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Background:
Systematic Review

Phototherapy Alone or Combined with Adjuvant Drugs for Neonatal Hyperbilirubinemia: A Systematic Review and Network Meta-Analysis

by
Qiang Fei
,
Huazi Liu
,
Xinning Wang
and
Tianming Yuan
*
Department of Neonatology, Children’s Hospital, School of Medicine, Zhejiang University, National Clinical Research Center for Child and Adolescents’ Health and Disease, Hangzhou 310000, China
*
Author to whom correspondence should be addressed.
Children 2026, 13(4), 573; https://doi.org/10.3390/children13040573
Submission received: 5 March 2026 / Revised: 4 April 2026 / Accepted: 16 April 2026 / Published: 20 April 2026
(This article belongs to the Section Pediatric Neonatology)
Browse Figures
Versions Notes

Highlights

What are the main findings?
  • Adjunctive therapies combined with phototherapy were associated with greater bilirubin reduction than phototherapy alone.
  • Fibrates and UDCA ranked higher in the analysis for improving bilirubin reduction and facilitating the resolution of jaundice, while probiotics, zinc, and agar showed modest effects, and phenobarbital showed no clear benefit.
What are the implications of the main findings?
  • This analysis provides a comparative overview of adjunctive therapies in resolving jaundice. Further well-designed RCTs are required to establish efficacy and safety before clinical use.

Abstract

Objectives: Neonatal hyperbilirubinemia is a common disease in the neonatal period. In this meta-analysis, we aim to evaluate the efficacy of adjuvant drugs combined with phototherapy in the treatment of neonatal hyperbilirubinemia. Methods: Randomized controlled trials (RCTs) published before September 2025 were searched from PubMed, Embase, Web of Science, and the Cochrane Library. A Bayesian random-effects network meta-analysis was performed to calculate mean differences and 95% confidence intervals. Interventions were ranked using the surface under the cumulative ranking curve (SUCRA) and probability of being the best treatment (PbBT). Results: Thirty-five RCTs involving 4060 neonates were included. Compared with phototherapy alone, clofibrate, ursodeoxycholic acid, fenofibrate, and calcium phosphate significantly reduced bilirubin levels and shortened admission duration. Clofibrate showed the greatest efficacy in bilirubin reduction within 48 h (SUCRA = 0.91, PbBT = 60.9%) and in shortening hospitalization (SUCRA = 0.84, PbBT = 40.83%). Probiotics, zinc, and agar exhibited relatively modest effects, while phenobarbital showed no significant benefit. Conclusions: Adjunctive therapies were associated with greater reductions in bilirubin levels compared with phototherapy alone. Future high-quality RCTs are needed to confirm the long-term efficacy and safety of these adjuvant therapies.

1. Introduction

Neonatal hyperbilirubinemia is one of the most common clinical conditions in the neonatal period, affecting approximately 50–90% of newborns within the first week of life [1,2,3]. Although jaundice is physiological in most cases, excessively elevated serum bilirubin levels can lead to severe neurological complications, including acute bilirubin encephalopathy and kernicterus [4]. Phototherapy remains the first-line treatment for neonatal hyperbilirubinemia, as it converts unconjugated bilirubin into water-soluble isomers that can be easily excreted [1,2,3]. However, phototherapy has several disadvantages, such as prolonged treatment duration, mother–infant separation, diarrhea, dehydration, temperature instability, and increased healthcare costs [5,6].
In recent years, a variety of adjuvant drugs have been studied for enhancing the effect of phototherapy, including fibric acid derivatives (such as clofibrate, fenofibrate), ursodeoxycholic acid (UDCA), probiotics (such as bifidobacterium, lactic acid bacteria), phenobarbital, agar, zinc, etc. [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41]. Although the efficacy of these adjuvant drugs has been evaluated by several randomized controlled trials, the research results show significant heterogeneity. Studies have found that probiotics can significantly reduce bilirubin levels in newborns and shorten admission duration [42], but some studies have not observed significant benefits [14]. Also in phenobarbital, Shah Farhat et al. [12] observed that there was no significant difference between the drug combined with phototherapy and phototherapy alone.
Although various adjuvant drugs can enhance phototherapy efficacy, medication use in newborns remains challenging, especially with multiple agents. The optimal adjuvant drug for use with phototherapy remains controversial, and no comprehensive systematic review has yet compared the relative efficacy of different adjuvant therapies. Therefore, this meta-analysis aims to evaluate the efficacy of adjuvant drugs combined with phototherapy in the treatment of neonatal hyperbilirubinemia. Primary outcomes include the levels of bilirubin reduction, phototherapy duration, and admission duration. This study quantitatively compares drugs to guide clinical decisions and improve the management of neonatal hyperbilirubinemia.

