Efficacy and Safety of Probiotic Supplementation for Neonatal Jaundice: a Systematic Review and Meta-Analysis

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Probiotics provide health benefits to the host and are widely used to treat various diseases, including neonatal gastrointestinal disorders. However, their efficacy and safety toward NJ remain uncertain. Given the relationship of the neonatal bilirubin metabolism to gastrointestinal function, we aimed to synthesize evidence on the effects of probiotics supplementation on NJ. We searched PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure up to January 2025. The eligibility criteria were randomized controlled trials (RCTs) that evaluated the efficacy of probiotics in treating NJ. Two reviewers individually completed evidence selection, data extraction, and quality evaluation. Mean differences (MDs) in total serum bilirubin (TSB) levels between two groups were pooled using random-effects model by the DerSimonian and Laird method, and heterogeneity was quantified using I 2 statistics. Thirty RCTs (2776 neonates) were included. Probiotics supplementation significantly reduced TSB from day 1 (MD:-0.35, 95% confidence interval [CI]:-0.63 to -0.06) to day 10 (MD:-1.74, 95% CI:-2.54 to -0.95) mg/dL. Infants Patients who received probiotics supplementation also showed a significantly shorter duration of phototherapy (MD:-17.09, 95% CI:-24.43 to -9.76) h and hospitalization (MD:-1.17, 95% CI:-1.60 to -0.74) days. Furthermore, probiotics supplementation was associated with a lower incidence of adverse effects, including diarrhea, rashes, and fevers. These benefits were consistent in both preterm and full-term infants. In conclusion, probiotic supplementation may be an effective and safe adjuvant treatment for NJ, with potential benefits observed in both preterm and full-term infants. probiotics neonatal jaundice hyperbilirubinemia preterm infant full-term infant Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1. Introduction Neonatal jaundice (NJ) is characterized by yellowish pigmentation of the skin, sclera, and mucous membranes due to elevated total serum bilirubin (TSB), a condition known as neonatal hyperbilirubinemia [ 1 – 3 ]. It is a common condition affecting over 60% of full-term and up to 80% of preterm infants globally, highlighting its importance in neonatal health [ 4 ]. NJ can be either physiologic or pathologic. Physiologic jaundice typically appears on days 2 to 3 after birth, peaks by days 5–7, and resolves within two weeks, resulting from the immature hepatic metabolism of bilirubin [ 5 ]. In contrast, pathological jaundice occurs within 24 h after birth or persists beyond 2 weeks, which may result from conditions such as blood group incompatibility, metabolic or genetic disorders, or other congenital anomalies causing cholestasis [ 6 , 7 ]. Excess unconjugated bilirubin can cross the immature blood-brain barrier in neonates, leading to bilirubin encephalopathy [ 8 ], with symptoms ranging from lethargy, abnormal muscle tone, and seizures [ 9 ]. If untreated, it may progress to kernicterus, an irreversible neurological complication with high mortality and morbidities [ 10 ]. The severity of NJ depends on bilirubin levels, gestational age (GA), and concurrent illnesses, highlighting the importance of early detection and treatment [ 11 ]. Current treatments for NJ include phototherapy (PT), hydration, blood exchange transfusion, and medications such as phenobarbital, albumin, and intravenous immunoglobulin (IVIG) [ 12 ]. Among these, PT is the most used therapy. The treatment converts bilirubin into water-soluble isomers which can be excreted without hepatic conjugation [ 13 ]. Despite its affordability, availability, and effectiveness in managing jaundice, PT often prolongs hospital stays, separating infants from their mothers, disrupting breastfeeding, and potentially leading to lactation failure [ 14 , 15 ]. Additionally, it can cause complications such as an unstable body temperature and dehydration, thus contributing to parental anxiety and increased healthcare costs [ 16 ]. Therefore, it is imperative to develop treatment strategies that enhance the efficacy of PT, reduce treatment durations, and address both the clinical outcomes and the socioeconomic burdens associated with NJ [ 17 ]. In recent years, probiotics, live microorganisms that provide health benefits to the host, have been widely utilized in managing various gastrointestinal (GI) disorders, including diarrhea, inflammatory bowel disease, and metabolic conditions such as obesity and diabetes in adults [ 18 – 20 ]. Probiotics have also been used in neonatal gastrointestinal disorders, particularly to prevent necrotizing enterocolitis [ 21 ] and improve postoperative gut function [ 22 ]. Studies suggested that probiotics may also play a role in regulating the TSB level and facilitating the resolution of NJ [ 23 ]. The mechanism involves modulating bilirubin metabolism in the enterohepatic circulation, balancing the intestinal microbiota, and promoting intestinal peristalsis and defecation [ 24 , 25 ]. However, evidence of the effects of probiotics on NJ remains inconclusive [ 26 ]. With recent randomized controlled trials (RCTs) contributing to the growing body of evidence, there is a need to integrate the latest findings and synthesize the current evidence of the effects of probiotics. In this study, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of probiotics supplementation in managing NJ. 2. Materials and Methods We included RCTs evaluating the efficacy and safety of probiotics supplementation for NJ in both preterm (GA < 37 weeks) and full-term (GA ≥ 37 weeks) infants. Jaundice was diagnosed based on clinical symptoms (yellowish skin and sclera) and serum bilirubin levels. Phototherapy (PT) thresholds were defined by authors using guidelines such as Bhutani’s nomogram [ 27 , 28 ], typically set at > 12 mg/dL for full-term and > 9 mg/dL for preterm infants, though these varied based on factors like birth weight, GA, and comorbidities. The intervention group received probiotics without restrictions on strain, dosage, frequency, or duration, in combination with phototherapy. Control groups could include PT, enzyme inducers, IVIG, or other forms of supportive therapy. 2.1. Selection Criteria Eligible studies met the following criteria: (a) the population consisted of neonates with jaundice meeting PT criteria; (b) the intervention group received probiotics supplementation and PT; (c) the control group receiving either PT alone, placebo, or any supplementary treatment; and (d) outcomes included at least one of the following: bilirubin levels, treatment efficacy, PT duration, days to jaundice resolution, hospitalization length, or adverse effects. Studies were excluded if they (a) enrolled neonates with comorbidities affecting bilirubin outcomes, such as hepatitis or metabolic disorders; (b) trials involving herbal medicines to minimize potential confounding effects on target outcomes; or (c) failed to report sufficient methodological or outcome details. 2.2. Data sources and search strategy We systematically searched PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure (CNKI) through January 2025 using the following terms and keywords: “probiotic” and “neonatal jaundice”. The present study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA) guidelines [ 29 ] and was registered with PROSPERO (CRD42025642453). No language or regional restrictions were applied. Each retrieved study was carefully screened for inclusion based on predefined selection criteria. Full search strategies were available in Supplementary File 1. 2.3. Data Extraction Two reviewers (H.M.H, and B.H.L) independently extracted data, including study characteristics, characteristics of participants, and regimens of probiotics and control. The reviewers extracted the mean and standard deviation (SD) for continuous outcomes, including bilirubin levels, PT duration, time to jaundice resolution, and hospitalization length. If the mean and SD were not available, other descriptive statistics were also extracted and then processed using valid methods and tools [ 30 ]. Discrepancies were resolved by discussion with a third reviewer (K.H.C.). 2.4. Methodological Quality Appraisal The methodological quality of the RCTs was independently assessed by two reviewers (H.M.H., and B.H.L.) using the Cochrane Risk-of-Bias tool (RoB 2.0) [ 31 ]. Disagreements were resolved through discussion with a third reviewer (K.H.C.), leading to a consensus. Furthermore, the GRADE (Grading of Recommendations Assessment, Development and Evaluation) [ 32 ] framework was used to evaluate the certainty of the evidence. 2.5. Statistical Analyses Data analyses were performed using Review Manager version 5.4 (The Cochrane Collaboration, Oxford, UK). Dichotomous outcomes were calculated as risk ratio (RR) with a 95% confidence interval (CI) using the Mantel-Haenszel method. Continuous outcomes were reported as mean difference (MD) with the corresponding 95% CI. Bilirubin values reported in mmol/L were converted to mg/dL using a conversion factor of 0.058 [ 33 ]. Data pooling was performed using a random-effects model, with statistical significance set to p < 0.05. Heterogeneity was assessed using the I² statistics [ 34 , 35 ], and I ² values were interpreted as follows: (a) 50% reflect substantial heterogeneity [ 35 ]. Additionally, subgroup analyses were conducted based on GA to evaluate the effects of probiotics in preterm and full-term infants. 3. Results 3.1. Study Screening and Selection The initial search yielded 2015 citations from PubMed, Embase, Cochrane Library, and CNKI. After removing 714 duplicates, the remaining 1301 records were screened for eligibility. Finally, 30 articles [ 2 , 23 – 26 , 36 – 60 ] met the inclusion criteria and were included in the final analysis (Fig. 1 ). 3.2. Study Characteristics The detailed baseline characteristics of participants were presented in Table 1 . The included studies were published between 2008 and 2024and involved a total of 2776 infants. Nine studies included preterm neonates [ 24 , 36 , 37 , 40 , 41 , 48 – 50 , 60 ], 20 studies included full-term neonates [ 2 , 23 , 25 , 26 , 38 , 39 , 42 – 47 , 51 – 55 , 57 – 59 ], and one study included both preterm and full-term neonates [ 56 ]. Among them, 1425 infants received probiotics treatment and usual care, while 1351 infants received usual care alone. The probiotics formulations varied across the included studies as detailed in Table 1 . The usual care in these trials primarily included blue-light PT and adjunct therapies such as liver enzyme inducers, IVIG, and albumin administration. Detailed information on usual care was described in Supplementary Table S1 . Table 1 Characteristics of the included trials Study Selection criteria No. of patients (males, %) Gestational age (weeks) Chronological age (days) Birth weight (kg) Total bilirubin level (mg/dL) Intervention regimen Chen et al. 2022 [ 38 ] Full-term neonates (aged ≤ 28 days) with pathological jaundice I: 49 (51.0%) C: 49 (51.3%) NI I: 13.28 ± 3.51 C: 13.46 ± 3.37 I: 3.1 ± 0.9 C: 3 ± 0.8 I: 17.41 ± 2.83 C: 17.31 ± 2.97 Bifidobacterium triple viable powder b 500 mg BID + UC a Cui 2024 [ 39 ] Full-term neonates (BW ≥ 1500 g) with jaundice I: 100 (57%) C: 100 (51%) NI I: 15.84 ± 1.68 C: 16.11 ± 1.94 I: 3.26 ± 0.25 C: 3.26 ± 0.26 I: 13.67 ± 1.20 C: 13.58 ± 1.15 Bifidobacterium quadruple viable tablet d 500 mg BID + UC a Dai 2020 [ 37 ] Preterm neonates (GA 28–37 weeks) with non-hemolytic jaundice I: 25 (56%) C: 25 (48%) NI I: 14.65 ± 2.82 C: 15.26 ± 2.51 I: 3.22 ± 0.54 C: 3.19 ± 0.52 I: 9.13 ± 3.00 C: 9.08 ± 3.04 Saccharomyces boulardii 250 mg QD + UC a Dong & Wu 2019 [ 36 ] Preterm neonates (GA 28–36 weeks) with non-hemolytic or liver dysfunction-related jaundice, excluding allergies I: 30 (60%) C: 30 (53.3%) I: 33.18 ± 0.53 C: 33.15 ± 0.56 I: 10.88 ± 2.27 C: 10.82 ± 2.31 NI I: 9.86 ± 1.37 C: 9.85 ± 1.37 Bifidobacterium triple viable powder b 500 mg BID + UC a Gao et al. 2021 [ 23 ] Full-term neonates with jaundice I: 50 (56%) C: 50 (58%) NI I: 3.58 ± 1.291 C: 3.25 ± 1.401 I: 3.39 ± 0.47 C: 3.28 ± 0.45 I: 18.01 ± 3.75 C: 17.24 ± 4.43 Clostridium butyricum 420 mg BID + UC a Hamed et al. 2019 [ 40 ] Neonates with physiological or hemolytic jaundice and sepsis I: 50 (66%) C: 50 (60%) I: 34.5 ± 2.3 C: 33.8 ± 3.5 I: 3.5 ± 1.2 C: 4 ± 1.7 I: 2.80 ± 0.89 C: 3.00 ± 0.60 I: 17.63 ± 1.53 C: 17.46 ± 2.33 Lactobacillus acidophilus, L. rhamnosus, Bifidobacterium lactis, B. bifidum + UC a Hu et al. 2023 [ 41 ] Premature neonates (< 35 weeks GA) with yellow skin/sclera, excluding bile duct obstruction I: 55 (61.8%) C: 45 (53.3%) I: 30.69 ± 1.16 C: 30.40 ± 1.07 NI I: 1.38 ± 0.14 C: 1.39 ± 0.12 I: 16.22 ± 1.73 C: 16.74 ± 2.22 S. boulardii 250 mg QD + UC a Jia 2021 [ 42 ] Neonates with physiological jaundice and normal liver function, excluding bile duct obstruction I: 36 (41.7%) C: 36 (52.8%) NI I: 6.28 ± 3.41 C: 6.08 ± 3.45 NI I: 15.76 ± 1.91 C: 15.60 ± 1.80 Bifidobacterium triple viable tablet c 250 mg BID + UC a Lai et al. 2022 [ 43 ] Neonates (TSB > 12 mg/dL) with physiological jaundice, yellow skin/mucosa/sclera, and normal liver function, excluding bile duct obstruction I: 30 (53.3%) C: 30 (50%) I: 38.3 ± 1.5 C: 38.1 ± 1.4 I: 6.2 ± 7.3 C: 6.0 ± 7.4 NI I: 16.36 ± 0.72 C: 16.36 ± 0.71 Compound Eosinophil-Lactobacillus 250 mg BID/TID + UC a Liang 2012 [ 45 ] Neonates with HBR (full-term TSB > 12 mg/dL, preterm TSB > 15 mg/dL) I: 40 (60%) C: 32 (53.1%) I: 38.2 ± 0.5 C: 38.2 ± 0.4 I: 10.0 ± 4.8 C: 10.0 ± 4.5 NI I: 18.64 ± 5.01 C: 18.73 ± 5.08 Bifidobacterium triple viable tablet c 500 mg TID + UC a Liang et al. 2023 [ 58 ] Neonates (aged 12 mg/dL) with physiological jaundice and normal liver function I: 36 (58.3%) C: 36 (55.6%) I: 38.20 ± 1.18 C: 38.35 ± 1.20 I: 10.14 ± 2.35 C: 10.38 ± 2.10 NI I: 16.88 ± 0.62 C: 17.00 ± 0.63 Bifidobacterium triple viable powder b 500 mg BID + UC a Lin & Lu 2021 [ 54 ] Neonates (primigravida, aged 12.9 mg/dL) with jaundice, excluding severe hemolytic