Clinical Drug Investigation

, Volume 39, Issue 1, pp 15–26 | Cite as

Is It Necessary to Perform the Pharmacological Interventions for Intrahepatic Cholestasis of Pregnancy? A Bayesian Network Meta-Analysis

  • Yi Shen
  • Jie Zhou
  • Sheng Zhang
  • Xu-Lin Wang
  • Yu-Long Jia
  • Shu He
  • Yuan-Yuan Wang
  • Wen-Chao Li
  • Jian-Guo Shao
  • Xun Zhuang
  • Yuan-Lin Liu
  • Gang QinEmail author
Systematic Review


Background and Objective

Although many meta-analyses have evaluated the pharmacotherapy of intrahepatic cholestasis of pregnancy (ICP) and recommended ursodeoxycholic acid (UDCA) as an effective treatment, the defect of the pair-wise analyses and the mixture of the control group made the outcome uncertain and unclear. We aimed to employ Bayesian network meta-analysis (NMA) to compare the maternal and fetal outcomes after UDCA, S-adenosylmethionine (SAMe) mono-therapy or the combination treatment of these two drugs for ICP patients.


Multiple electronic database searches were conducted for articles published up to 1 September 2018. The relevant information was extracted from the published reports with a predefined data extraction sheet, and the risk of bias was assessed with the Cochrane risk-of-bias tool. Poisson Bayesian network meta-analysis was employed to identify the synthesized evidence from the relevant trials, with reporting hazard risks (HRs) and 95% credible intervals (CrIs).


The pooled outcomes of the 13 randomized controlled trials (RCTs) with 625 participants indicated that none of the three regimens can significantly improve maternal and fetal outcomes.


This NMA of the RCTs clarified that the current intervention has no favorable effect on pruritus and other symptoms in ICP patients.



We are grateful to the guidelines of the National Institute for Health and Excellence Decision Support Units (NICEDSU) for providing the BUGS code.

Author contributions

Conceptualization: YS JZ GQ. Formal analysis: JZ SZ XLW YLJ SH YYW WCL JGS YLL XZ. Funding acquisition: GQ JGS JZ. Methodology: JZ SZ. Software: YS JZ SZ XLW GQ. Validation: YS JZ GQ. Writing – original draft: YS JZ SZ. Writing – review and editing: YS GQ. All authors approved the final version of the manuscript.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no competing interests.


This study was supported in part by grants from Jiangsu Provincial Department of Science and Technology (BE2015655), China, National Natural Science Foundation of China (81370520), the Nantong Municipal Bureau of Science and Technology (HS2016002), China, and the Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX17-1941). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Supplementary material

40261_2018_717_MOESM1_ESM.pdf (586 kb)
Supplementary material 1 (PDF 585 kb)