2. Materials and Methods

2.1. Search Strategy

The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and meta-analyses (PRISMA) 2020 standards [43], and it has been registered in advance on PROSPERO (CRD420251174122). We conducted a systematic search in Pubmed, Embase, Web of science and Cochrane library. The last search was conducted on 25 September 2025. The retrieval strategy is as follows: (“Infant OR Newborn”) AND (“Hyperbilirubinemia” OR”Bilirubinemia”) AND (“Phototherapy” OR “Blue Light Therapy”) AND (“randomized controlled trial” OR “randomized”) AND (“probiotics” OR “clofibrate” OR “zinc sulfate” OR “ursodeoxycholic acid” OR “calcium phosphate” OR “agar” OR “phenobarbital” OR “yinzhihuang” OR “fenofibrate”).

2.2. Inclusion and Exclusion Criteria

Studies were included if they met the following criteria: (1) randomized controlled trials (RCTs); (2) participants were newborns diagnosed with hyperbilirubinemia; (3) received phototherapy; (4) reported at least one of the following outcomes: phototherapy duration, admission duration, bilirubin levels at 24 or 48 h; (5) used one of the following adjuvant drugs: zinc sulfate, calcium phosphate, probiotics, agar, clofibrate, ursodeoxycholic acid, phenobarbital, Yingzhihuang oral liquid, or fenofibrate; and (6) published in English. For studies involving the same cohort, the one with the larger sample size or more comprehensive data was included. This analysis focused on drug types, not on dosage differences. Data from different dose groups of the same drug in one study were combined. The combined data were used to assess the overall efficacy.
Exclusion criteria were as follows: (1) meta-analyses, reviews, abstracts, letters, or case reports; (2) animal or basic research; (3) studies not reporting bilirubin levels, phototherapy duration, or admission duration; (4) non-randomized trials; and (5) newborns with pathological hemolysis (e.g., thalassemia, autoimmune hemolytic anemia, and hereditary spherocytosis et al.), infection, metabolic disorders, congenital anomalies, or other comorbid conditions.

2.3. Data Extraction

Extract the following information from all included studies: title, author, year of publication, country, gestational age, gender, initial bilirubin level, treatment, number of patients, 24 h and 48 h bilirubin levels (mean ± SD), duration of phototherapy and length of hospitalization (mean ± SD). After eliminating duplicate studies, the two researchers independently selected articles and extracted the data of the articles by reading the titles, abstracts and full texts. If the two parties have different opinions, the third evaluator shall discuss with them and make a decision.

2.4. Quality Evaluation

The methodological quality of the included randomized controlled trials was assessed using the Cochrane Risk of Bias tool (RoB 2.0). This tool evaluates five domains: (1) bias arising from the randomization process; (2) bias due to deviations from intended interventions; (3) bias due to missing outcome data; (4) bias in outcome measurement; and (5) bias in selection of the reported results. Each domain is rated as “low risk,” “some concerns,” or “high risk” based on the available information. The assessment was independently conducted by two reviewers, and any discrepancies were resolved through discussion with a third reviewer.

2.5. Statistical Methods

The primary outcomes were serum bilirubin levels at 24 and 48 h after treatment, and the secondary outcomes included the phototherapy duration and length of hospitalization. All outcomes in this study were continuous variables. The mean difference (MD) and standard deviation (SD) were used to assess the effect size between the intervention and phototherapy-only groups. A Bayesian random-effects network meta-analysis was performed using the Markov Chain Monte Carlo method to generate posterior distributions. Bayesian random-effects network meta-analysis was performed to calculate mean differences and 95% confidence intervals. The surface under the cumulative ranking curve (SUCRA) was calculated to rank the efficacy of interventions, with values ranging from 0 to 1; higher values indicate greater efficacy. The probability of being the best treatment (PbBT) was also estimated for each intervention. For treatment networks forming closed loops, consistency was assessed using node-splitting analysis and the Z-statistic (p < 0.05) to compare direct and indirect evidence. All analyses and visualizations were performed using R software (4.5.0) and JAGS (4.3.1)

3. Results

3.1. Selection Process

A systematic search was conducted in PubMed, Embase, Web of Science, and the Cochrane Library. A total of 267 records were identified, and 166 duplicates were removed. Based on the inclusion and exclusion criteria, 101 studies were screened, and the full texts of 53 articles were reviewed. After detailed evaluation, 18 studies were excluded—15 for not reporting relevant outcomes, one for duplicate patient data, and two for being non-English publications. Finally, 35 randomized controlled trials meeting all criteria were included in the analysis (Figure 1).

3.2. Data Characteristics

A total of 35 randomized controlled trials involving 4060 neonates with hyperbilirubinemia were included in the analysis (Table 1). All studies were published between 2007 and 2024, and the gestational age of the newborns ranged from 32.1 to 39.0 weeks. Most studies were conducted in Asian countries, with Iran contributing the largest number (n = 19), followed by India (n = 5), China (n = 3), Egypt (n = 3), and one study each from Bangladesh, Iraq, Turkey, Pakistan, and Jordan. Except for one trial comparing phototherapy combined with phenobarbital and probiotics versus phototherapy combined phenobarbital, all other studies used phototherapy alone or with placebo as the control group. The intervention groups included probiotics (n = 9), clofibrate (n = 7), ursodeoxycholic acid (n = 7), zinc (n = 6), fenofibrate (n = 5), phenobarbital (n = 2), agar (n = 1), and calcium phosphate (n = 1). Since this analysis focused on drug types rather than dosage differences, data from multiple dose groups of the same drug were combined and analyzed as the overall efficacy.
The quality of the included studies was assessed using the Cochrane RoB 2.0 tool (Figure 2). The main sources of bias were deviations from intended interventions and missing outcome data. Specifically, 17 studies were rated as high risk for deviations from intended interventions, two for missing data. The remaining studies were rated as having some concerns (n = 10) and low risk of bias (n = 8).

