Newborn

Register      Login

VOLUME 1 , ISSUE 4 ( October-December, 2022 ) > List of Articles

REVIEW ARTICLE

Effect of Ursodeoxycholic Acid in Unconjugated Hyperbilirubinemia in the Term Neonates Treated with Phototherapy: A Systematic Review

Keywords : Hyperbilirubinemia, Neonates, Phototherapy, Physiological jaundice, Systematic review, Ursodeoxycholic acid

Citation Information : Effect of Ursodeoxycholic Acid in Unconjugated Hyperbilirubinemia in the Term Neonates Treated with Phototherapy: A Systematic Review. 2022; 1 (4):356-367.

DOI: 10.5005/jp-journals-11002-0046

License: CC BY-NC 4.0

Published Online: 23-12-2022

Copyright Statement:  Copyright © 2022; The Author(s).


Abstract

Background: Neonatal hyperbilirubinemia is a common clinical condition worldwide. Phototherapy (PT) is the standard intervention for hyperbilirubinemia; however, it may have side effects. It has been suggested that the implementation of adjuvant therapy including ursodeoxycholic acid (UDCA), for example, may decrease the duration of PT. Objectives: To determine the efficacy and safety of UDCA in addition to PT in term neonates with unconjugated hyperbilirubinemia (UH) vs PT alone. Methods: A systemic review was undertaken using the following databases: PubMed, Medline, Cochrane database, Scopus, Google Scholar, and ClinicalTrials.gov. Randomized controlled trials (RCTs) assessing the efficacy and safety of UDCA combined with PT on the total serum bilirubin (TSB) and duration of PT were included. The data quality assessment was carried out. Results: Low–moderate quality evidence from seven RCTs reported significantly lower TSB levels in the UDCA group compared to the control group after 12, 24, 48, and 72 hours of treatment with a mean difference (MD) of –2.23 mg/dL (95% CI: from −2.49 to −1.96); −1.59 mg/dL (95% CI: from −1.83 to −1.35); −1.03 mg/dL (95% CI: from −1.27 to −0.79); and −1.32 mg/dL (95% CI: from −1.63 to −1.01), respectively, with heterogeneity of studies I2 = 92% (p < 0.00001). In addition, three studies observed that UDCA significantly decreased the duration of PT with MD −19.14 hours (95% CI: from −20.70 to −17.59) with heterogeneity I2 = 91% (p < 0.00001). None of the studies reported any significant adverse effects of UDCA. Conclusion: Ursodeoxycholic acid combined with PT in the treatment of UH significantly reduces the TSB and duration of PT without significant risk of adverse events. However, limited and low–moderate quality evidence exists to support the routine use of UDCA in neonates. We discuss the limitations of the review results for clinical practice.