anemia I: 45 (53.3%) C: 45 (51.1%) I: 39.23 ± 1.12 C: 38.55 ± 0.41 NI I: 2.63 ± 1.32 C: 2.57 ± 1.26 I: 20.18 ± 1.59 C: 20.03 ± 1.56 Bifidobacterium triple viable capsule b 105 mg BID + UC a Liu et al. 2015 [ 2 ] Neonates with jaundice (TcB > 12.9 mg/dL) I: 34 (64.7%) C: 34 (58.8%) I: 39.0 ± 0.4 C:39.5 ± 0.3 I: 11.3 ± 1.2 C: 11.2 ± 1.3 I: 3.86 ± 0.23 C: 3.75 ± 0.21 I: 20.29 ± 3.04 C: 20.53 ± 2.81 Bifidobacterium triple viable capsule b TID/QID 2 g/day + UC a Liu 2023 [ 57 ] Neonates with HBR I: 50 (50%) C: 50 (46%) I: 38.35 ± 1.68 C: 38.02 ± 1.45 I: 8.06 ± 6.55 C: 8.03 ± 6.58 I: 2.97 ± 0.56 C: 2.95 ± 0.56 I: 16.80 ± 1.82 C: 16.74 ± 1.82 Bifidobacterium triple viable capsule b 210 mg BID + UC a Lu & Ling 2017 [ 48 ] Preterm neonates (29–36 weeks GA, hospitalization > 7 days) with non-hemolytic jaundice I: 37 (NI) C: 41 (NI) NI NI NI I: 10.01 ± 2.60 C: 9.08 ± 2.93 S. boulardii 125 mg BID + UC a Matin et al. 2022 [ 24 ] Single or twin neonates (VLBW: 1000–1500 g, 2–3 days old) I: 26 (50%) C: 26 (50%) I: 31.7 ± 2.2 C: 30.8 ± 2.3 NI I: 1.39 ± 0.13 C: 1.36 ± 0.14 NI L. paracasei 500 mg QD Mutlu et al. 2020 [ 25 ] Neonates (35–42 weeks GA) with hemolysis and STB increase > 0.2 mg/dL/h I: 30 (47%) C: 30 (43%) I: 38.3 ± 1.3 C: 37.7 ± 1.3 NI I: 3.16 ± 0.33 C: 3.11 ± 0.49 I: 3.44 ± 0.95 C: 3.57 ± 1.03 L. rhamnosus GG QD + UC a Nasief et al. 2024 [ 60 ] Preterm neonates (< 37 weeks GA) with indirect HBR, excluding ABO/Rh incompatibility I: 36 (55.6%) C: 36 (38.9%) I: 33.5 ± 1.71 C: 33.62 ± 1.95 I: 4.91 ± 2.53 C: 4.86 ± 1.86 I: 2.47 ± 0.41 C: 2.25 ± 0.42 I: 16.68 ± 1.69 C: 16.92 ± 1.63 S. boulardii 125 mg BID + UC a Serce et al. 2015 [ 26 ] Neonates (35–42 weeks GA) with non-hemolytic indirect HBR I: 58 (44.8%) C: 61 (47.5%) I: 37.7 ± 1.7 C: 37.9 ± 2.02 I: 1.98 ± 1.5 C: 2.33 ± 0.75 I: 3.07 ± 0.59 C: 3.22 ± 0.60 I: 13.43 ± 2.96 C: 13.4 ± 2.43 S. boulardii 125 mg BID + UC a Tang et al. 2020 [ 53 ] Neonates (37–42 weeks GA, BW: 2500–4000 g) with indirect HBR, jaundice onset at 3–5 days, total bilirubin > 95th percentile (Bhutani nomogram), or unconjugated bilirubin ≥ 80%. I: 61 (44.3%) C: 63 (46.0%) I: 39.0 ± 1.1 C: 38.9 ± 0.9 NI I: 3.33 ± 0.41 C: 3.41 ± 0.37 I: 15.38 ± 2.40 C: 15.61 ± 2.51 S. boulardii 250 mg QD + UC a Tariq et al. 2021 [ 55 ] Neonates (BW ≥ 2500 g) with non-hemolytic indirect HBR I: 47 (59.6%) C: 47 (57.4%) I: 37.36 ± 2.02 C: 37.26 ± 2.09 I: 6.47 ± 4.75 C: 6.62 ± 5.21 I: 2.90 ± 0.51 C: 2.88 ± 0.50 I: 16.71 ± 1.25 C: 16.76 ± 1.14 Prokid probiotic e QD + UC a Torkaman et al. 2016 [ 47 ] Neonates (> 35 weeks GA, BW > 2500 g, bilirubin > 15 mg/dL, direct bilirubin < 1.5 mg/dL, aged ≥ 2 days) with non-hemolytic indirect HBR, excluding blood transfusion, IVIG, phenobarbital, or serum therapy I: 45 (37.7%) C: 47 (48.9%) NI I: 5.31 ± 2.19 C: 5.19 ± 2.51 I: 3.28 ± 0.38 C: 3.12 ± 0.28 I: 16.95 ± 2.67 C: 16.46 ± 2.33 Prokid probiotic e QD + UC a Tsai et al. 2022 [ 56 ] Neonates (> 35 weeks GA, SBL > 15 mg/dL on day 4) with jaundice, excluding maternal ABO incompatibility I: 43 (46.5%) C: 40 (62.5%) I: 38.0 ± 0.20 C: 37.88 ± 0.18 NI I: 3.05 ± 0.05 C: 3.11 ± 0.05 I: 16.78 ± 0.41 C: 16.13 ± 0.41 B. animalis subsp. lactis CP-9 BID + UC a Wang et al. 2014 [ 46 ] Full-term neonates with pathological jaundice, excluding Rh/ABO incompatibility I: 56 (51.8%) C: 50 (54%) NI I: 7.3 ± 1.1 C: 7.2 ± 1.3 NI I: 15.81 ± 1.71 C: 16.10 ± 1.70 S. boulardii 250 mg QD + UC a Wu et al. 2019 [ 50 ] Preterm neonates with jaundice and normal liver function I: 31 (48.4%) C: 33 (48.5%) NI I:45 ± 12 C: 36 ± 6 NI I: 15.81 ± 1.71 C: 16.10 ± 1.70 S. boulardii 250 mg BID/TID + UC a Xue 2023 [ 59 ] Infants (aged < 42 days) with pathological jaundice, excluding current alternative treatments I: 50 (48%) C: 50 (56%) NI I: 9.89 ± 0.24 C: 10.23 ± 3.12 I: 3.76 ± 0.42 C: 3.72 ± 0.44 I: 16.09 ± 1.77 C: 15.95 ± 1.88 Bifidobacterium quadruple viable tablet d 500 mg BID + UC a Zeng 2020 [ 52 ] Infants with pathological jaundice and normal liver function, excluding bile duct obstruction and IUGR I: 50 (58%) C: 50 (56%) NI I: 14.52 ± 3.64 C: 14.55 ± 3.59 I: 3.56 ± 1.28 C: 3.59 ± 1.21 I: 16.82 ± 0.62 C: 16.88 ± 0.62 Combined B. subtilis and Enterococcus faecium granules 500 mg TID + UC a Zhang & Deng 2008 [ 44 ] Neonates with HBR I: 25 (56%) C: 25 (52%) I: 37.4 ± 4.8 C: 38.2 ± 3.3 I: 4.26 ± 1.92 C: 4.18 ± 1.94 I: 3.87 ± 0.25 C: 2.75 ± 0.19 I: 17.62 ± 2.52 C: 17.54 ± 2.27 Bifidobacterium triple viable tablet c 250 mg TID + UC a Zhang 2019 [ 51 ] Neonates with jaundice and normal liver function, excluding bile duct obstruction I: 50 (60%) C: 50 (62%) NI I: 4.23 ± 1.02 C: 4.31 ± 1.13 NI I: 16.79 ± 1.76 C: 16.93 ± 1.82 Combined B. subtilis and E. faecium granules 1000 mg BID + UC a Zhong 2018 [ 49 ] Preterm neonates (GA: 28–37weeks, hospitalization > 1 week) with jaundice I: 120 (60%) C: 120 (61.7%) I: 34.28 ± 2.51 C: 34.12 ± 2.42 NI NI I: 9.08 ± 1.41 C: 8.97 ± 1.35 Bifidobacterium triple viable tablet c 125 mg BID + UC a BW: body weight, GA: gestational age, QD: once a day, BID: twice a day, TID: three times a day, UC: usual care, TcB: transcutaneous bilirubin, TSB: total serum bilirubin, HBR: hyperbilirubinemia, PT: phototherapy, IVIG: intravenous immunoglobulin, VLBW: very low birth weight, IUGR: intrauterine growth restriction, B. lactis: Bifidobacterium lactis, B. bifidum: Bifidobacterium bifidum, B. animalis subsp. lactis CP-9: Bifidobacterium animalis subsp. lactis CP-9, B. subtilis: Bacillus subtilis, C. butyricum: Clostridium butyricum, E. faecium: Enterococcus faecium, S. boulardii: Saccharomyces boulardii, L. paracasei: Lacticaseibacillus paracasei, L. rhamnosus: Lactobacillus rhamnosus, L. acidophilus: Lactobacillus acidophilus. a: Usual care (e.g. phototherapy, liver enzyme inducers, intravenous immunoglobulin, albumin, etc.). b: Bifidobacterium triple viable capsule/powder: containing Bifidobacterium longum, Lactobacillus acidophilus , and Enterococcus faecalis. c: Bifidobacterium triple viable tablet: containing Bifidobacterium longum, Lactobacillus bulgaricus , and Streptococcus thermophilus. d: Bifidobacterium quadruple viable tablet: containing Bifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis, and Bacillus cereus. e: Prokid probiotic: containing Bifidobacterium lactis, Lactobacillus acidophilus, Bifidobacterium bifidum , and Lactobacillus rhamnosus 3.3. Methodological Quality Figure 2 summarizes the methodological quality of the 30 included trials. Among these, nine trials had "some concerns" regarding the randomization process due to insufficient information on allocation concealment [ 44 , 46 , 49 – 53 , 55 , 59 ]. Two trials showed "some concerns" related to missing outcome data due to incomplete reporting [ 26 , 56 ]. Fifteen trials had "some concerns" in the measurement of outcomes since the blinding status of the outcome assessors was not specified [ 23 , 36 – 38 , 43 – 45 , 48 – 52 , 54 , 58 , 59 ]. Other domains were graded to be at low risk of bias. Overall, 10 trials had a low risk of bias, and 20 trials had some concerns. 3.4. Total Bilirubin Level The total bilirubin level after treatment was reported in 27 studies. The probiotics group showed significantly lower total bilirubin levels (mg/dL), compared to the control groups on day 1 (MD:-0.35, 95% CI:-0.63 to -0.06), day 2 (MD:-1.26, 95% CI:-1.73 to -0.79), day 3 (MD:-1.40, 95% CI:-2.50 to -0.29), day 4 (MD:-1.41, 95% CI:-2.12 to -0.69), day 5 (MD:-0.85, 95% CI:-1.19 to -0.52), day 7 (MD:-1.55, 95% CI:-2.50 to -0.60), day 8 (MD:-0.67, 95% CI:-1.14 to -0.20), and day 10 (MD:-1.74, 95% CI:-2.54 to -0.95). However, I 2 values were relatively high, with a range of 14–98% (Fig. 3 ). Subgroup analyses based on GA were conducted to explore the source of heterogeneity. Among the 27 RCTs, 19 RCTs focused on full-term infants, while eight RCTs focused on preterm infants. Probiotic supplements significantly reduced the bilirubin level at all time points among full-term babies ( p < 0.05). For the preterm subgroups, although probiotic supplementation did not significantly reduce bilirubin levels (mg/dL) on day 1 (MD:0.07, 95% CI:-0.53 to 0.66), it significantly lower bilirubin levels compared to the control group, with an increasing effect size over time, day 3 (MD:-0.63, 95% CI:-1.11 to -0.16), day 4 (MD:-0.76, 95% CI:-1.21 to -0.32), day 5 (MD:-1.17, 95% CI:-2.35 to 0.02), day 7 (MD:-2.50, 95% CI:-3.56 to -1.44) as shown in Supplementary Table S2. 3.5. Duration of Phototherapy The duration of PT was reported in nine studies. Four studies focused on preterm neonates [ 24 , 41 , 48 , 60 ], four on full-term neonates [ 25 , 26 , 53 , 55 ], and one study included both preterm and full-term neonates [ 56 ]. Overall, using probiotic supplements significantly reduced the duration of PT (MD: -17.09, 95% CI: -24.43 to -9.76) hours. In subgroup analyses, PT duration was similarly reduced in preterm (MD: -33.55 hours; 95% CI: -56.07 to -11.03) and full-term neonates (MD: -6.53 hours; 95% CI: -10.75 to -2.32) (Fig. 4 ). 3.6. Days to Jaundice Resolution The duration required for jaundice resolution was reported in 10 studies. One study focused on preterm neonates [ 41 ], and nine on full-term neonates [ 2 , 38 , 42 – 46 , 51 , 57 ]. Overall, the probiotics group showed a significant reduction in jaundice resolution time (MD: -2.23, 95% CI: -2.94 to -1.52) days. In subgroup analyses, probiotics significantly shortened the time to jaundice resolution in both preterm (MD: -7.26 days; 95% CI: -9.22 to -5.30) and full-term neonates (MD: -1.88 days; 95% CI: -2.49 to -1.26) (Supplementary Fig. S1 ). 3.7. Efficacy Rate The efficacy of jaundice treatment was determined based on the following criteria: complete resolution– complete resolution of jaundice symptoms and normalization of bilirubin levels; partial resolution– reduction in jaundice symptoms and a decrease in bilirubin levels, although not within the normal range; and ineffective – no improvement in jaundice symptoms or bilirubin levels [ 38 ]. The efficacy rate was calculated as (number of cured cases + number of effective cases) / total cases × 100% [ 38 ]. The efficacy rate was reported in 15 studies: three on preterm neonates [ 36 , 49 , 50 ] and 12 on full-term neonates [ 23 , 38 , 39 , 43 – 45 , 51 , 52 , 54 , 57 – 59 ]. Overall, the probiotics group showed a higher efficacy rate compared to the control group (RR: 1.16, 95% CI: 1.12 to 1.21). This trend was observed in both preterm (RR: 1.17, 95% CI: 1.03 to 1.31) and full-term subgroups (RR: 1.17, 95% CI: 1.12 to 1.22) (Supplementary Fig. S2). 3.8. Duration of Hospitalization The duration of hospitalization was reported in nine studies. Three studies focused on preterm neonates [ 24 , 40 , 60 ], five on full-term neonates [ 42 , 43 , 45 , 47 , 51 ], and one study included both preterm and full-term neonates [ 56 ]. The overall analysis demonstrated a significant reduction in the hospitalization duration in the probiotics group (MD:-1.17, 95% CI:-1.60 to -0.74) days. Subgroup analyses revealed significantly shorter hospital stays in both preterm (MD:-0.43 days; 95% CI:-0.65 to -0.20) and full-term neonates (MD:-1.93 days; 95% CI:-2.85 to -1.00) (Fig. 5 ). 3.9. Adverse Effects The main adverse effects reported in the included studies were diarrhea (14 RCTs) [ 23 , 37 – 39 , 42 , 43 , 46 , 49 , 51 , 52 , 54 , 57 , 58 , 60 ], rashes (15 RCTs) [ 23 , 36 – 39 , 42 , 43 , 46 , 49 , 51 , 52 , 54 , 57 , 58 , 60 ], and fevers (11 RCTs) [ 23 , 36 – 39 , 42 , 45 , 49 , 51 , 54 , 58 ]. The pooled data showed a significantly lower risk of diarrhea (RR:0.40, 95% CI:0.22 to 0.74), rashes (RR:0.57, 95% CI:0.33 to 0.98), and fever (RR:0.46, 95% CI:0.24 to 0.86) in the probiotics group compared to the control group. No heterogeneity was observed across the studies (Fig. 6 ). 3.10. Certainty of Evidence We evaluated the certainty of the evidence using the GRADE framework for TSB levels, duration of phototherapy and hospitalization. The certainty of evidence was downgraded from the default high level based on risk of bias, inconsistency, indirectness, imprecision, and publication bias. Moderate-certainty evidence suggested that probiotics modestly reduced TSB on day 1, with downgrading due to imprecision. Very low-certainty evidence supported a reduction in TSB on day 10, downgraded due to a large degree of heterogeneity (I²=96%) and imprecision. Low-certainty evidence indicated reductions in phototherapy duration and hospitalization, with downgrading due to substantial heterogeneity (I²=81–89%) (Supplementary Table S3). 