3.3. Bilirubin Levels at 24 H

Twenty-eight studies reported serum bilirubin levels at 24 h after treatment. The evidence network is shown in Figure 3A. The evaluated adjuvant drugs included phenobarbital, fenofibrate, clofibrate, calcium phosphate, agar, zinc, ursodeoxycholic acid, probiotics, and the combination of phenobarbital with probiotics. Compared with phototherapy alone, phototherapy combined with calcium phosphate (MD = −2.49, 95% CI: −4.94 to −0.03), clofibrate (MD = −1.88, 95% CI: −2.82 to −0.91), and UDCA (MD = −1.66, 95% CI: −2.52 to −0.80) significantly reduced bilirubin levels within 24 h (Figure 4A). The corresponding SUCRA values were 0.84, 0.78, and 0.71, respectively (Figure 5A and Table 2). Among them, calcium phosphate showed the highest probability of being the most effective treatment (PbBT = 53.89%) (Table 2). In contrast, phototherapy alone had the lowest SUCRA (0.10) and PbBT (0.00%) (Table 2), indicating the weakest effect. For the comparison between UDCA and probiotics, which formed a closed loop, node-splitting analysis showed no significant inconsistency between direct and indirect evidence (p = 0.58) (Figure 6).

3.4. Bilirubin Levels at 48 H

Twenty-one studies reported serum bilirubin levels within 48 h after treatment. The evidence network is shown in Figure 3B. The evaluated adjuvant drugs included phenobarbital, fenofibrate, clofibrate, zinc, ursodeoxycholic acid, and probiotics. Compared with phototherapy alone, phototherapy combined with clofibrate significantly reduced bilirubin levels at 48 h (MD = −3.34, 95% CI: −4.95 to −1.66) (Figure 4B), with a SUCRA value of 0.91 (Figure 5B and Table 2). Clofibrate showed the highest probability of being the most effective treatment (PbBT = 60.88%) (Table 2). Consistent with the 24 h analysis, phototherapy alone had the lowest SUCRA (0.09) and PbBT (0.00%) (Table 2), indicating the weakest efficacy in reducing bilirubin within 48 h.

3.5. Phototherapy Duration

Fifteen studies reported the duration of phototherapy. The evidence network is shown in Figure 3C. The evaluated adjuvant drugs included phenobarbital, fenofibrate, clofibrate, agar, zinc, ursodeoxycholic acid, probiotics, and the combination of phenobarbital with probiotics. Compared with phototherapy alone, no combination showed a statistically significant reduction in phototherapy duration (Figure 4C). However, clofibrate had a high SUCRA value (0.84) (Figure 5C and Table 2), and fenofibrate showed the highest probability of being the most effective in reducing phototherapy time (PbBT = 25.9%) (Table 2). Phototherapy alone had a SUCRA of 0.38 and the lowest likelihood of being the best option (PbBT = 0.03%) (Table 2).

3.6. Admission Duration

Fifteen studies reported the length of admission duration. The evidence network is shown in Figure 3D. The evaluated adjuvant drugs included phenobarbital, fenofibrate, clofibrate, calcium phosphate, zinc, ursodeoxycholic acid, and probiotics. Compared with phototherapy alone, the combination with clofibrate (MD = −24.31, 95% CI: −45.31 to −4.66), UDCA (MD = −23.50, 95% CI: −43.41 to −2.60), or fenofibrate (MD = −20.91, 95% CI: −37.74 to −4.60) significantly shortened admission duration (Figure 4D). The corresponding SUCRA values were 0.84, 0.82, and 0.79, respectively (Figure 5D and Table 2). Among them, clofibrate had the highest probability of being the most effective intervention (PbBT = 40.83%) (Table 2). In contrast, phototherapy alone had the lowest PbBT (0.00%) and was least likely to be the best option (Table 2).

3.7. Adverse Events

Analysis of 35 RCTs revealed that 33 reported only short-term adverse reactions (Table 3), primarily mild and transient GI symptoms, rashes, or laboratory abnormalities, with no long-term data available. Meta-analysis was precluded by low event rates and inconsistent reporting. Among the five studies reporting transfusions, rates were not lower with phototherapy alone versus combination therapy. No mortality was reported. Overall, adjuvant drugs combined with phototherapy may demonstrate good safety and tolerability in neonatal jaundice.