  1. 1.
    Hay JE. Liver disease in pregnancy. Med Clin North Am. 2008;73(3):1067.Google Scholar
  2. 2.
    Bacq Y, Besco ML, Lecuyer AI, Gendrot C, Potin J, Andres CR, et al. Ursodeoxycholic acid therapy in intrahepatic cholestasis of pregnancy: results in real-world conditions and factors predictive of response to treatment. Digest Liver Dis. 2017;49(1):63–9.CrossRefGoogle Scholar
  3. 3.
    Lee NM, Brady CW. Liver disease in pregnancy. World J Gastroenterol. 2009;1(8):608.Google Scholar
  4. 4.
    Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol. 2014;124(1):120–33.CrossRefGoogle Scholar
  5. 5.
    Williamson C, Nelson-Piercy C. Liver disease in pregnancy. Br J Hosp Med. 2011;58(5):213–6.Google Scholar
  6. 6.
    Ozkan S, Ceylan Y, Ozkan OV, Yildirim S. Review of a challenging clinical issue: Intrahepatic cholestasis of pregnancy. World J Gastroenterol. 2015;21(23):7134.CrossRefGoogle Scholar
  7. 7.
    Lammert F, Marschall HU, Glantz A, Matern S. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol. 2000;33(6):1012–21.CrossRefGoogle Scholar
  8. 8.
    Zhuang X, Cui AM, Wang Q, et al. Liver dysfunction during pregnancy and its association of with preterm birth in China: a prospective cohort study. EBioMedicine. 2017;26:152–6.CrossRefGoogle Scholar
  9. 9.
    Fisk NM, Bye WB, Storey GN. Maternal features of obstetric cholestasis: 20 years experience at King George V Hospital. Aust N Z J Obstet Gynaecol. 1988;28(3):172–6.CrossRefGoogle Scholar
  10. 10.
    Alsulyman OM, Ouzounian JG, Amescastro M, Goodwin TM. Intrahepatic cholestasis of pregnancy: perinatal outcome associated with expectant management. Am J Obstet Gynecol. 1996;175(4):957–60.CrossRefGoogle Scholar
  11. 11.
    Glantz A, Marschall HU, Mattsson LÅ. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology. 2004;40(2):467–74.CrossRefGoogle Scholar
  12. 12.
    Jain R, Suri V, Chopra S, Chawla YK, Kohli KK. Obstetric cholestasis: outcome with active management. J Obstetr Gynaecol Res. 2013;39(5):953–9.CrossRefGoogle Scholar
  13. 13.
    Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol. 2009;19(17):46–57.Google Scholar
  14. 14.
    Lorente S, Montoro MA. Cholestasis of pregnancy. Gastroenterol Hepatol. 2007;30(9):541.CrossRefGoogle Scholar
  15. 15.
    Zhang L, Liu XH, Qi HB, Li Z, Fu XD, Chen L, et al. Ursodeoxycholic acid and S-adenosylmethionine in the treatment of intrahepatic cholestasis of pregnancy: a multi-centered randomized controlled trial. Eur Rev Med Pharmacol Sci. 2015;19(19):3770.Google Scholar
  16. 16.
    Gurung V, Middleton P, Milan SJ, Hague W, Thornton JG. Interventions for treating cholestasis in pregnancy. Cochrane Database Syst Rev. 2013;6(6):CD000493.Google Scholar
  17. 17.
    Zhou F, Gao B, Wang X, Li J. Meta-analysis of ursodeoxycholic acid and S-adenosylmethionine for improving the outcomes of intrahepatic cholestasis of pregnancy. Chin J Hepatol. 2014;22(4):299–304.Google Scholar
  18. 18.
    Bacq Y, Sentilhes L, Reyes HB, Glantz A, Kondrackiene J, Binder T, et al. Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology. 2012;143(6):1492–501.CrossRefGoogle Scholar
  19. 19.
    Grand’Maison S, Durand M, Mahone M. The effects of ursodeoxycholic acid treatment for intrahepatic cholestasis of pregnancy on maternal and fetal outcomes: a meta-analysis including non-randomized studies. J Obstetr Gynaecol Canada. 2014;36(7):632.CrossRefGoogle Scholar
  20. 20.
    Zhang Y, Lu L, Victor DW, Xin Y, Xuan S. Ursodeoxycholic acid and s-adenosylmethionine for the treatment of intrahepatic cholestasis of pregnancy: a meta-analysis. Hepat Month. 2016;16(8):e38558.Google Scholar
  21. 21.
    Singh S, Khera R, Allen AM, Murad MH, Loomba R. Comparative effectiveness of pharmacological interventions for nonalcoholic steatohepatitis: a systematic review and network meta-analysis. Hepatology. 2015;149(4):958–70.Google Scholar
  22. 22.
    Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378(9799):1306–15.CrossRefGoogle Scholar
  23. 23.
    Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ. 2003;326(7387):472.CrossRefGoogle Scholar
  24. 24.
    Sutton A, Ades AE, Cooper N, Abrams K. Use of indirect and mixed treatment comparisons for technology assessment. Pharmacoeconomics. 2008;26(9):753–67.CrossRefGoogle Scholar
  25. 25.
    Cipriani A, Higgins JPT, Geddes JR, Salanti G. Conceptual and technical challenges in network meta-analysis. Ann Intern Med. 2013;159(2):130–7.CrossRefGoogle Scholar
  26. 26.
    Mills EJ, Ioannidis JP, Thorlund K, Schünemann HJ, Puhan MA, Guyatt GH. How to use an article reporting a multiple treatment comparison meta-analysis. JAMA. 2012;308(12):1246–53.CrossRefGoogle Scholar
