Comparative effectiveness of different probiotics combined with phototherapy for neonatal hyperbilirubinemia: a retrospective, non-randomized cohort study

Xiaohui Li, Feng Yp, Wanting Zhao, 刘飞兵, Zhen Cheng, Fengjie Sun

Objective This is a retrospective cohort study, not a clinical trial. No randomization, allocation concealment, or trial registration was performed. Phototherapy serves as the standard treatment for neonatal hyperbilirubinemia, yet clinical issues such as bilirubin rebound and prolonged hospital stay remain unresolved. This study compares the clinical efficacy and safety of two different probiotic regimens as adjuvant therapy to phototherapy. Methods A retrospective analysis was conducted on 377 infants diagnosed with neonatal hyperbilirubinemia who were hospitalized in the Department of Neonatology, The Fifth Affiliated Hospital of Guangzhou Medical University between January 2021 and December 2023. Patients were divided into three groups according to the actual treatment received (phototherapy alone, phototherapy + Bifidobacterium quadruple viable tablets, or phototherapy + Bacillus subtilis and Enterococcus faecium viable granules). No randomization or blinding was applied due to the retrospective design. No trial registration was performed. Outcome measures included the dynamic trend of transcutaneous bilirubin, duration of phototherapy, length of hospital stay, total medical cost, and incidence of adverse reactions. Results Both probiotic groups had shorter stays and fewer adverse reactions than phototherapy alone. After multivariable adjustment, Group B vs. A: hospital stay −0.52 days (95% CI: 0.24–0.80; P < 0.001); Group C vs. A: −0.29 days (95% CI: 0.01–0.56; P = 0.043); B vs. C: 0.24 days (95% CI: −0.04–0.51; P = 0.88). On day 3, estimated marginal mean transcutaneous bilirubin: B vs. A −2.83 mg/dL (95% CI: −3.63 to −2.03; P < 0.001); C vs. A −4.28 mg/dL (–5.07 to −3.50; P < 0.001); C vs. B −1.45 mg/dL (–2.24 to −0.67; P < 0.001). Bilirubin rebounded in Group A on day 3, while probiotic groups showed steady decline. Total serum bilirubin change and total cost did not differ among groups. Conclusions Phototherapy combined with probiotics, particularly *Bacillus subtilis* and Enterococcus faecium viable granules, was associated with faster and sustained bilirubin reduction, helps prevent bilirubin rebound in the mid-treatment stage and shortens hospital stay, which may represent a potentially beneficial strategy for neonatal hyperbilirubinemia.