4. Discussion The meta-analysis of 30 studies involving 2776 patients demonstrated that probiotics supplementation significantly reduced bilirubin levels, shortened the durations of PT and hospitalization, accelerated jaundice resolution, and resulted in a higher efficacy rate compared to the control groups. These findings are supported not only by the mechanisms outlined in the Introduction [ 23 – 25 ], but also by relevant RCTs, including the impact of probiotics on bilirubin levels in healthy infants and their influence on GI function in preterm neonates [ 61 , 62 ]. Additionally, the results showed that the addition of probiotics to usual care significantly improved safety profiles compared to routine care alone. A subgroup analysis by GA further indicated that most of these benefits remained consistent in both preterm and full-term neonates. Differential Effects of Probiotics in Preterm and Full-Term Infants During the First 3 Days We observed that the effect of probiotics in reducing TSB levels became increasingly evident over time. In the preterm infant group, a significant difference in TSB levels between the probiotics and control groups was observed by day 3. In contrast, in the full-term infant group, the reduction in TSB levels was significant from day 1 of probiotics administration. The differential effects of probiotics on preterm and full-term infants may be attributed to several factors. Preterm infants often exhibit lower serum albumin levels and an altered albumin/bilirubin-binding capacity, leading to higher levels of unbound bilirubin [ 63 , 64 ]. Additionally, preterm infants are more vulnerable to intestinal dysbiosis, which impairs bilirubin metabolism and excretion. This disruption contributes to elevated TSB levels over time as gut microbes play a critical role in converting bilirubin into excretable forms [ 65 – 67 ]. Since full-term infants generally have a more developed and healthier gut microbiota, the effects of probiotics on TSB reduction appeared more rapidly. In contrast, preterm infants require a longer period for probiotics to modulate the gut microbiotic composition, thereby facilitating bilirubin elimination. Although probiotics showed minimal effects on TSB levels in preterm infants on day 1, their efficacy became increasingly pronounced over time. This finding suggests that probiotics supplementation promotes the gut microbiotic health, thus contributing to mitigating neonatal hyperbilirubinemia [ 24 , 25 ]. Mechanisms of Different Probiotics The RCTs included in this meta-analysis utilized various strains of probiotics to evaluate their effects on NJ. Different probiotics strains may exert their effects through distinct mechanisms. For instance, patients with NJ were found to have significantly lower levels of Bifidobacterium species, such as Bifidobacterium adolescentis , Bifidobacterium bifidum , and Bifidobacterium longum , compared to healthy individuals in the fecal samples [ 68 ]. Bifidobacterium lowers bilirubin levels by inhibiting β-glucuronidase, an enzyme that hydrolyzes conjugated bilirubin and releases free bilirubin for reabsorption in the enterohepatic circulation [ 69 ]. By inhibiting β-glucuronidase, Bifidobacterium reduces bilirubin reabsorption, promoting its elimination [ 70 ]. Based on the proposed biological pathway, Bifidobacterium supplementation may represent a promising strategy for reducing TSB levels. Additionally, Lactobacillus rhamnosus GG had been reported to facilitate bilirubin clearance through stimulation of bowel movements [ 25 ]. Saccharomyces boulardii has been shown to suppress β-glucuronidase activity and reduce enterohepatic circulation by altering the enzyme’s structure, and activity, thereby contributing to a decrease in serum bilirubin levels [ 41 , 61 ]. Building upon these mechanistic insights, our study provides clinical evidence supporting the adjunctive use of probiotic supplementation to improve neonatal hyperbilirubinemia in clinical practice. Safety Regarding the safety of probiotics, our study revealed significantly lower risks of diarrhea, rashes, and fever in the probiotics group compared to the control group. These findings were consistent with previous research. Qian et al. conducted a meta-analysis of 55 RCTs with a total sample size of 8868 infants to investigate the effects of probiotics, prebiotics, or synbiotics on the growth of healthy infants [ 71 ]. Their results showed lower incidences of diarrhea, vomiting, hospitalization rates, and antimicrobial drug use in the intervention group compared to the control group (OR:0.88, 95% CI:0.70–1.11) [ 71 ]. Another systematic review of 74 clinical studies evaluating the safety of probiotics and synbiotics in children (0–18 years old) reported lower incidences of adverse events in the intervention groups across all common terminology clinical adverse event (CTCAE) categories [ 72 ]. The reported adverse effects included diarrhea, dysentery, and upper respiratory tract infections, with GI disorders being most frequent [ 72 ]. Additionally, superior safety was consistent across diverse populations, including healthy and immunodeficient children, as well as those with obesity, intestinal diseases, infections, or inflammatory disorders [ 72 ]. These findings highlight the good safety profile of probiotics, supporting their use as a well-tolerated adjuvant treatment for infants and children across various populations. Strengths The strengths of our study include a large sample size and rigorous methodology, which enhanced the reliability and generalizability of our findings. By incorporating ten recent studies published within the past three years, our analysis reflects the most up-to-date evidence. Subgroup analyses based on GA allowed for differentiation of probiotic effects between preterm and full-term infants, providing population-specific insights. Given the higher prevalence of neonatal jaundice in Asian populations, with up to 90% of Chinese infants affected in the first week of life compared to approximately 30% of European infants [ 73 ], we included studies from the CNK to ensure adequate population representation and to improve external validity. Additionally, our comprehensive analyses of key clinical parameters—such as TSB levels over time, PT durations, jaundice resolution times, hospital stay lengths, and intervention efficacy and safety—provide valuable insights into neonatal jaundice management, supporting evidence-based neonatal care. These findings are supported by the mechanisms outlined in the introduction [ 23 – 25 ], and relevant evidence, including the impact of probiotics on bilirubin levels in healthy infants and their influence on GI function in preterm neonates [ 61 , 62 ] Limitations There are some limitations to our study. First, high heterogeneity was observed across the included studies, which was likely due to variations in probiotic strains and dosages. Although we performed a subgroup analysis based on GA to explore this heterogeneity which revealed that probiotics efficacy was consistent in both preterm and full-term neonates, the GA did not sufficiently explain the degree of heterogeneity. While various probiotic strains appear effective in neonates, the limited available data prevented us from conducting strain-specific subgroup analyses to further reduce heterogeneity. Additionally, most included trials focused on relatively short follow-up periods of 2 weeks or less. Thus, the long-term effects and potential late-onset adverse events of probiotics supplementation remain unclear. To address these limitations, future research should focus on large-scale, long-term RCTs with standardized probiotics interventions, strain-specific analyses, and extended follow-up periods to comprehensively evaluate the long-term efficacy and safety. 5. Conclusions In light of the current evidence, probiotic supplementation demonstrated potential benefits for NJ by lowering bilirubin levels, shortening phototherapy and hospital stay durations, and reducing adverse effects in both preterm and full-term infants. Therefore, probiotics may be considered as an adjuvant treatment for neonates with jaundice. However, more studies are warranted to validate these findings and to provide a more-comprehensive understanding of the long-term efficacy and safety of probiotic use in this population. Abbreviations BID: twice a day BW: birth weight CI: confidence interval CNKI: China National Knowledge Infrastructure CTCAE: Common Terminology Clinical Adverse Events GA: gestational age GI: gastrointestinal HBR: hyperbilirubinemia IQR: interquartile range IUGR: intrauterine growth restriction IVIG: intravenous immunoglobulin MD: mean difference NI: no information NJ: neonatal jaundice OR: odds ratio PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement PT: phototherapy RCT: randomized controlled trial RoB 2.0: Cochrane Risk-of-Bias tool RR: risk ratio SD: standard deviation TcB: transcutaneous bilirubin TSB: total serum bilirubin TID: three times a day UC: usual care VLBW: very low birth weight QD: once a day Declarations Acknowledgments : The authors have no acknowledgments to declare. Contributions Hui-Min Huang : Conceptualization, data curation, formal analysis, investigation, methodology, software, validation, writing—original draft. Bing-Hua Lin : Conceptualization, data curation, formal analysis, investigation, methodology, software, validation, writing—original draft. Yi-No Kang : Conceptualization, formal analysis, investigation, methodology, validation, writing—original draft. Kee-Hsin Chen : Conceptualization, formal analysis, investigation, methodology, validation, writing— review and editing. Ethics declarations Funding : The authors received no support from any organization for the submitted work. Conflicts of interest : The authors have no conflicts of interest to declare that are relevant to the content of this article. Ethics approval : As this was a systematic review and meta-analysis, ethical approval was not required. Consent to participate/publish : As it was a systematic review, consent to participate and publish was not required. Data availability No datasets were generated or analyzed during the current study. References Ansong-Assoku B, Shah SD, Adnan M, Ankola PA. Neonatal Jaundice. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7286761","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":501558613,"identity":"4574f8c8-5e04-4928-98ac-9e6a9875c319","order_by":0,"name":"Hui-Min Huang","email":"","orcid":"","institution":"Taipei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hui-Min","middleName":"","lastName":"Huang","suffix":""},{"id":501558614,"identity":"de0870b4-cc4c-464c-ad28-a21d6ea981a2","order_by":1,"name":"Bing-Hua Lin","email":"","orcid":"","institution":"Taipei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Bing-Hua","middleName":"","lastName":"Lin","suffix":""},{"id":501558615,"identity":"dc820f22-bd12-4cc6-a9e6-44e32b6c516e","order_by":2,"name":"Yi-No Kang","email":"","orcid":"","institution":"Taipei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yi-No","middleName":"","lastName":"Kang","suffix":""},{"id":501558616,"identity":"7468f27d-4768-453c-a49b-fd253e851471","order_by":3,"name":"Nai Ming Lai","email":"","orcid":"","institution":"Taylor's University","correspondingAuthor":false,"prefix":"","firstName":"Nai","middleName":"Ming","lastName":"Lai","suffix":""},{"id":501558617,"identity":"d4e0954d-5af5-4141-b151-a109cb5f47b5","order_by":4,"name":"Kee-Hsin Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyUlEQVRIiWNgGAWjYBACCQYGNgYGAwY5CJeNBC3GPDAtPMRpYWBI7CFai2R787GHPwrupO8XO2PA8KHsMIO9RAJ+LdI8x9KNeQye5fZI5xgwzjh3mIGHkBY5iRwzaQaDw2AtzLxtQC3ShLTIv/8m+cPgcDoPSMtfYrRIS/CwSfAYHE4Aa2EkRotkT5qZNFCLYc/ttIKDPefSeXjuP8CvReL44WeSP/4clmefnbzxwY8yazn2ngP4taAAkFqC0TIKRsEoGAWjgAgAAPU6OlpRBqVDAAAAAElFTkSuQmCC","orcid":"","institution":"Taipei Medical University","correspondingAuthor":true,"prefix":"","firstName":"Kee-Hsin","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2025-08-04 04:23:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7286761/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7286761/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12602-025-10795-w","type":"published","date":"2025-10-09T15:57:39+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89633957,"identity":"53f5c285-349d-473e-ae12-bb0ece73923a","added_by":"auto","created_at":"2025-08-22 07:00:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1114413,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the selection process of the included studies.\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-7286761/v1/fb0be47b99c0408b7b800329.png"},{"id":89634782,"identity":"7cf35491-8e95-4b2c-b0c2-db8b97107ffb","added_by":"auto","created_at":"2025-08-22 07:08:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":18882134,"visible":true,"origin":"","legend":"\u003cp\u003eRisks of bias of the included studies.\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-7286761/v1/01ae16d404f175ef909c6e86.png"},{"id":89633971,"identity":"b7da5181-8c15-407b-b408-2d5ae34b8835","added_by":"auto","created_at":"2025-08-22 07:00:23","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1687537,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots of total bilirubin levels at different time points.\u003c/p\u003e","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-7286761/v1/bc9a13d6a33d4a020350e436.png"},{"id":89633961,"identity":"0ff8be01-898e-4c6c-93cc-591b9c15c8d7","added_by":"auto","created_at":"2025-08-22 07:00:22","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":570432,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots of the duration of phototherapy.\u003c/p\u003e","description":"","filename":"Fig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-7286761/v1/62cd6507b0dcde1e76396c55.png"},{"id":89633963,"identity":"94d710db-a80b-4a66-b684-e95d606c6b45","added_by":"auto","created_at":"2025-08-22 07:00:22","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":576283,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots of the duration of hospitalization.\u003c/p\u003e","description":"","filename":"Fig.5.png","url":"https://assets-eu.researchsquare.com/files/rs-7286761/v1/573344bf256f2e246d20e81f.png"},{"id":89633964,"identity":"ebb4aff1-ed53-49bc-bdea-4e3591349783","added_by":"auto","created_at":"2025-08-22 07:00:22","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1203949,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots of adverse effects.