4. Discussion

To our knowledge, this is the first study to comprehensively evaluate efficacy among adjuvant drugs combined with phototherapy via network meta-analysis. This study included 35 randomized controlled trials involving 4060 neonates with hyperbilirubinemia. The results show that, compared with phototherapy alone, most adjuvant drugs can promote bilirubin reduction and shorten both phototherapy duration and admission duration. In contrast, phototherapy alone consistently showed the lowest PbBT values across outcomes, suggesting relatively lower efficacy compared with combination therapy. Clofibrate, ursodeoxycholic acid, and fenofibrate demonstrated consistent therapeutic advantages across primary outcomes, while calcium phosphate only showed potential superiority in reducing bilirubin levels at 24 h. However, given the limited long-term safety data and lack of clinically meaningful endpoints, these findings should be interpreted with caution and considered hypothesis-generating rather than practice-changing.
Calcium phosphate adsorbs unconjugated bilirubin in the intestine and inhibits enterohepatic circulation [44], resulting in a significant reduction in bilirubin levels within 24 h. However, evidence supporting this effect remains limited. Ursodeoxycholic acid (UDCA), a bile acid preparation widely used for cholestatic liver disease, promotes bile flow and alleviates hepatic bile stasis [45]. In the present study, UDCA effectively reduced bilirubin levels at 24 h and shortened hospital stay, with SUCRA values of 0.71 and 0.82, respectively, consistent with previous systematic reviews [46]. Nevertheless, UDCA is primarily indicated for conjugated hyperbilirubinemia in cholestatic conditions, whereas neonatal hyperbilirubinemia is predominantly characterized by unconjugated hyperbilirubinemia. Although the biological rationale for its application in this setting remains to be fully elucidated, mechanistic studies [47] have shown that UDCA may upregulate UDP-glucuronosyltransferase 1A1 expression in the gut of neonatal mice, thereby enhancing bilirubin metabolism and reducing plasma and brain bilirubin levels. Well-designed RCTs and further exploration of underlying mechanisms are needed before UDCA can be routinely recommended.
Clofibrate provides the greatest benefit in reducing bilirubin levels at 48 h and also ranks highly in shortening phototherapy duration and admission duration. This finding is consistent with previous clinical studies [8,22,36]. Clofibrate is a peroxisome proliferator-activated receptor α agonist [48]. It enhances hepatic glucuronosyltransferase activity, bilirubin conjugation and excretion, which helps clear unconjugated bilirubin [48], while, due to increased non-cardiovascular mortality, clofibrate has been largely withdrawn from clinical use in many countries [49]. Fenofibrate shares a similar structure and demonstrates a favorable effect in lowering bilirubin levels. Although fenofibrate’s efficacy appears slightly lower than that of clofibrate, possibly due to differences in drug dosage or the developmental maturity of hepatic enzyme systems in neonates. However, data regarding the use of fibrates in children are limited. Given the lack of robust evidence on long-term safety, their use in pediatric patients should be approached with caution [50].
Probiotics, phenobarbital, zinc, and agar have shown some efficacy in certain studies, but there is no significant difference overall. Probiotics may assist by modulating intestinal flora, inhibiting β-glucuronidase activity, and reducing enterohepatic bilirubin circulation [42]. However, their effects are highly dependent on strain, dosage, and treatment duration. Phenobarbital can induce UDP glucuronosyltransferase 1A1 expression and promote bilirubin conjugation [51]. But phenobarbital has a long half—life and potential adverse effects, such as sedation and respiratory depression, which limit its widespread use in neonates [52]. Zinc and agar may reduce intestinal bilirubin recirculation through adsorption [53,54]. However, clinical evidence is limited. Larger studies are needed to confirm their efficacy.
Previous systematic reviews have primarily focused on single- or two-drug comparisons. This study is the first to apply Bayesian network meta-analysis to integrate direct and indirect evidence regarding multiple adjuvant drugs, providing a more comprehensive ranking of efficacy. A systematic review reported that clofibrate significantly shortened phototherapy and hospital stay [55], and another study found that UDCA effectively reduced bilirubin with fewer adverse effects [46]. Notably, even in our network meta-analysis, clofibrate and UDCA consistently ranked highest. Nevertheless, safety concerns necessitate caution when selecting combination regimens, and drugs with known risks, such as clofibrate, should be avoided. This is particularly relevant in neonates, in whom physiological immaturity may alter drug metabolism and increase susceptibility to adverse effects. For UDCA, fenofibrate and calcium phosphate, further high-quality RCTs are essential to confirm their therapeutic benefits and safety in neonates.
Despite the use of strict inclusion criteria and Bayesian network meta-analysis, several limitations should be noted. First, most included studies focused on short-term biochemical outcomes, such as bilirubin reduction. Clinically meaningful endpoints, including exchange transfusion and long-term safety outcomes, were rarely reported, limiting assessment of true clinical benefit. Therefore, the findings should be considered exploratory rather than practice-changing. Second, the included studies were geographically concentrated in a limited number of countries, primarily Iran, China, Egypt, and Bangladesh. This uneven distribution may introduce regional bias and limit the generalizability of the findings to other healthcare settings. In addition, many of the evaluated adjuvant agents, such as clofibrate and certain probiotic formulations, are not widely available or routinely used in many countries, further restricting the applicability of these results in broader clinical practice. Third, although most studies reported only mild and transient adverse events, the incidence of side effects may still represent an important limiting factor for the wider clinical use of these agents. The lack of standardized reporting and absence of long-term safety data make it difficult to draw firm conclusions regarding their safety profiles. Finally, the use of pharmacological adjuvants in neonates requires particular caution due to the unique physiological characteristics of this population. Immaturity of the intestinal microbiota, hepatic metabolism, and immune system may influence both drug efficacy and safety. These factors may further limit the generalizability and clinical adoption of these therapies. Future research should confirm the efficacy and safety of these drugs through multicenter, large-sample, head-to-head randomized controlled trials.

