Comparative Efficacy of Intranasal, Intramuscular, and Intravenous Vitamin B12 Therapy for Hematological Recovery in Vitamin B12 Deficiency Anemia: A Randomized Controlled Trial

Abstract

Vitamin B12 deficiency causes megaloblastic anemia and ineffective hematopoiesis. While intramuscular administration remains standard, intravenous and intranasal alternatives are increasingly used. Rigorous comparative data on hematological efficacy across routes remain limited. We thus aimed to compare intranasal, intramuscular, and intravenous vitamin B12 therapy for hematological recovery in vitamin B12 deficiency anemia, and to identify independent predictors of treatment response. In this prospective randomized controlled trial (IEC/2024/450; CTRI/2024/10/075521), 153 adults with vitamin B12 deficiency were randomized to intranasal (n = 55), intravenous (n = 56), or intramuscular (n = 42) administration. Hemoglobin (Hb), mean corpuscular volume (MCV), reticulocyte count, and lactate dehydrogenase (LDH) were assessed at baseline and on Days 7, 14, and 28. Inter-group comparisons used the Kruskal-Wallis test; covariate-adjusted analyzes employed ANCOVA and multiple linear regression. All three routes produced significant hematological recovery (all within-group p < 0.001). Mean ΔHb was +2.48, +1.80, and +2.18 g/dL for intranasal, intravenous, and intramuscular groups. Although the unadjusted analysis detected an intergroup difference (H = 7.23, p = 0.027), ANCOVA abolished the significance (all p > 0.06). MCV reduction was equivalent (Kruskal-Wallis p = 0.948). LDH normalization was greater with parenteral routes (H = 8.17, p = 0.017); intramuscular therapy produced the most pronounced reticulocytosis (H = 13.93, p = 0.001). In multivariate regression (adj. R ² = 0.575), baseline Hb (β = -0.298, p < 0.001), vegan diet (β = +1.30, p = 0.001), and age (β = -0.013/year, p = 0.039) were independent predictors; route was not. All three routes produce hemoglobin recovery at 28 days with no statistically significant adjusted differences. Intranasal vitamin B12 is a safe, effective, noninvasive alternative suitable for long-term maintenance and resource-limited settings. All conclusions are restricted to short-term hematological outcomes. Trial Registration: CTRI/2024/10/075521.

Keywords: intramuscular cyanocobalamin; intranasal cobalamin; intravenous cyanocobalamin; megaloblastic anemia; randomized controlled trial; vitamin B12 deficiency.