\u003c/p\u003e","description":"","filename":"Fig.6.png","url":"https://assets-eu.researchsquare.com/files/rs-7286761/v1/f33707f40e5f8602990170d4.png"},{"id":93419839,"identity":"02fdfea1-4059-40bc-8640-3e3d726997ad","added_by":"auto","created_at":"2025-10-13 16:08:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":23981783,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7286761/v1/6a8cb7ae-105b-4c5d-996b-fbf12fa0da23.pdf"},{"id":89634777,"identity":"057e931c-3405-4b8f-a4ff-9eb891334beb","added_by":"auto","created_at":"2025-08-22 07:08:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":397471,"visible":true,"origin":"","legend":"","description":"","filename":"ESM1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7286761/v1/a8837266e476c5ec5ae337b6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and Safety of Probiotic Supplementation for Neonatal Jaundice: a Systematic Review and Meta-Analysis","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eNeonatal jaundice (NJ) is characterized by yellowish pigmentation of the skin, sclera, and mucous membranes due to elevated total serum bilirubin (TSB), a condition known as neonatal hyperbilirubinemia [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. It is a common condition affecting over 60% of full-term and up to 80% of preterm infants globally, highlighting its importance in neonatal health [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. NJ can be either physiologic or pathologic. Physiologic jaundice typically appears on days 2 to 3 after birth, peaks by days 5\u0026ndash;7, and resolves within two weeks, resulting from the immature hepatic metabolism of bilirubin [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In contrast, pathological jaundice occurs within 24 h after birth or persists beyond 2 weeks, which may result from conditions such as blood group incompatibility, metabolic or genetic disorders, or other congenital anomalies causing cholestasis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Excess unconjugated bilirubin can cross the immature blood-brain barrier in neonates, leading to bilirubin encephalopathy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], with symptoms ranging from lethargy, abnormal muscle tone, and seizures [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. If untreated, it may progress to kernicterus, an irreversible neurological complication with high mortality and morbidities [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The severity of NJ depends on bilirubin levels, gestational age (GA), and concurrent illnesses, highlighting the importance of early detection and treatment [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eCurrent treatments for NJ include phototherapy (PT), hydration, blood exchange transfusion, and medications such as phenobarbital, albumin, and intravenous immunoglobulin (IVIG) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Among these, PT is the most used therapy. The treatment converts bilirubin into water-soluble isomers which can be excreted without hepatic conjugation [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Despite its affordability, availability, and effectiveness in managing jaundice, PT often prolongs hospital stays, separating infants from their mothers, disrupting breastfeeding, and potentially leading to lactation failure [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Additionally, it can cause complications such as an unstable body temperature and dehydration, thus contributing to parental anxiety and increased healthcare costs [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Therefore, it is imperative to develop treatment strategies that enhance the efficacy of PT, reduce treatment durations, and address both the clinical outcomes and the socioeconomic burdens associated with NJ [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn recent years, probiotics, live microorganisms that provide health benefits to the host, have been widely utilized in managing various gastrointestinal (GI) disorders, including diarrhea, inflammatory bowel disease, and metabolic conditions such as obesity and diabetes in adults [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Probiotics have also been used in neonatal gastrointestinal disorders, particularly to prevent necrotizing enterocolitis [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] and improve postoperative gut function [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Studies suggested that probiotics may also play a role in regulating the TSB level and facilitating the resolution of NJ [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The mechanism involves modulating bilirubin metabolism in the enterohepatic circulation, balancing the intestinal microbiota, and promoting intestinal peristalsis and defecation [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. However, evidence of the effects of probiotics on NJ remains inconclusive [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. With recent randomized controlled trials (RCTs) contributing to the growing body of evidence, there is a need to integrate the latest findings and synthesize the current evidence of the effects of probiotics. In this study, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of probiotics supplementation in managing NJ.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003eWe included RCTs evaluating the efficacy and safety of probiotics supplementation for NJ in both preterm (GA\u0026thinsp;\u0026lt;\u0026thinsp;37 weeks) and full-term (GA\u0026thinsp;\u0026ge;\u0026thinsp;37 weeks) infants. Jaundice was diagnosed based on clinical symptoms (yellowish skin and sclera) and serum bilirubin levels. Phototherapy (PT) thresholds were defined by authors using guidelines such as Bhutani\u0026rsquo;s nomogram [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], typically set at \u0026gt;\u0026thinsp;12 mg/dL for full-term and \u0026gt;\u0026thinsp;9 mg/dL for preterm infants, though these varied based on factors like birth weight, GA, and comorbidities. The intervention group received probiotics without restrictions on strain, dosage, frequency, or duration, in combination with phototherapy. Control groups could include PT, enzyme inducers, IVIG, or other forms of supportive therapy.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Selection Criteria\u003c/h2\u003e\u003cp\u003eEligible studies met the following criteria: (a) the population consisted of neonates with jaundice meeting PT criteria; (b) the intervention group received probiotics supplementation and PT; (c) the control group receiving either PT alone, placebo, or any supplementary treatment; and (d) outcomes included at least one of the following: bilirubin levels, treatment efficacy, PT duration, days to jaundice resolution, hospitalization length, or adverse effects.\u003c/p\u003e\u003cp\u003eStudies were excluded if they (a) enrolled neonates with comorbidities affecting bilirubin outcomes, such as hepatitis or metabolic disorders; (b) trials involving herbal medicines to minimize potential confounding effects on target outcomes; or (c) failed to report sufficient methodological or outcome details.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Data sources and search strategy\u003c/h2\u003e\u003cp\u003eWe systematically searched PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure (CNKI) through January 2025 using the following terms and keywords: \u0026ldquo;probiotic\u0026rdquo; and \u0026ldquo;neonatal jaundice\u0026rdquo;. The present study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA) guidelines [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] and was registered with PROSPERO (CRD42025642453). No language or regional restrictions were applied. Each retrieved study was carefully screened for inclusion based on predefined selection criteria. Full search strategies were available in Supplementary File 1.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. Data Extraction\u003c/h2\u003e\u003cp\u003eTwo reviewers (H.M.H, and B.H.L) independently extracted data, including study characteristics, characteristics of participants, and regimens of probiotics and control. The reviewers extracted the mean and standard deviation (SD) for continuous outcomes, including bilirubin levels, PT duration, time to jaundice resolution, and hospitalization length. If the mean and SD were not available, other descriptive statistics were also extracted and then processed using valid methods and tools [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Discrepancies were resolved by discussion with a third reviewer (K.H.C.).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4. Methodological Quality Appraisal\u003c/h2\u003e\u003cp\u003e The methodological quality of the RCTs was independently assessed by two reviewers (H.M.H., and B.H.L.) using the Cochrane Risk-of-Bias tool (RoB 2.0) [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Disagreements were resolved through discussion with a third reviewer (K.H.C.), leading to a consensus. Furthermore, the GRADE (Grading of Recommendations Assessment, Development and Evaluation) [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] framework was used to evaluate the certainty of the evidence.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5. Statistical Analyses\u003c/h2\u003e\u003cp\u003e Data analyses were performed using Review Manager version 5.4 (The Cochrane Collaboration, Oxford, UK). Dichotomous outcomes were calculated as risk ratio (RR) with a 95% confidence interval (CI) using the Mantel-Haenszel method. Continuous outcomes were reported as mean difference (MD) with the corresponding 95% CI. Bilirubin values reported in mmol/L were converted to mg/dL using a conversion factor of 0.058 [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Data pooling was performed using a random-effects model, with statistical significance set to \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Heterogeneity was assessed using the I\u0026sup2; statistics [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], and \u003cem\u003eI\u003c/em\u003e\u0026sup2; values were interpreted as follows: (a)\u0026thinsp;\u0026lt;\u0026thinsp;20% indicates minimal variability, (b) 20\u0026ndash;50% signals moderate variability, and (c)\u0026thinsp;\u0026gt;\u0026thinsp;50% reflect substantial heterogeneity [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Additionally, subgroup analyses were conducted based on GA to evaluate the effects of probiotics in preterm and full-term infants.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.1. Study Screening and Selection\u003c/h2\u003e\u003cp\u003eThe initial search yielded 2015 citations from PubMed, Embase, Cochrane Library, and CNKI. After removing 714 duplicates, the remaining 1301 records were screened for eligibility. Finally, 30 articles [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan additionalcitationids=\"CR24 CR25\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan additionalcitationids=\"CR37 CR38 CR39 CR40 CR41 CR42 CR43 CR44 CR45 CR46 CR47 CR48 CR49 CR50 CR51 CR52 CR53 CR54 CR55 CR56 CR57 CR58 CR59\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e] met the inclusion criteria and were included in the final analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.2. Study Characteristics\u003c/h2\u003e\u003cp\u003eThe detailed baseline characteristics of participants were presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The included studies were published between 2008 and 2024and involved a total of 2776 infants. Nine studies included preterm neonates [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan additionalcitationids=\"CR49\" citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e], 20 studies included full-term neonates [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan additionalcitationids=\"CR43 CR44 CR45 CR46\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan additionalcitationids=\"CR52 CR53 CR54\" citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan additionalcitationids=\"CR58\" citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e], and one study included both preterm and full-term neonates [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Among them, 1425 infants received probiotics treatment and usual care, while 1351 infants received usual care alone. The probiotics formulations varied across the included studies as detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The usual care in these trials primarily included blue-light PT and adjunct therapies such as liver enzyme inducers, IVIG, and albumin administration. Detailed information on usual care was described in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of the included trials\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSelection criteria\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo. of patients\u003c/p\u003e\u003cp\u003e(males, %)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGestational age (weeks)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eChronological age (days)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eBirth weight (kg)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTotal bilirubin level (mg/dL)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eIntervention regimen\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChen et al. 2022 [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFull-term neonates (aged\u0026thinsp;\u0026le;\u0026thinsp;28 days) with pathological jaundice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 49 (51.0%)\u003c/p\u003e\u003cp\u003eC: 49 (51.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 13.28\u0026thinsp;\u0026plusmn;\u0026thinsp;3.51\u003c/p\u003e\u003cp\u003eC: 13.46\u0026thinsp;\u0026plusmn;\u0026thinsp;3.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 3.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e\u003cp\u003eC: 3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 17.41\u0026thinsp;\u0026plusmn;\u0026thinsp;2.83\u003c/p\u003e\u003cp\u003eC: 17.31\u0026thinsp;\u0026plusmn;\u0026thinsp;2.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eBifidobacterium\u003c/em\u003e triple viable powder \u003csup\u003eb\u003c/sup\u003e 500 mg BID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCui 2024 [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFull-term neonates (BW\u0026thinsp;\u0026ge;\u0026thinsp;1500 g) with jaundice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 100 (57%)\u003c/p\u003e\u003cp\u003eC: 100 (51%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 15.84\u0026thinsp;\u0026plusmn;\u0026thinsp;1.68\u003c/p\u003e\u003cp\u003eC: 16.11\u0026thinsp;\u0026plusmn;\u0026thinsp;1.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 3.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25\u003c/p\u003e\u003cp\u003eC: 3.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 13.67\u0026thinsp;\u0026plusmn;\u0026thinsp;1.20\u003c/p\u003e\u003cp\u003eC: 13.58\u0026thinsp;\u0026plusmn;\u0026thinsp;1.