Efficacy and safety of different doses of intravenous immunoglobulin combined with phototherapy in neonatal hemolytic disease: a systematic review and meta-analysis.

Neonatal hemolytic disease is a major cause of neonatal hyperbilirubinemia and kernicterus. Intravenous immunoglobulin (IVIG) combined with phototherapy is a commonly used clinical intervention; however, the optimal dosing regimen remains controversial. This study aimed to systematically evaluate the efficacy and safety of different doses of IVIG combined with phototherapy in the treatment of neonatal hemolytic disease, and to provide evidence-based guidance for optimizing clinical dosing strategies. A comprehensive literature search was conducted in PubMed, Embase, the Cochrane Library, Web of Science, and Scopus, as well as Chinese databases including CNKI, Wanfang Data, VIP, and the Chinese Biomedical Literature Database, from inception to February 2026. Randomized controlled trials comparing high-dose versus low-dose IVIG combined with phototherapy in neonatal hemolytic disease were included. The primary outcomes included exchange transfusion rate, duration of phototherapy, length of hospital stay, serum bilirubin levels at 24 h, hemoglobin levels at 72 h, and incidence of adverse events. Meta-analysis was performed using RevMan 5.4.1, with fixed- or random-effects models applied according to heterogeneity. A total of 10 randomized controlled trials involving 690 neonates were included. Compared with the low-dose IVIG group, the high-dose IVIG group showed a significantly lower exchange transfusion rate (Peto OR = 0.24, 95% CI: 0.12-0.50, P = 0.0001), corresponding to an approximately 76% reduction in the odds of exchange transfusion. High-dose IVIG was also associated with a shorter duration of phototherapy (MD =  - 9.11 h, P = 0.002), a shorter length of hospital stay (MD =  - 1.83 days, P = 0.0008), and lower serum bilirubin levels at 24 h (MD =  - 38.86, P < 0.00001). No statistically significant differences were observed between the two groups in hemoglobin levels at 72 h or adverse reaction rates (all P > 0.05).

conclusionsCompared with low-dose IVIG, high-dose IVIG combined with phototherapy was associated with lower exchange transfusion rates, shorter phototherapy duration and hospital stay, and lower serum bilirubin levels in neonates with hemolytic disease. No statistically significant differences were observed in hemoglobin levels at 72 h or adverse reaction rates between the two groups. Further large-scale, high-quality randomized controlled trials are warranted to confirm these findings and to clarify the potential impact of blood group subtype on treatment response. WHAT IS KNOWN: •Neonatal hemolytic disease remains a common cause of severe neonatal hyperbilirubinemia. •Intravenous immunoglobulin (IVIG) is frequently used as an adjunctive treatment, but the optimal dosage remains uncertain. WHAT IS NEW: • This meta-analysis compared different IVIG dosing regimens using randomized controlled trials only. • High-dose IVIG was associated with lower exchange transfusion rates and improved several short-term clinical outcomes.