Study Covariates
We included baseline demographic characteristics, past medical history, drug history, family history, and syncopal history using the abovementioned databases. Other than demographic characteristics and past medical history, we carefully selected the study covariates that may interfere with serum levels of vitamin B12 or folate to minimize their confounding effects. For this purpose, we specifically recorded the history of hypo-/hyperthyroidism, and taking proton pump inhibitors, H2 receptor blockers, metformin, and oral contraceptive pills, which may interfere with levels of vitamin B12 or folate. We also investigated the family history of syncope, seizure, or sudden death. The evidence of possibly lower serum levels of thyroid-stimulating hormone (TSH) in pediatric patients with VVS and positive HUTT compared to negative HUTT23 encouraged us to measure serum TSH as a possible confounder in this study. We did so using the Abbott Diagnostic chemiluminescence kit and the abovementioned protocol. In the case group, we inquired about the last year and the lifetime number of syncopal episodes. According to the number of lifetime syncopal episodes, we categorized patients into frequent VVS with ≥3 episodes versus infrequent VVS with <3 episodes in the lifetime. All patients in the case group underwent HUTT according to the Italian protocol.28 According to the modified VASIS classification,29 we categorized the hemodynamic response in a positive HUTT into 1) Type 1, mixed; 2) Type 2A, cardioinhibition without asystole; 3) Type 2B, cardioinhibition with asystole; and 4) Type 3, vasodepressor.