|Year : 2019 | Volume
| Issue : 3 | Page : 1059-1063
Effect of ursodeoxycholic acid on indirect hyperbilirubinemia in neonates treated with phototherapy
Fady M El-Gendy1, Wael A Bahbah1, Eman El-Sayed Al Kafory2
1 Department of Pediatric, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Pediatric, El Sadat Central Hospital, Menoufia, Egypt
|Date of Submission||06-Jan-2018|
|Date of Acceptance||17-Mar-2018|
|Date of Web Publication||17-Oct-2019|
Eman El-Sayed Al Kafory
El-Sadat City, Menoufia
Source of Support: None, Conflict of Interest: None
The aim was to evaluate the role of ursodeoxycholic acid (UDCA) on neonatal indirect hyperbilirubinemia treated with phototherapy.
Hyperbilirubinemia is a common neonatal problem. The present study aimed to investigate the role of UDCA on neonatal hyperbilirubinemia treated with phototherapy.
Participants and methods
This randomized controlled clinical trial was conducted on 100 full-term neonates with unconjugated hyperbilirubinemia, who received phototherapy in the neonatal ICU of Menoufia University Hospital, and they were randomly divided into two groups: group 1, which is the case group (n = 50), received ursofalk (250 mg capsule) in dose of 10 mg/kg/day divided every 12 h with phototherapy, and group 2, which was the control group (n = 50), received only phototherapy. Total serum bilirubin levels measured every 24 h till phototherapy were disrupted. The duration of phototherapy was measured.
The mean total bilirubin level measured at 24, 48, 72, and 96 h of treatment in group I was 13.6 ± 1.47, 10.9 ± 1.19, 9.13 ± 0.74, and 7.00 ± 0.14, respectively, and in group II was 14.5 ± 1.63 at 24 h, 12.2 ± 2.34 at 48 h, 10.5 ± 1.35 at 72 h, and 9.42 ± 0.82 at 96 h. Moreover, the mean duration of phototherapy was 65.2 ± 12.8 h in group I and was 82.5 ± 19.4 h in group II, showing high significant reduction in group I (P < 0.001).
Addition of oral UDCA to phototherapy in treatment of indirect hyperbilirubinemia will be highly effective and the duration of phototherapy and admission of affected newborns will be shorter.
Keywords: neonatal indirect hyperbilirubinemia, phototherapy, ursodeoxycholic acid
|How to cite this article:|
El-Gendy FM, Bahbah WA, Al Kafory EE. Effect of ursodeoxycholic acid on indirect hyperbilirubinemia in neonates treated with phototherapy. Menoufia Med J 2019;32:1059-63
|How to cite this URL:|
El-Gendy FM, Bahbah WA, Al Kafory EE. Effect of ursodeoxycholic acid on indirect hyperbilirubinemia in neonates treated with phototherapy. Menoufia Med J [serial online] 2019 [cited 2020 Apr 4];32:1059-63. Available from: http://www.mmj.eg.net/text.asp?2019/32/3/1059/268859
| Introduction|| |
Hyperbilirubinemia is a common problem in neonates. It is observed during the first week of life in ~60% of term infants and 80% of preterm infants .
Although most jaundiced infants are otherwise perfectly healthy, and they make us anxious because bilirubin is potentially toxic to the central nervous system .
Typically, phototherapy is used for reducing bilirubin in neonates; however, it has disadvantages, such as being expensive and preventing the relationship between the mother and the baby because of the need for incubator and closure of the infants' eyes. Potential complications, such as retinal degenerative changes, water and electrolyte disorders, bronze baby syndrome, and thermal instability, also threaten such infants. Therefore, using adjuvant therapies, which reduce the duration of phototherapy and hyperbilirubinemia, can be highly effective .
Until now, several drugs, such as activated charcoal, d-penicillamine, phenobarbital, metalloporphyrin, clofibrate, and bile salts, have been used for the treatment of indirect hyperbilirubinemia .
Several studies have shown phenobarbital to be effective in reducing indirect hyperbilirubinemia and decreasing the duration of phototherapy . Nevertheless, it has complications, including increase in drowsiness, reduction of breastfeeding, dehydration, and neurological disorders ; thus, performing studies on medications with lower complications seems necessary.
On the contrary, ursodeoxycholic acid (UDCA) is a bile acid that is widely used in the treatment of cholestatic liver disorders in children. It protects the liver against oxidative stress, prevents cell apoptosis, stimulates the bile flow, and suppresses the confounding factors in immunological mechanisms . UDCA is a safe and well-tolerated medication and has limited adverse effects in pediatrics .
One study, which was conducted on the effect of UDCA and phototherapy on unconjugated bilirubin (UCB) in rats, showed that UDCA increased the turnover of UCB by its fecal disposal .
Previous studies revealed that there were three major mechanisms of action for UDCA: first, changes in the composition of mixed phospholipid-rich micelles, reduction of bile acid cytotoxicity of bile, and may be reduction of the hydrophobic bile acid concentration in the cholangiocytes could protect cholangiocytes against cytotoxicity of hydrophobic bile acids; second, stimulation of hepatobiliary secretion, through Ca-dependent mechanisms and protein kinase Ca-dependent mechanisms, may cause insertion of transporter molecules into the hepatocyte canalicular membrane and, maybe, activation of inserted carriers; and third, hepatocytes' protection against bile acid-induced apoptosis .
