Ursodeoxycholic acid and phototherapy versus phototherapy and placebo on neonatal indirect hyperbilirubinemia

Introduction


Introduction
Neonatal hyperbilirubinemia is common during infancy (1).If the portion of unconjugated bilirubin is very high, untreated unconjugated hyperbilirubinemia can cause bilirubin-induced neurological dysfunction (2).This neurological dysfunction is permanent or even may lead to death (3).Phototherapy is the mainstay of therapy (4).Several drugs in addition to phototherapy are recommended in the literature.
Recently, ursodeoxycholic acid (UDCA) is recommended in the literature for the treatment of indirect hyperbilirubinemia (5,6).UDCA had a role in the treatment of neonatal cholestasis (7).UDCA induces biliary flow and reduces intestinal absorption of biliary acid (8).Moreover, UDCA inhibits the apoptotic effect of unconjugated bilirubin on hepatocytes and neuronal cells (9).Studies about the effect of UDCA on indirect hyperbilirubinemia are limited following the search of Medline and Scopus.

Objectives
This study aimed to compare conventional phototherapy and conventional phototherapy and UDCA in the treatment of unconjugated hyperbilirubinemia in healthy appearance term neonates.

Study design
This randomized double-blind study was carried out in the department of neonatology at the children's medical center of Ahvaz Jundishapur of the University of Medical Sciences.Inclusion criteria were weight 2500-4200 g and exclusive breastfeeding.Gestational age between 38-41 weeks and age between 3-7 days also were included.Total bilirubin between 14-20 mg/dL according to the Bhutani curve and direct bilirubin was less than 2 mg/dL was included.
Exclusion criteria were ABO incompatibility, Rh incompatibility, glucose-6-phosphate dehydrogenase (G6PD) deficiency, sepsis, hypothyroidism, liver problem, prematurity and newborn of diabetic mother.A dose of 5 mg/kg per dose of UDCA was prescribed for neonates every 12 hours.Placebo is also prescribed for other neonates.Unconjugated bilirubin was measured after 4 hours and every 12 hours till total bilirubin = 12 mg/dL.Neonates in case group received treatment with UDCA and phototherapy.Neonates who received phototherapy and placebo were allocated in the control group.

Statistical analysis
Data were analyzed using SPSS version 16.0.Kolmogorov-Smirnov test was conducted to evaluate data distribution.Intention-to-treat analysis was employed.Mann-Whitney U test was conducted for data analysis.The flow chart of the study was seen in Figure 1.

Results
In the current study 30 case and 30 control were included.The age of the case and control according to hours were shown in Table 1.Total bilirubin among case and control before starting treatment was shown in Table 1.As seen in Table 2, the duration of phototherapy was shorter in the case group than in the control group; however, there was no significant between the two groups in terms of duration of phototherapy (P = 0.198).A comparison between total bilirubin levels between the control and case group in terms of 4, 12, and 24 hours following treatment was shown in Table 3.
Discharged neonates were 96% among cases and 87% among the control group in the 1 st 24 hours after admission.Among the case group, 100% were discharged at the 2 nd 24 hours of admission, and 96% were among the control (Table 4).

Key point
Recently ursodeoxycholic acid was recommended for the treatment of neonatal indirect hyperbilirubinemia according to the some published papers.This randomized clinical trial was conducted to compare ursodeoxycholic acid+ phototherapy versus placebo+phototherapy on lowering bilirubin among healthy term neonates.This study showed, no statistically significant difference between two methods regarding indirect bilirubin level and discharge of neonates.group was shorter than in the control group, however this difference was not statistically significant.In the study by Ughasoro et al, UDCA accentuates the effect of phototherapy in reducing total serum bilirubin and reducing the duration of treatment (10).The sample size of the study by Ughasoro et al (10) was less than the current study.
In the study by El-Gendy et al, duration of phototherapy was significantly shorter among neonates who received UDCA treatment (6).
In another study, UDCA has a beneficial effect in reducing bilirubin levels and duration of hospital admission in neonatal indirect hyperbilirubinemia.In a recent study on mice, UDCA reduces both plasma and brain bilirubin (5).It should remember that no adverse effect of this drug was seen in our study.The result of these studies differs from our studies.It may be due to different sample sizes or genetic backgrounds.In a previous metaanalysis by Kuitunen et al (11), they found low-quality evidence that UDCA as an adjuvant to phototherapy decreases the indirect bilirubin.Furthermore, the dose of UDCA was different between studies (11).Most of the studies published were conducted in Middle East region (6,11), therefore larger studies from different geographical region and more sample size are recommended.

Conclusion
In this study, we did not find statistical significance to recommend UDCA as an adjunct therapy for neonates with physiologic hyperbilirubinemia; however, another large multi-centric study is recommended.

Limitations of the study
Limitations of this study include a single-center study and a lack of longer follow-up to check rebound hyperbilirubinemia in two groups.publication) have been completely observed by the authors.

Funding/Support
Funding was supported by Ahvaz Jundishapur University of Medical Sciences (Grant#U-97221).

Figure 1 .
Figure 1.CONSORT flow diagram of the study.