5. Conclusions

In summary, this study systematically integrated evidence and performed network comparisons to clarify the efficacy of various adjuvant drugs combined with phototherapy for neonatal hyperbilirubinemia. Fibrates and UDCA ranked higher in the analysis, while probiotics, zinc, and agar showed modest effects, and phenobarbital showed no clear benefit. Adjunctive pharmacological therapies may be associated with reductions in bilirubin levels when combined with phototherapy. However, given the limited long-term safety data, restricted geographical representation of included studies, and potential limitations in drug availability across different regions, these findings should be interpreted cautiously. Further high-quality randomized controlled trials are required before clinical application.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/children13040573/s1.

Author Contributions

Q.F., X.W., H.L. and T.Y.: conception and design of the work; Q.F., X.W. and H.L.: article screening; Q.F., X.W. and H.L.: analysis, and interpretation of data; Q.F., X.W. and T.Y.: writing the first draft of the manuscript; Q.F., X.W., H.L. and T.Y.: revised the final document. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data necessary for interpreting the meta-analysis are available in the main text or the Supplementary Materials.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

The following abbreviations are used in this manuscript:
UDCAursodeoxycholic acid
RCTsrandomized controlled trials
MDmean difference
SDstandard deviation
SUCRAsurface under the cumulative ranking curve
PbBTprobability of being the best treatment