Our study aimed to investigate the effect of UDCA on indirect hyperbilirubinemia of neonates receiving phototherapy with the hope to reduce the duration of phototherapy and hospitalization. Owing to lack of similar study in Egypt, we conduct this study in NICU of Menoufia University.
| Participants and Methods|| |
This randomized controlled clinical trial was performed on a sample of 100 full-term healthy newborns who received phototherapy in the neonatal ICUs of Menoufia University Hospital in the period from April 2016 to March 2017 after taking a written consent from their parents. The study protocol was approved by the local ethics committee of the Menoufia University.
Sample size calculation
The sample sized was based on review of past literature of Hassan and colleagues 'Effect of ursodeoxycholic acid in lowering neonatal indirect hyperbilirubinemia'. The mean total serum bilirubin (TSB) in group A (receive UDCA and phototherapy) was 7.6 ± 0.9 mg/dl, whereas in group B (receive phototherapy only) was 10.2 ± 1.4 after 36 h. Based on this, data sample size was calculated by Epi info program (2000), CDC, USA at power 80%, confidence level 95% and margin of error 0.05. Accordingly, the calculated sample size was 100 participants (50 in each group).
Neonates included were aged 3 days or more, weighed 2.5–4 kg with total bilirubin between 14 and 20 mg/dl. Premature neonates and neonates with severe hemolysis, sepsis, and cholestasis were excluded from the study. The neonates included in the study were divided into two groups: group I was treated with single phototherapy and oral UDCA agent, and group II was treated with single phototherapy only.
Randomization sequence was created using NCSS PASS 11 (11.0.8 portable, Kaysville, Utah, USA) statistical software with a 1:1 allocation using random block sizes of 50 patients per block.
Randomization or random allocation process was done using block randomization method in which 100 participants were randomized into two blocks.
Allocation concealment mechanism
The allocation sequence was concealed from the researcher enrolling and assessing participants in sequentially numbered, opaque, sealed, and stapled envelopes. Corresponding envelopes were opened only after the enrolled participants completed all baseline assessments and it was time to allocate the intervention.
Both patient and personnel involved in assessment of the effect of UDCA in lowering neonatal indirect hyperbilirubinemia were blinded to allocation.
All patients were subjected to the following:
- History: prenatal, natal history, and postnatal history
- Clinical examination: complete general and local examination
- Laboratory investigation: complete blood count (by kits from Prokan PE Company, Egypt), serum total, and direct bilirubin level by spectrophotometry using blood samples (kits from Biomed Company, New Cairo, Cairo, Egypt), blood film and reticulocytic count, blood grouping and Rh for infant and mother, C-reactive protein, and liver function tests
- Follow-up: patients were followed up by clinical examination, and total bilirubin level was measured every 24 h by blood sampling. The two groups were compared regarding total bilirubin levels at different time points, the time duration in which bilirubin levels reached less than 10, and the duration of phototherapy.
Data were collected, tabulated, and statistically analyzed using an IBM personal computer with statistical package for the social sciences (SPSS; SPSS Inc., Chicago, Illinois, USA) version 20 where the following statistics were applied.
For descriptive statistics, quantitative data were presented in the form of mean, SD, and range and qualitative data were presented in the form numbers and percentages.
Analytical statistics were used to find out the possible association between studied factors and the targeted disease. The used tests of significance included the following:
χ2-test was used to study association between two qualitative variables.
Student's t-test is a test of significance used for comparison between two groups having quantitative variables.
Mann–Whitney test (nonparametric test) is a test of significance used for comparison between two groups not normally distributed having quantitative variables.
P value of greater than 0.05 was considered statistically nonsignificant.
P value of less than 0.05 was considered statistically significant.
P value of less than 0.001 was considered statistically highly significant.
| Results|| |
Considering sex distributions in the group I, 20 were female and 30 were male. In the control group II, 24 were female and 26 were male, with no significant difference was found between the two groups (P = 0.420).
The mean age of the studied neonates was 4.90 ± 1.44 days (3–7 days) in the intervention group and 4.86 ± 1.60 days (3–7 days) in the control group, and no significant difference was found between the two groups in this regard (P = 0.706).
The mean total bilirubin level at the time of admission was 16.5 ± 1.51 (range: 14.5–20 mg/dl) and 16.4 ± 1.57 (range: 14–20 mg/dl) in the intervention and the control groups, respectively (P = 0.713).