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eBifidobacterium\u003c/em\u003e quadruple viable tablet \u003csup\u003ed\u003c/sup\u003e 500 mg BID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDai 2020 [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePreterm neonates (GA 28\u0026ndash;37 weeks) with non-hemolytic jaundice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 25 (56%)\u003c/p\u003e\u003cp\u003eC: 25 (48%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 14.65\u0026thinsp;\u0026plusmn;\u0026thinsp;2.82\u003c/p\u003e\u003cp\u003eC: 15.26\u0026thinsp;\u0026plusmn;\u0026thinsp;2.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 3.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.54\u003c/p\u003e\u003cp\u003eC: 3.19\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 9.13\u0026thinsp;\u0026plusmn;\u0026thinsp;3.00\u003c/p\u003e\u003cp\u003eC: 9.08\u0026thinsp;\u0026plusmn;\u0026thinsp;3.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eSaccharomyces boulardii\u003c/em\u003e 250 mg QD\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDong \u0026amp; Wu 2019 [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePreterm neonates (GA 28\u0026ndash;36 weeks) with non-hemolytic or liver dysfunction-related jaundice, excluding allergies\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 30 (60%)\u003c/p\u003e\u003cp\u003eC: 30 (53.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 33.18\u0026thinsp;\u0026plusmn;\u0026thinsp;0.53\u003c/p\u003e\u003cp\u003eC: 33.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 10.88\u0026thinsp;\u0026plusmn;\u0026thinsp;2.27\u003c/p\u003e\u003cp\u003eC: 10.82\u0026thinsp;\u0026plusmn;\u0026thinsp;2.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 9.86\u0026thinsp;\u0026plusmn;\u0026thinsp;1.37\u003c/p\u003e\u003cp\u003eC: 9.85\u0026thinsp;\u0026plusmn;\u0026thinsp;1.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eBifidobacterium\u003c/em\u003e triple viable powder \u003csup\u003eb\u003c/sup\u003e 500 mg BID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGao et al. 2021 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFull-term neonates with jaundice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 50 (56%)\u003c/p\u003e\u003cp\u003eC: 50 (58%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 3.58\u0026thinsp;\u0026plusmn;\u0026thinsp;1.291\u003c/p\u003e\u003cp\u003eC: 3.25\u0026thinsp;\u0026plusmn;\u0026thinsp;1.401\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 3.39\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47\u003c/p\u003e\u003cp\u003eC: 3.28\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 18.01\u0026thinsp;\u0026plusmn;\u0026thinsp;3.75\u003c/p\u003e\u003cp\u003eC: 17.24\u0026thinsp;\u0026plusmn;\u0026thinsp;4.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eClostridium butyricum\u003c/em\u003e 420 mg BID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHamed et al. 2019 [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeonates with physiological or hemolytic jaundice and sepsis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 50 (66%)\u003c/p\u003e\u003cp\u003eC: 50 (60%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 34.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/p\u003e\u003cp\u003eC: 33.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 3.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\u003cp\u003eC: 4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 2.80\u0026thinsp;\u0026plusmn;\u0026thinsp;0.89\u003c/p\u003e\u003cp\u003eC: 3.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 17.63\u0026thinsp;\u0026plusmn;\u0026thinsp;1.53\u003c/p\u003e\u003cp\u003eC: 17.46\u0026thinsp;\u0026plusmn;\u0026thinsp;2.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eLactobacillus acidophilus, L. rhamnosus, Bifidobacterium lactis, B. bifidum\u003c/em\u003e\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHu et al. 2023 [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePremature neonates (\u0026lt;\u0026thinsp;35 weeks GA) with yellow skin/sclera, excluding bile duct obstruction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 55 (61.8%)\u003c/p\u003e\u003cp\u003eC: 45 (53.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 30.69\u0026thinsp;\u0026plusmn;\u0026thinsp;1.16\u003c/p\u003e\u003cp\u003eC: 30.40\u0026thinsp;\u0026plusmn;\u0026thinsp;1.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 1.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e\u003cp\u003eC: 1.39\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 16.22\u0026thinsp;\u0026plusmn;\u0026thinsp;1.73\u003c/p\u003e\u003cp\u003eC: 16.74\u0026thinsp;\u0026plusmn;\u0026thinsp;2.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eS. boulardii\u003c/em\u003e 250 mg QD\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJia 2021 [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeonates with physiological jaundice and normal liver function, excluding bile duct obstruction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 36 (41.7%)\u003c/p\u003e\u003cp\u003eC: 36 (52.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 6.28\u0026thinsp;\u0026plusmn;\u0026thinsp;3.41\u003c/p\u003e\u003cp\u003eC: 6.08\u0026thinsp;\u0026plusmn;\u0026thinsp;3.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 15.76\u0026thinsp;\u0026plusmn;\u0026thinsp;1.91\u003c/p\u003e\u003cp\u003eC: 15.60\u0026thinsp;\u0026plusmn;\u0026thinsp;1.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eBifidobacterium\u003c/em\u003e triple viable tablet \u003csup\u003ec\u003c/sup\u003e 250 mg BID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLai et al. 2022 [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeonates (TSB\u0026thinsp;\u0026gt;\u0026thinsp;12 mg/dL) with physiological jaundice, yellow skin/mucosa/sclera, and normal liver function, excluding bile duct obstruction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 30 (53.3%)\u003c/p\u003e\u003cp\u003eC: 30 (50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 38.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e\u003cp\u003eC: 38.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 6.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3\u003c/p\u003e\u003cp\u003eC: 6.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 16.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.72\u003c/p\u003e\u003cp\u003eC: 16.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCompound \u003cem\u003eEosinophil-Lactobacillus\u003c/em\u003e 250 mg BID/TID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiang 2012 [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeonates with HBR (full-term TSB\u0026thinsp;\u0026gt;\u0026thinsp;12 mg/dL, preterm TSB\u0026thinsp;\u0026gt;\u0026thinsp;15 mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 40 (60%)\u003c/p\u003e\u003cp\u003eC: 32 (53.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 38.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e\u003cp\u003eC: 38.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 10.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8\u003c/p\u003e\u003cp\u003eC: 10.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 18.64\u0026thinsp;\u0026plusmn;\u0026thinsp;5.01\u003c/p\u003e\u003cp\u003eC: 18.73\u0026thinsp;\u0026plusmn;\u0026thinsp;5.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eBifidobacterium\u003c/em\u003e triple viable tablet \u003csup\u003ec\u003c/sup\u003e 500 mg TID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiang et al. 2023 [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeonates (aged\u0026thinsp;\u0026lt;\u0026thinsp;28 days, TSB\u0026thinsp;\u0026gt;\u0026thinsp;12 mg/dL) with physiological jaundice and normal liver function\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 36 (58.3%)\u003c/p\u003e\u003cp\u003eC: 36 (55.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 38.20\u0026thinsp;\u0026plusmn;\u0026thinsp;1.18\u003c/p\u003e\u003cp\u003eC: 38.35\u0026thinsp;\u0026plusmn;\u0026thinsp;1.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 10.14\u0026thinsp;\u0026plusmn;\u0026thinsp;2.35\u003c/p\u003e\u003cp\u003eC: 10.38\u0026thinsp;\u0026plusmn;\u0026thinsp;2.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 16.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62\u003c/p\u003e\u003cp\u003eC: 17.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eBifidobacterium\u003c/em\u003e triple viable powder \u003csup\u003eb\u003c/sup\u003e 500 mg BID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLin \u0026amp; Lu 2021 [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeonates (primigravida, aged\u0026thinsp;\u0026lt;\u0026thinsp;28 days, TSB\u0026thinsp;\u0026gt;\u0026thinsp;12.9 mg/dL) with jaundice, excluding severe hemolytic anemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 45 (53.3%)\u003c/p\u003e\u003cp\u003eC: 45 (51.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 39.23\u0026thinsp;\u0026plusmn;\u0026thinsp;1.12\u003c/p\u003e\u003cp\u003eC: 38.55\u0026thinsp;\u0026plusmn;\u0026thinsp;0.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 2.63\u0026thinsp;\u0026plusmn;\u0026thinsp;1.32\u003c/p\u003e\u003cp\u003eC: 2.57\u0026thinsp;\u0026plusmn;\u0026thinsp;1.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 20.18\u0026thinsp;\u0026plusmn;\u0026thinsp;1.59\u003c/p\u003e\u003cp\u003eC: 20.03\u0026thinsp;\u0026plusmn;\u0026thinsp;1.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eBifidobacterium\u003c/em\u003e triple viable capsule \u003csup\u003eb\u003c/sup\u003e 105 mg BID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiu et al. 2015 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeonates with jaundice (TcB\u0026thinsp;\u0026gt;\u0026thinsp;12.9 mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 34 (64.7%)\u003c/p\u003e\u003cp\u003eC: 34 (58.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 39.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e\u003cp\u003eC:39.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 11.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\u003cp\u003eC: 11.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 3.86\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e\u003cp\u003eC: 3.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 20.29\u0026thinsp;\u0026plusmn;\u0026thinsp;3.04\u003c/p\u003e\u003cp\u003eC: 20.53\u0026thinsp;\u0026plusmn;\u0026thinsp;2.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eBifidobacterium\u003c/em\u003e triple viable capsule \u003csup\u003eb\u003c/sup\u003e TID/QID 2 g/day\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiu 2023 [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeonates with HBR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 50 (50%)\u003c/p\u003e\u003cp\u003eC: 50 (46%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 38.35\u0026thinsp;\u0026plusmn;\u0026thinsp;1.68\u003c/p\u003e\u003cp\u003eC: 38.02\u0026thinsp;\u0026plusmn;\u0026thinsp;1.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 8.06\u0026thinsp;\u0026plusmn;\u0026thinsp;6.55\u003c/p\u003e\u003cp\u003eC: 8.03\u0026thinsp;\u0026plusmn;\u0026thinsp;6.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 2.97\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56\u003c/p\u003e\u003cp\u003eC: 2.95\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 16.80\u0026thinsp;\u0026plusmn;\u0026thinsp;1.82\u003c/p\u003e\u003cp\u003eC: 16.74\u0026thinsp;\u0026plusmn;\u0026thinsp;1.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eBifidobacterium\u003c/em\u003e triple viable capsule \u003csup\u003eb\u003c/sup\u003e 210 mg BID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLu \u0026amp; Ling 2017 [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePreterm neonates (29\u0026ndash;36 weeks GA, hospitalization\u0026thinsp;\u0026gt;\u0026thinsp;7 days) with non-hemolytic jaundice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 37 (NI)\u003c/p\u003e\u003cp\u003eC: 41 (NI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 10.01\u0026thinsp;\u0026plusmn;\u0026thinsp;2.60\u003c/p\u003e\u003cp\u003eC: 9.08\u0026thinsp;\u0026plusmn;\u0026thinsp;2.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eS. boulardii\u003c/em\u003e 125 mg BID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMatin et al. 2022 [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSingle or twin neonates (VLBW: 1000\u0026ndash;1500 g, 2\u0026ndash;3 days old)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 26 (50%)\u003c/p\u003e\u003cp\u003eC: 26 (50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 31.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e\u003cp\u003eC: 30.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 1.39\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u003c/p\u003e\u003cp\u003eC: 1.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eL. paracasei\u003c/em\u003e 500 mg QD\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMutlu et al. 2020 [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeonates (35\u0026ndash;42 weeks GA) with hemolysis and STB increase\u0026thinsp;\u0026gt;\u0026thinsp;0.2 mg/dL/h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 30 (47%)\u003c/p\u003e\u003cp\u003eC: 30 (43%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 38.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e\u003cp\u003eC: 37.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 3.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33\u003c/p\u003e\u003cp\u003eC: 3.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 3.44\u0026thinsp;\u0026plusmn;\u0026thinsp;0.95\u003c/p\u003e\u003cp\u003eC: 3.57\u0026thinsp;\u0026plusmn;\u0026thinsp;1.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eL. rhamnosus\u003c/em\u003e GG QD\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNasief et al. 2024 [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePreterm neonates (\u0026lt;\u0026thinsp;37 weeks GA) with indirect HBR, excluding ABO/Rh incompatibility\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 36 (55.6%)\u003c/p\u003e\u003cp\u003eC: 36 (38.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 33.