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Vitamin B12 deficiency is significantly more likely among patients taking prescription medications for gastroesophageal reflux disease (GERD), researchers found.

Taking either a proton pump inhibitor or a histamine 2 receptor antagonist over 2 years was associated with a greater risk for B12 deficiency (OR 1.65, 95% CI 1.58-1.73 and OR 1.25, 95% CI 1.17-1.34, respectively), according to , of Kaiser Permanente in Oakland, Calif., and colleagues.

Patients who received more than 1.5 pills daily of proton pump inhibitors had significantly greater vitamin B12 deficiency than those who received doses smaller than 0.75 pills per day (P=0.007 for interaction), they wrote online in the Journal of the American Medical Association.

Vitamin B12 deficiency can have a detrimental impact across cognitive function in older patients, while long-term -- across years -- use of proton pump inhibitors have been associated with osteoporotic fracture risks.

The authors noted that other gastric acid suppressants can lead to malabsorption of vitamin B12, though prior research has not evaluated the impact of long-term exposure. To test this, they conducted a nested case-control study of 25,956 patients with an incident diagnoses of vitamin B12 deficiency at a single center and compared that group with 184,199 control patients who were not deficient.

Patients were all adults, were members of the Kaiser Permanente Northern California integrated healthcare system for at least 1 year, and had a diagnosis of vitamin B12 deficiency at baseline. Deficiency was defined as diagnostic coding for deficiency in the International Classification of Diseases, Ninth Revision as pernicious anemia, other vitamin B12 deficiency anemia, center-specified vitamin B12 deficiency, or specific text diagnoses, as well as an abnormally low serum measure or a new and at least 6-month supply of injectable supplements.

Controls were matched up to 10-to-one by sex, region of home facility, race, birth year within 1 year of the case, and membership duration to the nearest year.

Confounders included conditions associated with vitamin B12 deficiency -- such as dementia, diabetes, and thyroid disease. They also evaluated health service utilization and whether other medications patients used were associated with deficiency.

Patients who were deficient were mostly female (57.4%), 60 or older (67.2%), and were white (68.4%). Some 12% had received proton pump inhibitors for 2 or more years, 4.2% received histamine 2 receptor antagonists for 2 or more years, and 83.8% had received neither medication.

Among controls, 7.2% had received proton pump inhibitors for 2 or more years, 3.2% had received histamine 2 receptor antagonists for 2 or more years, and 89.6% had received neither anti-reflux drug.

Longer duration of proton pump inhibitors increased associations with vitamin B12 deficiency, "although this was primarily attributable to the difference between nonusers and users," they wrote. Additionally, "the strength of the association between proton pump inhibitor use and vitamin B12 deficiency diminished after discontinuation of use."

Patients younger than 30 had a stronger association with deficiency (OR 8.12, 95% CI 3.36-19.59cq), which decreased with age. Women were also at greater odds for deficiency than men.

The study was limited by its case control design and associations with short periods of use.

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