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Children 13 00573 g001
Figure 1. Flow diagram of selection process.
Figure 1. Flow diagram of selection process.
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Children 13 00573 g002
Figure 2. Results of risk of bias assessment. (A) Overall distribution of risk of bias judgments across domains. (B) Study-level risk of bias judgments across all domains.
Figure 2. Results of risk of bias assessment. (A) Overall distribution of risk of bias judgments across domains. (B) Study-level risk of bias judgments across all domains.
Children 13 00573 g002
Children 13 00573 g003
Figure 3. Network meta-analysis of eligible comparisons. The network interventions regarding serum bilirubin levels at 24 h (A). Serum bilirubin levels at 48 h (B), phototherapy duration (C), and admission duration (D).
Figure 3. Network meta-analysis of eligible comparisons. The network interventions regarding serum bilirubin levels at 24 h (A). Serum bilirubin levels at 48 h (B), phototherapy duration (C), and admission duration (D).
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Children 13 00573 g004
Figure 4. Heatmap of network meta-analysis results. The images show the pairwise comparison of different treatments based on serum bilirubin levels at 24 h (A), serum bilirubin levels at 48 h (B), phototherapy duration (C), and admission duration (D). Note: UDCA means ursodeoxycholic acid, PB&Pro means phenobarbital and probiotic. * notes p < 0.05.
Figure 4. Heatmap of network meta-analysis results. The images show the pairwise comparison of different treatments based on serum bilirubin levels at 24 h (A), serum bilirubin levels at 48 h (B), phototherapy duration (C), and admission duration (D). Note: UDCA means ursodeoxycholic acid, PB&Pro means phenobarbital and probiotic. * notes p < 0.05.
Children 13 00573 g004
Children 13 00573 g005
Figure 5. Surface under the cumulative ranking (SUCRA) curves. SUCRA curves regarding serum bilirubin levels at 24 h (A), serum bilirubin levels at 48 h (B), duration (C), and admission duration (D).
Figure 5. Surface under the cumulative ranking (SUCRA) curves. SUCRA curves regarding serum bilirubin levels at 24 h (A), serum bilirubin levels at 48 h (B), duration (C), and admission duration (D).
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Children 13 00573 g006
Figure 6. Node-splitting analysis between direct and indirect evidence.
Figure 6. Node-splitting analysis between direct and indirect evidence.
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Table 1. Characteristics of the studies.
Table 1. Characteristics of the studies.
IDStudyCountrySampleSex (Female/Male)Gestational Age (Week)Initial Bilirubin (mg/dL)Adjuvant DrugsGroup SampleOutcome Reported
1M. L. Tsai 2022 [9]China8320/2338.0 ± 0.2016.78 ± 0.41probiotic 43bilirubin levels at 24 h; phototherapy duration
25/1537.88 ± 0.1816.13 ± 0.41phototherapy only40
2P. Kumar 2017 [24]India9021/2438.7 ± 1.218 ± 2.1clofibrate45bilirubin levels at 24, 48 h; phototherapy duration
22/2338.2 ± 1.218.6 ± 2.0phototherapy only45
3A. Shah Farhat 2024 [12]Iran80NR36.4 ± 2.3917.52 ± 1.54phenobarbital40bilirubin levels at 24 h; phototherapy duration;
admission duration
NR36.9 ± 2.1617.84 ± 1.41phototherapy only40
4E. Babaie 2023 [37]Iran12020/20NR16.67 ± 2.08ursodeoxycholic acid40bilirubin levels at 24 h
27/13NR17.34 ± 2.15probiotic 40
17/23NR17.28 ± 2.23phototherapy only40
5Y. Zahedpasha 2007 [8]Iran6014/16NR18.21 ± 1.85clofibrate30bilirubin levels at 24, 48 h
14/16NR17.50 ± 2.34phototherapy only30
6T. H. Mandlecha 2023 [21]India10626/27NR19.11 ± 2.16zinc53bilirubin levels at 24, 48 h
30/23NR18.57 ± 2.144phototherapy only53
7S. Ahmadipour 2019 [40]Iran83NR39.20 ± 3.90NRprobiotic 40admission duration
NR39.00 ± 4.10NRphototherapy only43
8N. Honar 2016 [28]Iran8021/19NR15.9 ± 1.7ursodeoxycholic acid40bilirubin levels at 24, 48 h; phototherapy duration
22/18NR16.3 ± 1.5phototherapy only40
9P. Khoshnevisasl 2020 [26]Iran11227/2938.8 ± 1.03NRzinc56bilirubin levels at 24, 48 h; admission duration
31/2538.8 ± 0.98NRphototherapy only56
10H. Nassif 2024 [19]Pakistan7220/1633.5 ± 1.7116.68 ± 1.69probiotic 36admission duration
14/2233.62 ± 1.9516.92 ± 1.63phototherapy only36
11M.-L. Tsai 2025 [10]China27746/4337.93  ±  0.1215.84  ±  0.25Probiotic (AP-32) 89admission duration
41/5537.99  ±  0.1216.08  ±  0.23Probiotic (CP-9)96
51/4138.08  ±  0.1215.67 ± 0.23phototherapy only92
12O. Serce 2014 [14]Turkey11926/1237.7 ± 1.713.6 ± 2.9probiotic 58bilirubin levels at 24, 48 h; admission duration
29/3237.9 ± 2.0213.6 ± 2.4phototherapy only61
13S. M. Abdel-Aziz Ali 2022 [41]Egypt6013/1738.10 ± 2.1116.70 ± 1.58agar 30bilirubin levels at 24 h; phototherapy duration
