Incidence and risk factors for intravenous immunoglobulin-related hemolysis: A systematic review of clinical trial and real-world populations

Background: Severe hemolysis rarely occurs in patients receiving intravenous immunoglobulin (IVIG) therapy. A systematic review was performed to assess the incidence of IVIG-related hemolysis and the impact of patient and product risk factors.

Study design and methods: A systematic literature search for terms related to "IVIG products", "hemolysis," and "adverse events" was conducted in Embase for articles published between January 1, 2015, and May 31, 2021. Studies with no clinical datasets, no IVIG treatment, or where IVIG was used to treat hemolytic conditions were excluded. Of the 430 articles retrieved, 383 were excluded based on titles/abstracts and 14 were excluded after in-depth review.

Results: In total, 33 articles were analyzed and separated into observational studies (n = 16), clinical trials (n = 8), and case reports (n = 9). The incidence proportion for IVIG-related hemolysis ranged from 0% to 19% in observational studies and 0%-21% in clinical trials. A higher incidence of IVIG-related hemolysis was consistently reported in patients with blood groups A and AB. Hemolysis occurred more frequently in patients treated with IVIG for some conditions such as Kawasaki disease; however, this may be confounded by the high dose of IVIG therapy. IVIG-related hemolysis incidence was lower in studies using IVIG products citing manufacturing processes to reduce isoagglutinin levels than products that did not.

Conclusion: This analysis identified patient and product risk factors including blood group, IVIG dose, and IVIG manufacturing processes associated with elevated IVIG-related hemolysis incidence.