Table 5. Baseline characteristics of the included studies.

PPI: proton pump inhibitors; MMA: methylmalonic acid; holoTC: holotranscobalamin; Hcy: homocysteine; H2RAs: histamine receptor antagonists; ZES: Zollinger-Ellison syndrome; MCV: mean corpuscular volume; GERD: gastro-esophageal reflux disease; H. pylori: Helicobacter pylori

Author and year of publication	Interventions studied	Number of patients	Type of study	Primary outcome measured	Results
Porter KM, 2021 [15]	Proton pump inhibitors	Total sample size (3299), 1216 PPI users, and 2083 non-PPI users	Cohort study	Serum total vitamin B12, MMA, and holo-TC concentration levels	25% of PPI users have a high prevalence of vitamin B12 deficiency compared to 15% of controls (p<0.001). High PPI doses (≥30mg/d) associated with low holoTC, high MMA concentration (p<0.001)
Qorraj-B H, 2018 [16]	Proton pump inhibitors	Total sample size: 250; 200 long-term PPI users; 50 controls (non-PPI users).	Prospective cohort study	Baseline serum vitamin B12, iron, ferritin, and homocysteine levels after 12 months	For 12 months, there was no significant difference in vitamin B12, ferritin, and iron levels between PPI users and controls. After 12 months, there was a significant association and a 35.4% incidence of increased Hcy. However, 3.8% and 2.9% of the study group were diagnosed with hypoferremia and hypovitaminosis B12 at 12 months, respectively.
Lewis JR, 2014 [17]	Proton pump inhibitors	Total sample size: 94; 46 long-term PPI users; 48 controls (non-PPI users).	Prospective cohort study	Serum total vitamin B12 levels	Twenty three of 46 (50%) PPI users had low total serum Vitamin B12 levels in contrast to 10 of 48 (20.8%) non-PPI users, p = 0.003; PPI users had 18% lower total serum Vitamin B12 levels compared to controls. (p=0.030)
Lam J R, 2013 [7]	Proton pump inhibitors and H2 receptor antagonists	Total sample size (44,105), 25956 cases (vitamin B12 deficiency), and 18149 controls (no deficiency)	Case-control study	Vitamin B12 deficiency	≥2 yrs. of PPIs (OR, 1.65) and H2 RAs (OR, 1.25) associated with vitamin B12 deficiency.
Hirschowitz, 2008 [18]   A	Proton pump inhibitors	61 acid hypersecretors (46 ZES, 15 others) are taking PPI.	Longitudinal study	Yearly Vitamin B12 levels	Six of 61 (10%) had low vitamin B12 levels without signs of vitamin B12 deficiency. 13 of 41 people (31% of the total) had normal vitamin B12 levels but higher MMA and hydroxycitric acid levels with normal folate levels. Prolonged acid suppression does not explain vitamin B12 deficiency.
Den Elzen, 2008 [20]	Proton pump inhibitors	Total sample size: 250; 125 long-term (> 3 years) PPI users; 125 partners (non-PPI users).	Cross-sectional study	Serum vitamin B12, homocysteine levels, and MCV	There was no difference in vitamin B12 levels between PPI users and nonusers. Furthermore, there was no difference in homocysteine or MCV levels. However, 2.3% of users and 2% of nonusers had low vitamin B12 levels.
Schenk BE, 2001 [19]	Proton pump inhibitors	49 PPI users (H. pylori-positive GERD)	Prospective cohort study	Serum cobalamin levels, atrophic gastritis	Fifteen of 49 (33%) PPI users developed atrophic gastritis, of whom nine had moderate-to-severe atrophy. There was a significant decrease in serum cobalamin levels in patients with atrophic gastritis (more pronounced in nine PPI users). However, no difference was reported between atrophic gastritis and non-gastritis concerning age, dose, or duration.