton pump inhibitors, cardia adenocarcinoma, and lack of adjustment for\n                      <jats:italic>Helicobacter pylori<\/jats:italic>\n                      related variables.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Long term proton pump inhibitor use may not be associated with an increased risk of gastric adenocarcinoma.<\/jats:p>\n                  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