HTML PDF Share
  1. Hansen TW. The epidemiology of neonatal jaundice. Pediatr Med 2021;4:18. DOI: 10.21037/pm-21-4.
  2. Aiswarya AT, Sajeeth CI. The incidence, risk factors and management of neonatal jaundice in a government hospital, Palakkad district, Kerala. Int. J. Health Sci Res 2016;6(6):123–129.
  3. Althomali R, Aloqayli R, Alyafi B, et al. Neonatal jaundice causes and management. Int J Community Med Public Health 2018;11:4992–4996. DOI: 10.18203/2394-6040.ijcmph20184604.
  4. Maisel MJ. Neonatal jaundice. Pediatr Rev 2006;27(12):443–453. DOI: 10.1542/pir.27-12-443.
  5. Hameed NN, Na’ Ma AM, Vilms R, et al. Severe neonatal hyperbilirubinemia and adverse short-term consequences in Baghdad, Iraq. Neonatol 2011;100(1):57–63. DOI: 10.1159/000321990.
  6. Bhutani VK, Zipursky A, Blencowe H, et al. Neonatal hyperbilirubinemia and Rhesus disease of the newborn: Incidence and impairment estimate for 2010 at regional and global levels. Pediatric Res J 2013;74(1):86–100. DOI: 10.1038/pr.2013.208.
  7. Olusanya BO, Kaplan M, Hansen TW. Neonatal hyperbilirubinemia: A global perspective. Lancet Child Adolesc Health 2018; 2(8):610–620. DOI: 10.1016/S2352-4642(18)30139-1.
  8. Arnolda G, Thein AA, Trevisanuto D, et al. Evaluation of a simple intervention to reduce exchange transfusion rates among inborn and outborn neonates in Myanmar, comparing pre- and post-intervention rates. BioMed Central Pediatr 2015;15:216. DOI: 10.1186/s12887-015-0530-5.
  9. Knapp AA, Metterville DR, Co PT, et al. Hyperbilirubinemia evidence review revised final draft, 2012; 2012.
  10. Maisels MJ and McDonagh AD. Phototherapy for neonatal jaundice. New Eng J Med 2008;358(9):920–928. DOI: 10.1056/NEJMct0708376.
  11. Muchowski KE. Evaluation and treatment of neonatal hyperbilirubinemia. Am Fam Physician 2014;89(11):873–878. PMID: 25077393.
  12. Fernandes JI, Reis AT, da Silva CV, et al. Motherly challenges when facing neonatal phototherapy treatment: A descriptive study. Online Brazn J Nurs 2016;15(2):188–195. DOI: 10.17665/1676-4285.20165348.
  13. Xiong T, Tang J, Mu DZ. Side effects of phototherapy for neonatal hyperbilirubinemia. Chinese J Contemp Pediatr 2012;14(5):396–400. PMID: 22613117.
  14. Wickremasinghe AC, Kuzniewicz MW, Grimes BA, et al. Neonatal phototherapy and infantile cancer. Pediatrics 2016;137(6):e20151353. DOI: 10.1542/peds.2015-1353.
  15. Auger N, Laverdiere C, Ayoub A, et al. Neonatal phototherapy and future risk of childhood cancer. Int J Cancer 2019;145(8):2061–2069. DOI: 10.1002/ijc.32158.
  16. Maisels MJ. Managing the jaundiced newborn: A persistent challenge. Canad Med Assoc J 2015;187(5):335–343. DOI: 10.1503/cmaj.122117.
  17. Behairy BE, Saber MA, Hassan RE, et al. Role of ursodeoxycholic acid in lowering indirect hyperbilirubinemia in neonates under phototherapy. Acta Sci Gastroin Disord 2020;3(10):7–11.
  18. EL-Gendy FM, Bahbah WA, Kafory EE. Effect of ursodeoxycholic acid on indirect hyperbilirubinemia in neonates treated with phototherapy. Menoufia Med J 2019;32(3):1059–1063. DOI: 10.4103/mmj.mmj_885_17.
  19. Jafari S, Khan KA, Bhatnagar S, et al. Role of ursodeoxycholic acid in neonates with indirect hyperbilirubinemia: An open labelled randomized control trial. Int J Contemp Pediatr 2018; 5(2):432–435. DOI: 10.18203/2349-3291.ijcp20180530.
  20. Best C, Gourley GR. Management of neonatal cholestasis. Therapy 2009;6:75–81. DOI: 10.2217/14750708.6.1.75.
  21. Beuers UT, Trauner M, Jansen P, et al. New paradigms in the treatment of hepatic cholestasis: From UDCA to FXR, PXR and beyond. J Hepatol 2015;62:S25–S37. DOI: 10.1016/j.jhep.2015.02.023.