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.71\u003c/p\u003e\u003cp\u003eC: 33.62\u0026thinsp;\u0026plusmn;\u0026thinsp;1.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 4.91\u0026thinsp;\u0026plusmn;\u0026thinsp;2.53\u003c/p\u003e\u003cp\u003eC: 4.86\u0026thinsp;\u0026plusmn;\u0026thinsp;1.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 2.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.41\u003c/p\u003e\u003cp\u003eC: 2.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 16.68\u0026thinsp;\u0026plusmn;\u0026thinsp;1.69\u003c/p\u003e\u003cp\u003eC: 16.92\u0026thinsp;\u0026plusmn;\u0026thinsp;1.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eS. boulardii\u003c/em\u003e 125 mg BID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerce et al. 2015 [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeonates (35\u0026ndash;42 weeks GA) with non-hemolytic indirect HBR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 58 (44.8%)\u003c/p\u003e\u003cp\u003eC: 61 (47.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 37.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e\u003cp\u003eC: 37.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 1.98\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e\u003cp\u003eC: 2.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 3.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.59\u003c/p\u003e\u003cp\u003eC: 3.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 13.43\u0026thinsp;\u0026plusmn;\u0026thinsp;2.96\u003c/p\u003e\u003cp\u003eC: 13.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eS. boulardii\u003c/em\u003e 125 mg BID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTang et al. 2020 [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeonates (37\u0026ndash;42 weeks GA, BW: 2500\u0026ndash;4000 g) with indirect HBR, jaundice onset at 3\u0026ndash;5 days, total bilirubin\u0026thinsp;\u0026gt;\u0026thinsp;95th percentile (Bhutani nomogram), or unconjugated bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;80%.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 61 (44.3%)\u003c/p\u003e\u003cp\u003eC: 63 (46.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 39.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e\u003cp\u003eC: 38.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 3.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.41\u003c/p\u003e\u003cp\u003eC: 3.41\u0026thinsp;\u0026plusmn;\u0026thinsp;0.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 15.38\u0026thinsp;\u0026plusmn;\u0026thinsp;2.40\u003c/p\u003e\u003cp\u003eC: 15.61\u0026thinsp;\u0026plusmn;\u0026thinsp;2.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eS. boulardii\u003c/em\u003e 250 mg QD\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTariq et al. 2021 [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeonates (BW\u0026thinsp;\u0026ge;\u0026thinsp;2500 g) with non-hemolytic indirect HBR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 47 (59.6%)\u003c/p\u003e\u003cp\u003eC: 47 (57.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 37.36\u0026thinsp;\u0026plusmn;\u0026thinsp;2.02\u003c/p\u003e\u003cp\u003eC: 37.26\u0026thinsp;\u0026plusmn;\u0026thinsp;2.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 6.47\u0026thinsp;\u0026plusmn;\u0026thinsp;4.75\u003c/p\u003e\u003cp\u003eC: 6.62\u0026thinsp;\u0026plusmn;\u0026thinsp;5.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 2.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.51\u003c/p\u003e\u003cp\u003eC: 2.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 16.71\u0026thinsp;\u0026plusmn;\u0026thinsp;1.25\u003c/p\u003e\u003cp\u003eC: 16.76\u0026thinsp;\u0026plusmn;\u0026thinsp;1.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eProkid probiotic \u003csup\u003ee\u003c/sup\u003e QD\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTorkaman et al. 2016 [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeonates (\u0026gt;\u0026thinsp;35 weeks GA, BW\u0026thinsp;\u0026gt;\u0026thinsp;2500 g, bilirubin\u0026thinsp;\u0026gt;\u0026thinsp;15 mg/dL, direct bilirubin\u0026thinsp;\u0026lt;\u0026thinsp;1.5 mg/dL, aged\u0026thinsp;\u0026ge;\u0026thinsp;2 days) with non-hemolytic indirect HBR, excluding blood transfusion, IVIG, phenobarbital, or serum therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 45 (37.7%)\u003c/p\u003e\u003cp\u003eC: 47 (48.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 5.31\u0026thinsp;\u0026plusmn;\u0026thinsp;2.19\u003c/p\u003e\u003cp\u003eC: 5.19\u0026thinsp;\u0026plusmn;\u0026thinsp;2.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 3.28\u0026thinsp;\u0026plusmn;\u0026thinsp;0.38\u003c/p\u003e\u003cp\u003eC: 3.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 16.95\u0026thinsp;\u0026plusmn;\u0026thinsp;2.67\u003c/p\u003e\u003cp\u003eC: 16.46\u0026thinsp;\u0026plusmn;\u0026thinsp;2.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eProkid probiotic \u003csup\u003ee\u003c/sup\u003e QD\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTsai et al. 2022 [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeonates (\u0026gt;\u0026thinsp;35 weeks GA, SBL\u0026thinsp;\u0026gt;\u0026thinsp;15 mg/dL on day 4) with jaundice, excluding maternal ABO incompatibility\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 43 (46.5%)\u003c/p\u003e\u003cp\u003eC: 40 (62.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 38.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.20\u003c/p\u003e\u003cp\u003eC: 37.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 3.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e\u003cp\u003eC: 3.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 16.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.41\u003c/p\u003e\u003cp\u003eC: 16.13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eB. animalis\u003c/em\u003e subsp. \u003cem\u003elactis\u003c/em\u003e CP-9 BID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWang et al. 2014 [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFull-term neonates with pathological jaundice, excluding Rh/ABO incompatibility\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 56 (51.8%)\u003c/p\u003e\u003cp\u003eC: 50 (54%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 7.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e\u003cp\u003eC: 7.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 15.81\u0026thinsp;\u0026plusmn;\u0026thinsp;1.71\u003c/p\u003e\u003cp\u003eC: 16.10\u0026thinsp;\u0026plusmn;\u0026thinsp;1.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eS. boulardii\u003c/em\u003e 250 mg QD\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWu et al. 2019 [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePreterm neonates with jaundice and normal liver function\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 31 (48.4%)\u003c/p\u003e\u003cp\u003eC: 33 (48.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI:45\u0026thinsp;\u0026plusmn;\u0026thinsp;12\u003c/p\u003e\u003cp\u003eC: 36\u0026thinsp;\u0026plusmn;\u0026thinsp;6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 15.81\u0026thinsp;\u0026plusmn;\u0026thinsp;1.71\u003c/p\u003e\u003cp\u003eC: 16.10\u0026thinsp;\u0026plusmn;\u0026thinsp;1.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eS. boulardii\u003c/em\u003e 250 mg BID/TID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eXue 2023 [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInfants (aged\u0026thinsp;\u0026lt;\u0026thinsp;42 days) with pathological jaundice, excluding current alternative treatments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 50 (48%)\u003c/p\u003e\u003cp\u003eC: 50 (56%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 9.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.24\u003c/p\u003e\u003cp\u003eC: 10.23\u0026thinsp;\u0026plusmn;\u0026thinsp;3.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 3.76\u0026thinsp;\u0026plusmn;\u0026thinsp;0.42\u003c/p\u003e\u003cp\u003eC: 3.72\u0026thinsp;\u0026plusmn;\u0026thinsp;0.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 16.09\u0026thinsp;\u0026plusmn;\u0026thinsp;1.77\u003c/p\u003e\u003cp\u003eC: 15.95\u0026thinsp;\u0026plusmn;\u0026thinsp;1.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eBifidobacterium\u003c/em\u003e quadruple viable tablet \u003csup\u003ed\u003c/sup\u003e 500 mg BID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZeng 2020 [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInfants with pathological jaundice and normal liver function, excluding bile duct obstruction and IUGR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 50 (58%)\u003c/p\u003e\u003cp\u003eC: 50 (56%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 14.52\u0026thinsp;\u0026plusmn;\u0026thinsp;3.64\u003c/p\u003e\u003cp\u003eC: 14.55\u0026thinsp;\u0026plusmn;\u0026thinsp;3.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 3.56\u0026thinsp;\u0026plusmn;\u0026thinsp;1.28\u003c/p\u003e\u003cp\u003eC: 3.59\u0026thinsp;\u0026plusmn;\u0026thinsp;1.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 16.82\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62\u003c/p\u003e\u003cp\u003eC: 16.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCombined \u003cem\u003eB. subtilis\u003c/em\u003e and \u003cem\u003eEnterococcus faecium\u003c/em\u003e granules 500 mg TID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZhang \u0026amp; Deng 2008 [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeonates with HBR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 25 (56%)\u003c/p\u003e\u003cp\u003eC: 25 (52%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 37.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8\u003c/p\u003e\u003cp\u003eC: 38.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 4.26\u0026thinsp;\u0026plusmn;\u0026thinsp;1.92\u003c/p\u003e\u003cp\u003eC: 4.18\u0026thinsp;\u0026plusmn;\u0026thinsp;1.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eI: 3.87\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25\u003c/p\u003e\u003cp\u003eC: 2.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 17.62\u0026thinsp;\u0026plusmn;\u0026thinsp;2.52\u003c/p\u003e\u003cp\u003eC: 17.54\u0026thinsp;\u0026plusmn;\u0026thinsp;2.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eBifidobacterium\u003c/em\u003e triple viable tablet \u003csup\u003ec\u003c/sup\u003e 250 mg TID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZhang 2019 [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeonates with jaundice and normal liver function, excluding bile duct obstruction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 50 (60%)\u003c/p\u003e\u003cp\u003eC: 50 (62%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI: 4.23\u0026thinsp;\u0026plusmn;\u0026thinsp;1.02\u003c/p\u003e\u003cp\u003eC: 4.31\u0026thinsp;\u0026plusmn;\u0026thinsp;1.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 16.79\u0026thinsp;\u0026plusmn;\u0026thinsp;1.76\u003c/p\u003e\u003cp\u003eC: 16.93\u0026thinsp;\u0026plusmn;\u0026thinsp;1.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCombined \u003cem\u003eB. subtilis\u003c/em\u003e and \u003cem\u003eE. faecium\u003c/em\u003e granules 1000 mg BID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZhong 2018 [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePreterm neonates (GA: 28\u0026ndash;37weeks, hospitalization\u0026thinsp;\u0026gt;\u0026thinsp;1 week) with jaundice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI: 120 (60%)\u003c/p\u003e\u003cp\u003eC: 120 (61.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI: 34.28\u0026thinsp;\u0026plusmn;\u0026thinsp;2.51\u003c/p\u003e\u003cp\u003eC: 34.12\u0026thinsp;\u0026plusmn;\u0026thinsp;2.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eI: 9.08\u0026thinsp;\u0026plusmn;\u0026thinsp;1.41\u003c/p\u003e\u003cp\u003eC: 8.97\u0026thinsp;\u0026plusmn;\u0026thinsp;1.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eBifidobacterium\u003c/em\u003e triple viable tablet \u003csup\u003ec\u003c/sup\u003e 125 mg BID\u0026thinsp;+\u0026thinsp;UC \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003eBW: body weight, GA: gestational age, QD: once a day, BID: twice a day, TID: three times a day, UC: usual care, TcB: transcutaneous bilirubin, TSB: total serum bilirubin, HBR: hyperbilirubinemia, PT: phototherapy, IVIG: intravenous immunoglobulin, VLBW: very low birth weight, IUGR: intrauterine growth restriction, \u003cem\u003eB. lactis: Bifidobacterium lactis, B. bifidum: Bifidobacterium bifidum, B. animalis\u003c/em\u003e subsp. \u003cem\u003elactis\u003c/em\u003e CP-9: \u003cem\u003eBifidobacterium animalis\u003c/em\u003e subsp. \u003cem\u003elactis\u003c/em\u003e CP-9, \u003cem\u003eB. subtilis: Bacillus subtilis, C. butyricum: Clostridium butyricum, E. faecium: Enterococcus faecium, S. boulardii: Saccharomyces boulardii, L. paracasei: Lacticaseibacillus paracasei, L. rhamnosus: Lactobacillus rhamnosus, L. acidophilus: Lactobacillus acidophilus.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003ea: Usual care (e.g. phototherapy, liver enzyme inducers, intravenous immunoglobulin, albumin, etc.).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003eb: \u003cem\u003eBifidobacterium\u003c/em\u003e triple viable capsule/powder: containing \u003cem\u003eBifidobacterium longum, Lactobacillus acidophilus\u003c/em\u003e, and \u003cem\u003eEnterococcus faecalis.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003ec: \u003cem\u003eBifidobacterium\u003c/em\u003e triple viable tablet: containing \u003cem\u003eBifidobacterium longum, Lactobacillus bulgaricus\u003c/em\u003e, and \u003cem\u003eStreptococcus thermophilus.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003ed: \u003cem\u003eBifidobacterium\u003c/em\u003e quadruple viable tablet: containing \u003cem\u003eBifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis, and Bacillus cereus.