The mean total bilirubin measured at 24, 48, 72, and 96 h of treatment in group I was 13.6 ± 1.47, 10.9 ± 1.19, 9.13 ± 0.74, and 7.00 ± 0.14, respectively, and in group II was 14.5 ± 1.63 at 24 h, 12.2 ± 2.34 at 48 h, 10.5 ± 1.35 at 72 h, and 9.42 ± 0.82 at 96 h. These results show that the mean total bilirubin level has significantly decreased in patients receiving UDCA and phototherapy compared with those only treated with phototherapy (P < 0.05) after 24 h of treatment. After 48 h of treatment, there was a high significant reduction in the level of total bilirubin in group I than that in group II (P < 0.001); after 72 h of treatment, there was also a high significant reduction in the level of total bilirubin in group I than that in group II (P < 0.001); and after 96 h of treatment, there was also a high significant decrease in the level of total bilirubin in group I than that in group II (P < 0.001; [Table 1]). Duration of phototherapy in group I was 65.2 ± 12.8 h and in group II was 82.5 ± 19.4 h, with significant difference (P < 0.001), as showed in [Table 2] and [Figure 1].
|Table 1: Total bilirubin (mg/dl) after 24, 48, 72, and 96 h of phototherapy among studied groups (n=100)|
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|Figure 1: Comparison between duration of phototherapy in both groups. UDCA, ursodeoxycholic acid.|
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| Discussion|| |
Neonatal hyperbilirubinemia is a common problem and in most cases a benign problem in neonates. It is defined as a TSB above 5 mg/dl or a TSB greater than 95th percentile. It affects half of the full-term infants and almost all of the preterm infants .
Although most jaundiced infants are otherwise perfectly healthy, they make us anxious because bilirubin is potentially toxic to the central nervous system .
Typically, phototherapy is used for reducing bilirubin in neonates; however, it has disadvantages, such as being expensive and preventing the relationship between the mother and the baby because of the need for incubator and closure of the infant's eyes Therefore, using adjuvant therapies, which reduce the duration of phototherapy and hyperbilirubinemia, can be highly effective ,.
UDCA is a bile acid that is widely used in the treatment of cholestatic liver disorders. It protects the liver against oxidative stress, prevents cell apoptosis, stimulates the bile flow, and suppresses the confounding factors in immunological mechanisms. UDCA is well tolerated and has limited adverse effects in pediatrics . Most common adverse effects reported in children are nausea, diarrhea, constipation, and headache .
A study on the effect of UDCA on decreasing UCB was conducted by Cuperus et al.  on rats in 2009; the findings of that study showed that UDCA increased UCB turnover through increasing its fecal disposal. Nonetheless, Méndez-Sánchez et al.  investigated the effect of UDCA in rats and mice and showed the increase of enterohepatic UCB after the oral consumption of UDCA. Many studies have confirmed the safety and tolerability of this medication for children .
Furthermore; Palmela et al.  in an in-vitro study found that UDCA protect human blood–brain barrier endothelial cells from disruption by UCB and showed that UDCA have protective properties in reducing the UCB-mediated induction of cell death in both neurons and astrocytes.
The results of the present study show the effect of UDCA on indirect hyperbilirubinemia in addition to phototherapy, and compare this effect with treatment with phototherapy only with the hope to reduce the length of phototherapy and hospitalization to avoid their complications. Although similar studies were done in other countries, we performed the study in Egypt owing to different population and slightly different methodology.
In our trial, a total of 100 full-term healthy infants, aged 3–7 days, weighed 2.5–4 kg with total bilirubin between 14 and 20 mg/dl were enrolled in the study. Regarding the demographic data of studied cases, there were no significant differences observed between the two groups regarding the sex, mean age, mean weight of the newborn, gestational age, or total bilirubin level at the beginning of the study.
The mean total bilirubin measured at 24, 48, 72, and 96 h of treatment in group I was 13.6 ± 1.47, 10.9 ± 1.19, 9.13 ± 0.74, and 7.00 ± 0.14, respectively, and in group II was 14.5 ± 1.63 at 24 h, 12.2 ± 2.34 at 48 h, 10.5 ± 1.35 at 72 h, and 9.42 ± 0.82 at 96 h. These results show that the mean total bilirubin level has significantly decreased in patients receiving UDCA and phototherapy compared with those only treated with phototherapy. Moreover, the mean duration of phototherapy showed high significant reduction in the neonates receiving phototherapy and UDCA compared with those who only underwent phototherapy (P < 0.001) as showed in [Table 2].
We did not find short-time adverse reactions of ursofalk on newborns at time of the study.
In agreement with our study, Honar et al.  reported the additive effect of UDCA in reducing indirect hyperbilirubinemia in neonates receiving phototherapy.
Honar et al.  concluded that UDCA led to ~24-h reduction in the duration of phototherapy in the neonates having indirect hyperbilirubinemia, most probably by increasing UCB turnover through its fecal disposal.
Hassan et al.  also assessed the additive effect of UDCA on reducing indirect hyperbilirubinemia in neonates receiving phototherapy and concluded that the addition of oral UDCA to phototherapy in the treatment of neonatal indirect hyperbilirubinemia will be highly effective in reduction of hyperbilirubinemia as well as the time period required for phototherapy.
| Conclusion|| |
We concluded that addition of oral UDCA to phototherapy in the treatment of neonatal indirect hyperbilirubinemia will be highly effective in reduction of hyperbilirubinemia as well as the time period required for phototherapy and therefore reducing period of admission of affected newborns.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]