  22. Hassan AM, Abdulrahman A, Husain RH. Effect of ursodeoxycholic acid in lowering neonatal indirect hyperbilirubinemia: A randomized controlled trial. Merit Res J 2015;3(9):402–405. DOI: 10.15574/SP.2016. 74.56.
  23. Honar N, Saadi EG, Saki F, et al. Effect of ursodeoxycholic acid on indirect hyperbilirubinemia in neonates treated with phototherapy: A randomized trial. J Pediatr Gastroenterol 2016;62(1):97–100. DOI: 10.1097/MPG.0000000000000874.
  24. Shahramian I, Tabrizian K, Ostadrahimi P, et al. Therapeutic effects of ursodeoxycholic acid in neonatal indirect hyperbilirubinemia: A randomized double-blinded clinical trial. Arch Anesthesiol Crit Care 2019;5(3):99–103. DOI: 10.18502/aacc.v5i3.1211.
  25. Ughasoro MD, Adimorah GN, Chukwudi NK, et al. Reductive effect of ursodeoxycholic acid on bilirubin levels in neonates on phototherapy. Clin Exp Gastroenterol 2019;12: 349–354. DOI: 10.2147/CEG.S207523.
  26. Akefi R, Hashemi SM, Alinejad S, et al. The effect of ursodeoxycholic acid on indirect hyperbilirubinemia in neonates treated with phototherapy: A randomized clinical trial. J Matern Fetal Neonatal Med 2022;35(21):4075–4080. DOI: 10.1080/14767058.2020.1846705.
  27. Mirzarahimi M, Barak M, Moghaddan SS, et al. Effect of ursodeoxycholic acid (USDA) on indirect hyperbilirubinemia in neonates treated with phototherapy. Progressing Aspects in Pediatrics and Neonatology 2019;2(3):138–141. DOI: 10.32474/PAPN.2019.02.000136.
  28. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: Updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c869. DOI: 10.1136/bmj.c869.
  29. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0. The Cochrane Collaboration, 2011. Available at: www.cochrane-handbook.org. DOI: 10.1136/bmj.c86930.
  30. Andrews JC, Schünemann HJ, Oxman AD, et al. GRADE guidelines: 15. Going from evidence to recommendation-determinants of a recommendation's direction and strength. J Clin Epidemiol 2013;66(7):726–735. DOI: 10.1016/j.jclinepi.2013.02.003.
  31. Gharehbaghi MM, Mokhallegh AS, et al. Evaluating the effects of different doses of ursodeoxycholic acid on neonatal jaundice. Turk J Pediatr 2020; 62: 424-430. DOI: 10.24953/turkjped.2020.03.009.
  32. Ishani D, Karnawat BS, Bohra M, et al. Therapeutic role of ursodeoxycholic acid in management of neonates with indirect hyperbilirubinemia. Int J Sci Res 2020;9(9):74–75. DOI: 10.36106/IJSR.
  33. Bhardwaj S, Gupta S, Jagrwal S, et al. Effect of oral ursodeoxycholic acid on indirect hyperbilirubinemia in neonates treated with phototherapy at tertiary care centre, Jaipur. Eur J Mol Clin Med 2020;7(11):5738–5747.
  34. Hariton E, Locascio JJ. Randomised controlled trials – the gold standard for effectiveness research: Study design: randomised controlled trials. Int J Obstetr Gynaecol 2018;125(13):1716. DOI: 10.1111/1471-0528.15199.
  35. Kuitunen I, Kiviranta P, Sankilampi U, et al. Ursodeoxycholic acid as adjuvant treatment to phototherapy for neonatal hyperbilirubinemia: A systematic review and meta-analysis. World J Pediatr 2022:18(9): 589–597. DOI: 10.1007/s12519-022-00563-z.
  36. Lazarus G, Francie J, Roeslani RD, et al. Role of ursodeoxycholic acid in neonatal indirect hyperbilirubinemia: A systematic review and meta-analysis of randomized controlled trials. Italian J Pediatr 2022;48:179. DOI: 10.1186/s13052-022-01372-w.
  37. Cuperus FJC, Iemhoff AA, Verkade HJ. Combined treatment strategies for unconjugated hyperbilirubinemia in gunn rats. Pediatr Res 2011;70(6):560–565. DOI: 10.1203/PDR.0b013e31823240bc.