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003ee: Prokid probiotic: containing \u003cem\u003eBifidobacterium lactis, Lactobacillus acidophilus, Bifidobacterium bifidum\u003c/em\u003e, and \u003cem\u003eLactobacillus rhamnosus\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.3. Methodological Quality\u003c/h2\u003e\u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarizes the methodological quality of the 30 included trials. Among these, nine trials had \"some concerns\" regarding the randomization process due to insufficient information on allocation concealment [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan additionalcitationids=\"CR50 CR51 CR52\" citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. Two trials showed \"some concerns\" related to missing outcome data due to incomplete reporting [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Fifteen trials had \"some concerns\" in the measurement of outcomes since the blinding status of the outcome assessors was not specified [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan additionalcitationids=\"CR44\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan additionalcitationids=\"CR49 CR50 CR51\" citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e, \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. Other domains were graded to be at low risk of bias. Overall, 10 trials had a low risk of bias, and 20 trials had some concerns.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.4. Total Bilirubin Level\u003c/h2\u003e\u003cp\u003eThe total bilirubin level after treatment was reported in 27 studies. The probiotics group showed significantly lower total bilirubin levels (mg/dL), compared to the control groups on day 1 (MD:-0.35, 95% CI:-0.63 to -0.06), day 2 (MD:-1.26, 95% CI:-1.73 to -0.79), day 3 (MD:-1.40, 95% CI:-2.50 to -0.29), day 4 (MD:-1.41, 95% CI:-2.12 to -0.69), day 5 (MD:-0.85, 95% CI:-1.19 to -0.52), day 7 (MD:-1.55, 95% CI:-2.50 to -0.60), day 8 (MD:-0.67, 95% CI:-1.14 to -0.20), and day 10 (MD:-1.74, 95% CI:-2.54 to -0.95). However, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e values were relatively high, with a range of 14\u0026ndash;98% (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eSubgroup analyses based on GA were conducted to explore the source of heterogeneity. Among the 27 RCTs, 19 RCTs focused on full-term infants, while eight RCTs focused on preterm infants. Probiotic supplements significantly reduced the bilirubin level at all time points among full-term babies (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). For the preterm subgroups, although probiotic supplementation did not significantly reduce bilirubin levels (mg/dL) on day 1 (MD:0.07, 95% CI:-0.53 to 0.66), it significantly lower bilirubin levels compared to the control group, with an increasing effect size over time, day 3 (MD:-0.63, 95% CI:-1.11 to -0.16), day 4 (MD:-0.76, 95% CI:-1.21 to -0.32), day 5 (MD:-1.17, 95% CI:-2.35 to 0.02), day 7 (MD:-2.50, 95% CI:-3.56 to -1.44) as shown in Supplementary Table S2.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.5. Duration of Phototherapy\u003c/h2\u003e\u003cp\u003eThe duration of PT was reported in nine studies. Four studies focused on preterm neonates [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e], four on full-term neonates [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e], and one study included both preterm and full-term neonates [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Overall, using probiotic supplements significantly reduced the duration of PT (MD: -17.09, 95% CI: -24.43 to -9.76) hours. In subgroup analyses, PT duration was similarly reduced in preterm (MD: -33.55 hours; 95% CI: -56.07 to -11.03) and full-term neonates (MD: -6.53 hours; 95% CI: -10.75 to -2.32) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e3.6. Days to Jaundice Resolution\u003c/h2\u003e\u003cp\u003eThe duration required for jaundice resolution was reported in 10 studies. One study focused on preterm neonates [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], and nine on full-term neonates [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan additionalcitationids=\"CR43 CR44 CR45\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. Overall, the probiotics group showed a significant reduction in jaundice resolution time (MD: -2.23, 95% CI: -2.94 to -1.52) days. In subgroup analyses, probiotics significantly shortened the time to jaundice resolution in both preterm (MD: -7.26 days; 95% CI: -9.22 to -5.30) and full-term neonates (MD: -1.88 days; 95% CI: -2.49 to -1.26) (Supplementary Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e3.7. Efficacy Rate\u003c/h2\u003e\u003cp\u003eThe efficacy of jaundice treatment was determined based on the following criteria: complete resolution\u0026ndash; complete resolution of jaundice symptoms and normalization of bilirubin levels; partial resolution\u0026ndash; reduction in jaundice symptoms and a decrease in bilirubin levels, although not within the normal range; and ineffective \u0026ndash; no improvement in jaundice symptoms or bilirubin levels [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. The efficacy rate was calculated as (number of cured cases\u0026thinsp;+\u0026thinsp;number of effective cases) / total cases \u0026times; 100% [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. The efficacy rate was reported in 15 studies: three on preterm neonates [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e] and 12 on full-term neonates [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan additionalcitationids=\"CR44\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan additionalcitationids=\"CR58\" citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. Overall, the probiotics group showed a higher efficacy rate compared to the control group (RR: 1.16, 95% CI: 1.12 to 1.21). This trend was observed in both preterm (RR: 1.17, 95% CI: 1.03 to 1.31) and full-term subgroups (RR: 1.17, 95% CI: 1.12 to 1.22) (Supplementary Fig. S2).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003e3.8. Duration of Hospitalization\u003c/h2\u003e\u003cp\u003eThe duration of hospitalization was reported in nine studies. Three studies focused on preterm neonates [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e], five on full-term neonates [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e], and one study included both preterm and full-term neonates [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. The overall analysis demonstrated a significant reduction in the hospitalization duration in the probiotics group (MD:-1.17, 95% CI:-1.60 to -0.74) days. Subgroup analyses revealed significantly shorter hospital stays in both preterm (MD:-0.43 days; 95% CI:-0.65 to -0.20) and full-term neonates (MD:-1.93 days; 95% CI:-2.85 to -1.00) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003e3.9. Adverse Effects\u003c/h2\u003e\u003cp\u003eThe main adverse effects reported in the included studies were diarrhea (14 RCTs) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan additionalcitationids=\"CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e], rashes (15 RCTs) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan additionalcitationids=\"CR37 CR38\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e], and fevers (11 RCTs) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan additionalcitationids=\"CR37 CR38\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. The pooled data showed a significantly lower risk of diarrhea (RR:0.40, 95% CI:0.22 to 0.74), rashes (RR:0.57, 95% CI:0.33 to 0.98), and fever (RR:0.46, 95% CI:0.24 to 0.86) in the probiotics group compared to the control group. No heterogeneity was observed across the studies (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003e3.10. Certainty of Evidence\u003c/h2\u003e\u003cp\u003eWe evaluated the certainty of the evidence using the GRADE framework for TSB levels, duration of phototherapy and hospitalization. The certainty of evidence was downgraded from the default high level based on risk of bias, inconsistency, indirectness, imprecision, and publication bias. Moderate-certainty evidence suggested that probiotics modestly reduced TSB on day 1, with downgrading due to imprecision. Very low-certainty evidence supported a reduction in TSB on day 10, downgraded due to a large degree of heterogeneity (I\u0026sup2;=96%) and imprecision. Low-certainty evidence indicated reductions in phototherapy duration and hospitalization, with downgrading due to substantial heterogeneity (I\u0026sup2;=81\u0026ndash;89%) (Supplementary Table S3).\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe meta-analysis of 30 studies involving 2776 patients demonstrated that probiotics supplementation significantly reduced bilirubin levels, shortened the durations of PT and hospitalization, accelerated jaundice resolution, and resulted in a higher efficacy rate compared to the control groups. These findings are supported not only by the mechanisms outlined in the Introduction [\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], but also by relevant RCTs, including the impact of probiotics on bilirubin levels in healthy infants and their influence on GI function in preterm neonates [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e, \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. Additionally, the results showed that the addition of probiotics to usual care significantly improved safety profiles compared to routine care alone. A subgroup analysis by GA further indicated that most of these benefits remained consistent in both preterm and full-term neonates.\u003c/p\u003e\u003cp\u003e\u003cb\u003eDifferential Effects of Probiotics in Preterm and Full-Term Infants During the First 3 Days\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe observed that the effect of probiotics in reducing TSB levels became increasingly evident over time. In the preterm infant group, a significant difference in TSB levels between the probiotics and control groups was observed by day 3. In contrast, in the full-term infant group, the reduction in TSB levels was significant from day 1 of probiotics administration. The differential effects of probiotics on preterm and full-term infants may be attributed to several factors. Preterm infants often exhibit lower serum albumin levels and an altered albumin/bilirubin-binding capacity, leading to higher levels of unbound bilirubin [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e, \u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]. Additionally, preterm infants are more vulnerable to intestinal dysbiosis, which impairs bilirubin metabolism and excretion. This disruption contributes to elevated TSB levels over time as gut microbes play a critical role in converting bilirubin into excretable forms [\u003cspan additionalcitationids=\"CR66\" citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSince full-term infants generally have a more developed and healthier gut microbiota, the effects of probiotics on TSB reduction appeared more rapidly. In contrast, preterm infants require a longer period for probiotics to modulate the gut microbiotic composition, thereby facilitating bilirubin elimination. Although probiotics showed minimal effects on TSB levels in preterm infants on day 1, their efficacy became increasingly pronounced over time. This finding suggests that probiotics supplementation promotes the gut microbiotic health, thus contributing to mitigating neonatal hyperbilirubinemia [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003eMechanisms of Different Probiotics\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe RCTs included in this meta-analysis utilized various strains of probiotics to evaluate their effects on NJ. Different probiotics strains may exert their effects through distinct mechanisms. For instance, patients with NJ were found to have significantly lower levels of Bifidobacterium species, such as \u003cem\u003eBifidobacterium adolescentis\u003c/em\u003e, \u003cem\u003eBifidobacterium bifidum\u003c/em\u003e, and \u003cem\u003eBifidobacterium longum\u003c/em\u003e, compared to healthy individuals in the fecal samples [\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e]. \u003cem\u003eBifidobacterium\u003c/em\u003e lowers bilirubin levels by inhibiting β-glucuronidase, an enzyme that hydrolyzes conjugated bilirubin and releases free bilirubin for reabsorption in the enterohepatic circulation [\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e]. By inhibiting β-glucuronidase, \u003cem\u003eBifidobacterium\u003c/em\u003e reduces bilirubin reabsorption, promoting its elimination [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e]. Based on the proposed biological pathway, \u003cem\u003eBifidobacterium\u003c/em\u003e supplementation may represent a promising strategy for reducing TSB levels.\u003c/p\u003e\u003cp\u003eAdditionally, \u003cem\u003eLactobacillus rhamnosus\u003c/em\u003e GG had been reported to facilitate bilirubin clearance through stimulation of bowel movements [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. \u003cem\u003eSaccharomyces boulardii\u003c/em\u003e has been shown to suppress β-glucuronidase activity and reduce enterohepatic circulation by altering the enzyme\u0026rsquo;s structure, and activity, thereby contributing to a decrease in serum bilirubin levels [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]. Building upon these mechanistic insights, our study provides clinical evidence supporting the adjunctive use of probiotic supplementation to improve neonatal hyperbilirubinemia in clinical practice.