Efficacy of probiotics and synbiotics combined with phototherapy vs phototherapy alone in neonatal hyperbilirubinemia: a systematic review and meta-analysis of randomized controlled trials.

The current gold standard for neonatal hyperbilirubinemia is phototherapy. However, phototherapy for a longer duration has side effects like fluid imbalance and diarrhea. Probiotics and synbiotics are used as adjuncts to reduce the duration of phototherapy. Three electronic databases, namely PubMed, clinicalTrials.gov, and the Cochrane Library, cover the period from inception up to May 2025. Neonates with hyperbilirubinemia treated with probiotics/synbiotics in addition to phototherapy were included. Review Manager (5.4.1) was used for data analysis. Subgrouping based on gestational age and probiotic and synbiotic strains was done. The risk of bias was assessed using the Cochrane RoB2 tool. A total of 17 RCTs involving 2017 neonates were included. Our analysis revealed that neonates who received probiotic/synbiotic supplementation along with phototherapy showed statistically significant reductions in duration of hospitalization (MD, - 0.35; 95% CI, - 0.49 to - 0.20) and phototherapy (MD, - 13.10; 95% CI, - 19.19 to - 7.01). Moreover, neonates in the probiotic/synbiotic group demonstrated significant reductions in serum bilirubin levels at 24 h (MD, - 1.45; 95% CI, - 2.19 to - 0.72) and a borderline difference between the two groups at 72 h (MD, - 0.54; 95% CI, - 1.07 to - 0.02). In contrast, discharge bilirubin favored phototherapy alone (MD, 0.22; 95% CI, 0.19 to 0.26).

conclusionProbiotics/synbiotics, in combination with phototherapy, may reduce the duration of phototherapy, hospitalization, and serum bilirubin levels at 24 and 72 h; however, the findings are heterogeneous, and the results for discharge bilirubin are inconsistent. This emphasizes the need for further population- and strain-specific multicenter RCTs. WHAT IS KNOWN: • Probiotics/Synbiotics combined with phototherapy may shorten phototherapy duration and hospitalization, but subgroup effects, strain-specific efficacy, and the impact on bilirubin at specific time points remain unclear due to variable study quality and mixed populations. WHAT IS NEW: • This meta-analysis provides a more refined and clinically meaningful evaluation by focusing specifically on live-strain probiotics/synbiotics, prespecified subgroups (term vs preterm), and standardized outcomes (24h, 72h bilirubin, discharge bilirubin). • We identified a consistent reduction in hospitalization and phototherapy duration, but importantly found that bilirubin at discharge was lower in the phototherapyonly group, a novel finding likely influenced by study design differences (including blinding status).