14/1637.80 ± 1.6317.20 ± 1.27phototherapy only30
14N. Rana 2011 [16]India286NRNRNRzinc145phototherapy duration
NRNRNRphototherapy only141
15G. Faal 2020 [33]Iran60NR33.2 ± 1.2712.2 ± 71.67zinc30bilirubin levels at 24 h; phototherapy duration
NR32.1 ± 1.7710.2 ± 35.24phototherapy only30
16M. M. Gharehbaghi 2020 [31]Iran120NR37.75 ± 4.9319.88 ± 2.33ursodeoxycholic acid (5 mg/kg/dose, q12 h)40bilirubin levels at 24, 48 h
NR38.1 ± 1.0519.33 ± 2.51ursodeoxycholic acid (7.5 mg/kg/dose, q12 h)40
NR38.55 ± 1.0119.76 ± 2.64phototherapy only40
17A. Ghorui 2024 [30]India8021/19NR15 ± 3.19calcium phosphate40bilirubin levels at 24 h;
admission duration
16/24NR16.1 ± 2.64phototherapy only40
18M. Zarkesh 2023 [7]Iran92NRNR17.03 ± 1.81ursodeoxycholic acid49bilirubin levels at 24, 48 h; admission duration
NRNR17.49 ± 1.92phototherapy only43
19M. H. Awad 2021 [38]Egypt12028/32NR19.4 ± 3.8Fenofibrate (10 mg/kg/day for 1 day)60bilirubin levels at 24, 48 h; phototherapy duration
28/32NR19.4 ± 4.4Fenofibrate (10 mg/kg/day for 2 days)60
36/24NR18.8 ± 4.1phototherapy only60
20S. K. Shabo 2023 [13]Iraq10022/2838.58 ± 0.75819.28 ± 0.427fenofibrate50bilirubin levels at 24, 48 h; admission duration
29/2138.52 ± 0.99519.21 ± 0.518phototherapy only50
21S. H. Saadat 2023 [15]Iran8622/2138.19 ± 0.9817.31 ± 1.56fenofibrate43bilirubin levels at 24, 48 h; phototherapy duration;
admission duration
16/2738.21 ± 1.2517.61 ± 1.67phototherapy only43
22M. A. Kaabneh 2015 [27]Jordan20052/5139 ± 114.7 ± 1.6phenobarbital103bilirubin levels at 24, 48 h;
50/4739 ± 114.6 ± 1.5phototherapy only97
23R. Fallah 2012 [32]Iran60NR38.23 ± 0.97119.54 ± 3.07clofibrate30bilirubin levels at 24, 48 h; phototherapy duration;
admission duration
NR37.87 ± 1.0719.5 ± 2.21phototherapy only30
24F. Eghbalian 2023 [36]Iran100NRNR19.49 ± 1.17clofibrate50admission duration
NRNR18.13 ± 2.5phototherapy only50
25R. Sharafi 2010 [11]Iran60NRNR17.24 ± 1.48clofibrate30bilirubin levels at 24, 48 h; phototherapy duration
NRNR17.42 ± 1.44phototherapy only30
26M. Habibi 2012 [29]Iran5211/15NR20.788 ± 2.3852clofibrate26bilirubin levels at 24 h;
11/15NR20.523 ± 2.4458phototherapy only26
27M. Nikouei 2024 [18]Iran29081/7938.25 ± 1.05316.65 ± 2.90ursodeoxycholic acid160bilirubin levels at 24, 48 h; admission duration
64/6638.27 ± 1.09216.36 ± 2.96phototherapy only130
28F. Eghbalian 2024 [35]Iran15043/3237.8 ± 0.8NRprobiotic 75bilirubin levels at 24, 48 h; phototherapy duration;
admission duration
39/3637.6 ± 0.7NRphototherapy only75
29A. Mahyar 2019 [22]Iran409/1138.5 ± 218 ± 2.4clofibrate20bilirubin levels at 24, 48 h;
12/817.9 ± 3.139 ± 1phototherapy only20
30R. Akefi 2022 [39]Iran22048/62NR16.8 ± 2.4ursodeoxycholic acid110bilirubin levels at 24 h; phototherapy duration
58/52NR15.7 ± 2.5phototherapy only110
31W. Liu 2015 [23]China68NRNR20.29 ± 3.04phenobarbital and probiotic 34bilirubin levels at 24 h; phototherapy duration
NRNR20.53 ± 2.81phenobarbital34
32S. A. H. Nouri 2022 [17]Iran19451/46NR16.93 ± 1.43probiotic 97bilirubin levels at 24, 48 h;
57/40NR16.73 ± 1.53phototherapy only97
33A. Kumar 2014 [25]India8028/1237.6 ± 1.513.9 ± 2.5zinc40bilirubin levels at 48 h; phototherapy duration
25/1537.7 ± 1.413.4 ± 1.9phototherapy only40
34M. S. Elfarargy 2021 [34]Egypt20054/4635.7 ± 0.617.7 ± 1.1zinc100bilirubin levels at 48 h;
58/4235.8 ± 0.517.6 ± 1.2phototherapy only100
35M. Mosharref 2021 [20]Bangladesh6010/2038.1 ± 1.817.19 ± 1.98fenofibrate30bilirubin levels at 24, 48 h; admission duration
13/1737.8 ± 1.117.02 ± 2.26phototherapy only30
Note: NR means not reported.
Table 2. Ranking of adjuvant drugs.
Table 2. Ranking of adjuvant drugs.
Adjuvant DrugsBilirubin Levels at 24 hBilirubin Levels at 48 hPhototherapy DurationAdmission Duration
SUCRAPbBTSUCRAPbBTSUCRAPbBTSUCRAPbBT
phototherapy only 0.100.00%0.090.00%0.380.03%0.280.00%
clofibrate0.7813.89%0.9160.88%0.270.85%0.8440.83%
ursodeoxycholic acid0.716.43%0.563.77%0.6213.36%0.8232.72%
calcium phosphate0.8453.89%NANANANA0.362.61%
probiotics0.320.06%0.371.46%0.538.9%0.500.59%
fenofibrate0.511.43%0.563.83%0.7325.9%0.7920.8%
agar0.5812.86%NANA0.5919.68%NANA
phenobarbital0.280.21%0.7129.59%0.393.55%0.070.23%
zinc sulfate0.514.29%0.310.47%0.433.31%0.332.23%
Phenobarbital& probiotics0.386.94%NANA0.5524.42%NANA
Note: SUCRA means surface under the cumulative ranking curve. NA means not applicable. PbBT means probability of being the best treatment.
Table 3. Safety data of included studies.
Table 3. Safety data of included studies.
IDStudyAdjuvant DrugsGroup SampleAdverse EventsBlood TransfusionMortality
1M. L. Tsai 2022 [9]probiotic 43NoneNoneNone
phototherapy only40NoneNoneNone
2P. Kumar 2017 [24]clofibrate45NoneNANone