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSafety\u003c/b\u003e\u003c/p\u003e\u003cp\u003eRegarding the safety of probiotics, our study revealed significantly lower risks of diarrhea, rashes, and fever in the probiotics group compared to the control group. These findings were consistent with previous research. Qian et al. conducted a meta-analysis of 55 RCTs with a total sample size of 8868 infants to investigate the effects of probiotics, prebiotics, or synbiotics on the growth of healthy infants [\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e]. Their results showed lower incidences of diarrhea, vomiting, hospitalization rates, and antimicrobial drug use in the intervention group compared to the control group (OR:0.88, 95% CI:0.70\u0026ndash;1.11) [\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAnother systematic review of 74 clinical studies evaluating the safety of probiotics and synbiotics in children (0\u0026ndash;18 years old) reported lower incidences of adverse events in the intervention groups across all common terminology clinical adverse event (CTCAE) categories [\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e]. The reported adverse effects included diarrhea, dysentery, and upper respiratory tract infections, with GI disorders being most frequent [\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e]. Additionally, superior safety was consistent across diverse populations, including healthy and immunodeficient children, as well as those with obesity, intestinal diseases, infections, or inflammatory disorders [\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e]. These findings highlight the good safety profile of probiotics, supporting their use as a well-tolerated adjuvant treatment for infants and children across various populations.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStrengths\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe strengths of our study include a large sample size and rigorous methodology, which enhanced the reliability and generalizability of our findings. By incorporating ten recent studies published within the past three years, our analysis reflects the most up-to-date evidence. Subgroup analyses based on GA allowed for differentiation of probiotic effects between preterm and full-term infants, providing population-specific insights.\u003c/p\u003e\u003cp\u003eGiven the higher prevalence of neonatal jaundice in Asian populations, with up to 90% of Chinese infants affected in the first week of life compared to approximately 30% of European infants [\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e], we included studies from the CNK to ensure adequate population representation and to improve external validity. Additionally, our comprehensive analyses of key clinical parameters\u0026mdash;such as TSB levels over time, PT durations, jaundice resolution times, hospital stay lengths, and intervention efficacy and safety\u0026mdash;provide valuable insights into neonatal jaundice management, supporting evidence-based neonatal care. These findings are supported by the mechanisms outlined in the introduction [\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], and relevant evidence, including the impact of probiotics on bilirubin levels in healthy infants and their influence on GI function in preterm neonates [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e, \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]\u003c/p\u003e\u003cp\u003e\u003cb\u003eLimitations\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThere are some limitations to our study. First, high heterogeneity was observed across the included studies, which was likely due to variations in probiotic strains and dosages. Although we performed a subgroup analysis based on GA to explore this heterogeneity which revealed that probiotics efficacy was consistent in both preterm and full-term neonates, the GA did not sufficiently explain the degree of heterogeneity. While various probiotic strains appear effective in neonates, the limited available data prevented us from conducting strain-specific subgroup analyses to further reduce heterogeneity.\u003c/p\u003e\u003cp\u003eAdditionally, most included trials focused on relatively short follow-up periods of 2 weeks or less. Thus, the long-term effects and potential late-onset adverse events of probiotics supplementation remain unclear. To address these limitations, future research should focus on large-scale, long-term RCTs with standardized probiotics interventions, strain-specific analyses, and extended follow-up periods to comprehensively evaluate the long-term efficacy and safety.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eIn light of the current evidence, probiotic supplementation demonstrated potential benefits for NJ by lowering bilirubin levels, shortening phototherapy and hospital stay durations, and reducing adverse effects in both preterm and full-term infants. Therefore, probiotics may be considered as an adjuvant treatment for neonates with jaundice. However, more studies are warranted to validate these findings and to provide a more-comprehensive understanding of the long-term efficacy and safety of probiotic use in this population.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBID: twice a day \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBW: birth weight \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCI: confidence interval \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCNKI: China National Knowledge Infrastructure \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCTCAE: Common Terminology Clinical Adverse Events \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGA: gestational age \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGI: gastrointestinal \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHBR: hyperbilirubinemia \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIQR: interquartile range \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIUGR: intrauterine growth restriction \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIVIG: intravenous immunoglobulin \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMD: mean difference \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNI: no information \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNJ: neonatal jaundice\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOR: odds ratio \u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement \u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePT: phototherapy \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRCT: randomized controlled trial \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRoB 2.0: Cochrane Risk-of-Bias tool \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRR: risk ratio \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSD: standard deviation \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTcB: transcutaneous bilirubin \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTSB: total serum bilirubin \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTID: three times a day \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUC: usual care \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVLBW: very low birth weight \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eQD: once a day\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e: The authors have no acknowledgments to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHui-Min Huang\u003c/strong\u003e: Conceptualization, data curation, formal analysis, investigation, methodology, software, validation, writing\u0026mdash;original draft. \u003cstrong\u003eBing-Hua Lin\u003c/strong\u003e: Conceptualization, data curation, formal analysis, investigation, methodology, software, validation, writing\u0026mdash;original draft. \u003cstrong\u003eYi-No Kang\u003c/strong\u003e: Conceptualization, formal analysis, investigation, methodology, validation, writing\u0026mdash;original draft.\u003cstrong\u003e\u0026nbsp;Kee-Hsin Chen\u003c/strong\u003e: Conceptualization, formal analysis, investigation, methodology, validation, writing\u0026mdash; review and editing.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: The authors received no support from any organization for the submitted work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e: The authors have no conflicts of interest to declare that are relevant to the content of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e: As this was a systematic review and meta-analysis, ethical approval was not required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate/publish\u003c/strong\u003e: As it was a systematic review, consent to participate and publish was not required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analyzed during the current study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAnsong-Assoku B, Shah SD, Adnan M, Ankola PA. 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Effectiveness and safety study of formula containing probiotics, prebiotics, synbiotics on fullterm infants\u0026apos; growth - a systematic review and meta-analysis of randomized controlled study. Eur J Clin Nutr. 2024. doi: 10.1038/s41430-024-01506-9.\u003c/li\u003e\n\u003cli\u003evan den Nieuwboer M, Brummer RJ, Guarner F, Morelli L, Cabana M, Claassen E. Safety of probiotics and synbiotics in children under 18 years of age. Benef Microbes. 2015;6(5):615-30. doi: 10.3920/bm2014.0157.\u003c/li\u003e\n\u003cli\u003eBrown WR, Boon WH. Ethnic group differences in plasma bilirubin levels of full-term, healthy Singapore newborns. Pediatrics. 1965;36(5):745-51. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"probiotics-and-antimicrobial-proteins","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"paap","sideBox":"Learn more about [Probiotics and Antimicrobial Proteins](http://link.springer.com/journal/12601)","snPcode":"12602","submissionUrl":"https://submission.nature.com/new-submission/12602/3","title":"Probiotics and Antimicrobial Proteins","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"probiotics, neonatal jaundice, hyperbilirubinemia, preterm infant, full-term infant","lastPublishedDoi":"10.21203/rs.3.rs-7286761/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7286761/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eNeonatal jaundice (NJ) is a common condition in newborns. Probiotics provide health benefits to the host and are widely used to treat various diseases, including neonatal gastrointestinal disorders. However, their efficacy and safety toward NJ remain uncertain. Given the relationship of the neonatal bilirubin metabolism to gastrointestinal function, we aimed to synthesize evidence on the effects of probiotics supplementation on NJ. We searched PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure up to January 2025. The eligibility criteria were randomized controlled trials (RCTs) that evaluated the efficacy of probiotics in treating NJ. Two reviewers individually completed evidence selection, data extraction, and quality evaluation. Mean differences (MDs) in total serum bilirubin (TSB) levels between two groups were pooled using random-effects model by the DerSimonian and Laird method, and heterogeneity was quantified using \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e statistics. Thirty RCTs (2776 neonates) were included. Probiotics supplementation significantly reduced TSB from day 1 (MD:-0.35, 95% confidence interval [CI]:-0.63 to -0.06) to day 10 (MD:-1.74, 95% CI:-2.54 to -0.95) mg/dL. Infants Patients who received probiotics supplementation also showed a significantly shorter duration of phototherapy (MD:-17.09, 95% CI:-24.43 to -9.76) h and hospitalization (MD:-1.17, 95% CI:-1.60 to -0.74) days. Furthermore, probiotics supplementation was associated with a lower incidence of adverse effects, including diarrhea, rashes, and fevers. These benefits were consistent in both preterm and full-term infants. In conclusion, probiotic supplementation may be an effective and safe adjuvant treatment for NJ, with potential benefits observed in both preterm and full-term infants.\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of Probiotic Supplementation for Neonatal Jaundice: a Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-22 07:00:17","doi":"10.21203/rs.3.rs-7286761/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-07T20:03:15+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-07T16:58:28+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-06T14:20:30+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-04T09:09:01+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-03T00:33:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"288976579078235361832005585625161279106","date":"2025-08-17T16:42:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"166236809627948339791484054920505778358","date":"2025-08-16T00:10:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"14527555770726238364708312338085529505","date":"2025-08-15T08:50:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"122868933318182861460390678599601135944","date":"2025-08-14T12:46:22+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-13T20:01:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-05T03:13:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-05T03:12:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"Probiotics and Antimicrobial Proteins","date":"2025-08-04T04:16:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"probiotics-and-antimicrobial-proteins","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"paap","sideBox":"Learn more about [Probiotics and Antimicrobial Proteins](http://link.springer.com/journal/12601)","snPcode":"12602","submissionUrl":"https://submission.nature.com/new-submission/12602/3","title":"Probiotics and Antimicrobial Proteins","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e144cc47-9354-4b12-9c1f-eeba22b3b406","owner":[],"postedDate":"August 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-13T16:03:59+00:00","versionOfRecord":{"articleIdentity":"rs-7286761","link":"https://doi.org/10.1007/s12602-025-10795-w","journal":{"identity":"probiotics-and-antimicrobial-proteins","isVorOnly":false,"title":"Probiotics and Antimicrobial Proteins"},"publishedOn":"2025-10-09 15:57:39","publishedOnDateReadable":"October 9th, 2025"},"versionCreatedAt":"2025-08-22 07:00:17","video":"","vorDoi":"10.1007/s12602-025-10795-w","vorDoiUrl":"https://doi.org/10.1007/s12602-025-10795-w","workflowStages":[]},"version":"v1","identity":"rs-7286761","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7286761","identity":"rs-7286761","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}