  38. Colecchia A, Mazzella G, Sandri L, et al. Ursodeoxycholic acid improves gastrointestinal motility defects in gallstone patients. World J Gastroenterol 2006;12(33):5336–5343. DOI: 10.3748/wjg.v12.i33.5336.
  39. Bondarenko LB, Gorchakove NO, Galkin OY. Promising new fixed combination for the treatment of diseases of the hepatobiliar system: Substantiation of pharmacotherapeutic properties and pharmaceutical quality profile. Regul Mech Biosyst 2018;9(1):23–40. DOI: https://doi.org/10.15421/021804.
  40. Alizadeh P, Sajjadian N, Asadi M, et al. Declining pattern of bilirubin in the first and second six hours of intensive versus double phototherapy in neonatal jaundice. Pediatr Dimensions 2016;1(5): 120–122. DOI: 10.15761/PD.1000128.
  41. Nizam MA, Alvi AS, Hamdani M, et al. Efficacy of double versus single phototherapy in treatment of neonatal jaundice: A meta-analysis. Eur J Pediatr 2020;179(6):865–874. DOI: 10.1007/s00431-020-03583-x.
  42. Memon N, Weinberger BI, Hegyi T, et al. Inherited disorders of bilirubin clearance. Pediatr Res 2016;79(3):378–386. DOI: 10.1038/pr.2015.247.
  43. Chu L, Xue X, Qiao J. Efficacy of intermittent phototherapy versus continuous phototherapy for treatment of neonatal hyperbilirubinaemia: A systematic review and meta-analysis. J Adv Nurs 2021;77(1):12–22. DOI: 10.1111/jan.14535.
  44. EL Sakka, Iman SS, El Barbary, et al. Does type of infant feeding effect phototherapy for neonatal hyperbilirubinemia? Childhood Obesity and Nutrition 2012;4(6):334–339. 10.1177/1941406412455689.
  45. Itoh S, Okada H, Kruboi T, et al. Phototherapy for neonatal hyperbilirubinemia. Pediatr int 2017;59(9):959–966. DOI: 10.1111/ped.13332.
  46. Borden AR, Satrom KM, Wratkowski P, et al. Variation in the phototherapy practices and irradiance of devices in a major metropolitan area. Neonatology 2018;113(3):269–274. DOI: 10.1159/000485369.
  47. Stephen AI, Ubwa ST, Igbum OG, et al. Analytical methods comparison for the determination of bilirubin in blood samples of neonates. Adv Anal Chem 2017;7(1):1–6. DOI: 10.5923/j.aac.20170701.01.
  48. Padmanabhan P, Hotkar KN, Nagarkar VD, et al. Estimation of various fractions of bilirubin in cases of neonatal jaundice. Int J Clin Biochem Res 2016;3(2):194–200. DOI: 10.5958/2394-6377.2016.00039.3.
  49. Apperloo JJ, van der Graaf F, Scharnhorst V, et al. Do we measure bilirubin correctly anno 2005? Clin Chem Lab Med 2005;43(5): 531–535. DOI: 10.1515/CCLM.2005.092.
  50. Kotb MA. Review of historical cohort: Ursodeoxycholic acid in extrahepatic biliary atresia. J Pediatr Surg 2008;43:1321–1327. DOI: 10.1016/j.jpedsurg.2007.11.043.
  51. Marcia L, Buck ML. Use of ursodiol in infants and children. Pediatr Pharmacol 2009;15(2).
  52. Arslanoglu S, Moro GE, Tauschel HD, et al. Ursodeoxycholic acid treatment in preterm infants: a pilot study for the prevention of cholestasis associated with total parenteral nutrition. J Pediatr Gastroenterol Nutr 2008;46(2):228–231. DOI: 10.1097/MPG.0b013e3181560524.
  53. Gokmen T, Oguz S, Bozdag S, et al. A controlled trial of erythromycin and UDCA in premature infants during parenteral nutrition in minimizing feeding intolerance and liver function abnormalities. J Perinatol 2012; 32:123–128. DOI: 10.1038/jp.2011.56.
  54. British National Formulary for Children 2016–2017. Ursodeoxycholic Acid, 1st edition. London: BMJ Group, Pharmaceutical Press, Pharmaceutical Society, pp. 60.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.