phototherapy only45None4None
3A. Shah Farhat 2024 [12]phenobarbital40NANANA
phototherapy only40NANANA
4E. Babaie 2023 [37]ursodeoxycholic acid40NoneNANone
probiotic 405 mild abdominal painNANone
phototherapy only40NoneNANone
5Y. Zahedpasha 2007 [8]clofibrate30NoneNoneNone
phototherapy only30NoneNoneNone
6T. H. Mandlecha 2023 [21]zinc53NoneNANone
phototherapy only53NoneNANone
7S. Ahmadipour 2019 [40]probiotic 40NoneNANone
phototherapy only43NoneNANone
8N. Honar 2016 [28]ursodeoxycholic acid40NoneNANone
phototherapy only40NoneNANone
9P. Khoshnevisasl 2020 [26]zinc56NoneNANone
phototherapy only56NoneNANone
10H. Nassif 2024 [19]probiotic 361 case of rash, 1 case of diarrhea, and 1 case of unstable body temperatureNANone
phototherapy only363 case of rash, 1 case of diarrhea, and 3case of unstable body temperatureNANone
11M.-L. Tsai 2025 [10]Probiotic (AP-32) 89NoneNANone
Probiotic (CP-9)96NoneNANone
phototherapy only92NoneNANone
12O. Serce 2014 [14]probiotic 58NoneNANone
phototherapy only61NoneNANone
13S. M. Abdel-Aziz Ali 2022 [41]agar 30NoneNANone
phototherapy only30NoneNANone
14N. Rana 2011 [16]zinc1453 cases of diarrhea, 4 cases of vomiting, and 1 case of rashNANone
phototherapy only1411 case of diarrhea, 6 cases of vomitingNANone
15G. Faal 2020 [33]zinc30NoneNANone
phototherapy only30NoneNANone
16M. M. Gharehbaghi 2020 [31]ursodeoxycholic acid (5 mg/kg/dose, q12h)40NoneNANone
ursodeoxycholic acid (7.5 mg/kg/dose, q12 h)40NoneNANone
phototherapy only40NoneNANone
17A. Ghorui 2024 [30]calcium phosphate40NoneNANone
phototherapy only40NoneNANone
18M. Zarkesh 2023 [7]ursodeoxycholic acid49NoneNANone
phototherapy only43NoneNANone
19M. H. Awad 2021 [38]Fenofibrate (10 mg/kg/day for 1 day)601 case of anemia and 1 case of leukopenia; 8 cases of abdominal distension and diarrhea; 4 cases of elevated liver enzymes1None
Fenofibrate (10 mg/kg/day for 2 days)601 case of anemia, 6 cases of abdominal distension and diarrhea, and 3 cases of elevated liver enzymes1None
phototherapy only603 cases of anemia; 1 case of leukopenia; 8 cases of abdominal distension and diarrhea; 4 cases of elevated liver enzymes3None
20S. K. Shabo 2023 [13]fenofibrate50NoneNANone
phototherapy only50NoneNANone
21S. H. Saadat 2023 [15]fenofibrate43NoneNANone
phototherapy only43NoneNANone
22M. A. Kaabneh 2015 [27]phenobarbital103NA7NA
phototherapy only97NA15NA
23R. Fallah 2012 [32]clofibrate301 case of gastrointestinal reactionNANone
phototherapy only30NoneNANone
24F. Eghbalian 2023 [36]clofibrate50NoneNANone
phototherapy only50NoneNANone
25R. Sharafi 2010 [11]clofibrate30NoneNANone
phototherapy only30NoneNANone
26M. Habibi 2012 [29]clofibrate26NoneNANone
phototherapy only26NoneNANone
27M. Nikouei 2024 [18]ursodeoxycholic acid160NoneNANone
phototherapy only130NoneNANone
28F. Eghbalian 2024 [35]probiotic 75NoneNANone
phototherapy only75NoneNANone
29A. Mahyar 2019 [22]clofibrate20NoneNANone
phototherapy only201 case of rashNANone
30R. Akefi 2022 [39]ursodeoxycholic acid110NoneNANone
phototherapy only110NoneNANone
31W. Liu 2015 [23]phenobarbital and probiotic 34NoneNANone
phenobarbital34NoneNANone
32S. A. H. Nouri 2022 [17]probiotic 97NoneNANone
phototherapy only97NoneNANone
33A. Kumar 2014 [25]zinc403 cases of vomiting; 3 cases of rash; 4 cases of diarrheaNoneNone
phototherapy only402 cases of vomiting; 3 cases of rash; 3 cases of diarrhea NoneNone
34M. S. Elfarargy 2021 [34]zinc100NoneNANone
phototherapy only100NoneNANone
35M. Mosharref 2021 [20]fenofibrate30NoneNANone
M. L. Tsai 2022 [9]phototherapy only30NoneNANone
NA means not applicable.
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Fei, Q.; Liu, H.; Wang, X.; Yuan, T. Phototherapy Alone or Combined with Adjuvant Drugs for Neonatal Hyperbilirubinemia: A Systematic Review and Network Meta-Analysis. Children 2026, 13, 573. https://doi.org/10.3390/children13040573

AMA Style

Fei Q, Liu H, Wang X, Yuan T. Phototherapy Alone or Combined with Adjuvant Drugs for Neonatal Hyperbilirubinemia: A Systematic Review and Network Meta-Analysis. Children. 2026; 13(4):573. https://doi.org/10.3390/children13040573

Chicago/Turabian Style

Fei, Qiang, Huazi Liu, Xinning Wang, and Tianming Yuan. 2026. "Phototherapy Alone or Combined with Adjuvant Drugs for Neonatal Hyperbilirubinemia: A Systematic Review and Network Meta-Analysis" Children 13, no. 4: 573. https://doi.org/10.3390/children13040573

APA Style

Fei, Q., Liu, H., Wang, X., & Yuan, T. (2026). Phototherapy Alone or Combined with Adjuvant Drugs for Neonatal Hyperbilirubinemia: A Systematic Review and Network Meta-Analysis. Children, 13(4), 573. https://doi.org/10.3390/children13040573

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