  27. 27.
    Cortese S. Guidance on conducting systematic reviews/meta-analyses of pharmacoepidemiological studies of safety outcomes: the gap is now filled. Epidemiol Psychiatr Sci. 2016;1(5):1.Google Scholar
  28. 28.
    Moher D, Liberati A, Tetzlaff J, Altman DG, Group TP. Preferred reporting items for systematic reviews and meta-analyses: the prisma statement. Revista Española De Nutrición Humana Y Dietética. 2009;18(3):e123.Google Scholar
  29. 29.
    Hutton B, Salanti G, Chaimani A, Caldwell DM, Schmid C, Thorlund K, et al. The Quality of reporting methods and results in network meta-analyses: an overview of reviews and suggestions for improvement. PLoS One. 2014;9(3):e92508.CrossRefGoogle Scholar
  30. 30.
    Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ Br Med J. 2011;343(7829):889–93.Google Scholar
  31. 31.
    Dias S, Sutton AJ, Ades AE, Welton NJ. Evidence synthesis for decision making 2: a generalized linear modeling framework for pairwise and network meta-analysis of randomized controlled trials. Med Decis Making. 2013;33(5):607–17.CrossRefGoogle Scholar
  32. 32.
    Dias S, Sutton AJ, Welton NJ, Ades AE. Evidence synthesis for decision making 3: heterogeneity–subgroups, meta-regression, bias, and bias-adjustment. Med Decis Making. 2013;33(5):618–40.CrossRefGoogle Scholar
  33. 33.
    Dias S, Welton NJ, Sutton AJ, Caldwell DM, Guobing L, Ades AE. Evidence synthesis for decision making 4: inconsistency in networks of evidence based on randomized controlled trials. Med Decis Making. 2013;33(5):641–56.CrossRefGoogle Scholar
  34. 34.
    Böhning D, Mylona K, Kimber A. Meta-analysis of clinical trials with rare events. Biom J. 2015;57(4):633–48.CrossRefGoogle Scholar
  35. 35.
    Cai T, Parast L, Ryan L. Meta-analysis for rare events. Stat Med. 2010;29(20):2078.CrossRefGoogle Scholar
  36. 36.
    Lunn D, Spiegelhalter D, Thomas A, Best N. The BUGS project: evolution, critique and future directions. Stat Med. 2009;28(25):3049–67.CrossRefGoogle Scholar
  37. 37.
    Lambert PC, Sutton AJ, Burton PR, Abrams KR, Jones DR. How vague is vague? A simulation study of the impact of the use of vague prior distributions in MCMC using WinBUGS. Stat Med. 2005;24(15):2401–28.CrossRefGoogle Scholar
  38. 38.
    Salanti G, Ades AE, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol. 2011;64(2):163–71.CrossRefGoogle Scholar
  39. 39.
    Held U, Brunner F, Steurer J, Wertli MM. Bayesian meta-analysis of test accuracy in the absence of a perfect reference test applied to bone scintigraphy for the diagnosis of complex regional pain syndrome. Biom J. 2015;57(6):1020–37.CrossRefGoogle Scholar
  40. 40.
    Turner RM, Davey J, Clarke MJ, Thompson SG, Higgins JP. Predicting the extent of heterogeneity in meta-analysis, using empirical data from the Cochrane Database of Systematic Reviews. Int J Epidemiol. 2012;41(3):818–27.CrossRefGoogle Scholar
  41. 41.
    Frezza M, Surrenti C, Manzillo G, Fiaccadori F, Bortolini M, Di PC. Oral S-adenosylmethionine in the symptomatic treatment of intrahepatic cholestasis. A double-blind, placebo-controlled study. Gastroenterology. 1990;99(1):211.Google Scholar
  42. 42.
    Ribalta J, Reyes H, Gonzalez MC, Iglesias J, Arrese M, Poniachik J, et al. S-Adenosyl-L-methionine in the treatment of patients with intrahepatic cholestasis of pregnancy: A randomized, double-blind, placebo-controlled study with negative results. Hepatology. 1991;13(6):1084–9.Google Scholar
  43. 43.
    Diaferia A, Nicastri PL, Tartagni M, Loizzi P, Iacovizzi C, Di LA. Ursodeoxycholic acid therapy in pregnant women with cholestasis. Int J Gynecol Obstetr. 1996;52(2):133–40.CrossRefGoogle Scholar
  44. 44.
    Floreani A, Paternoster D, Melis A, Grella PV. S-adenosylmethionine versus ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy: preliminary results of a controlled trial. Eur J Obstetr Gynecol Reprod Biol. 1996;67(2):109.CrossRefGoogle Scholar
  45. 45.
    Palma J, Reyes H, Ribalta J, Hernández I, Sandoval L, Almuna R, et al. Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized, double-blind study controlled with placebo. J Hepatol. 1997;27(6):1022.CrossRefGoogle Scholar
  46. 46.
    Nicastri PL, Diaferia A, Tartagni M, Loizzi P, Fanelli M. A randomised placebo-controlled trial of ursodeoxycholic acid and S-adenosylmethionine in the treatment of intrahepatic cholestasis of pregnancy. Br J Obstet Gynaecol. 1998;105(11):1205.CrossRefGoogle Scholar
  47. 47.
    Roncaglia N, Locatelli A, Arreghini A, Assi F, Cameroni I, Pezzullo JC, et al. A randomised controlled trial of ursodeoxycholic acid and S-adenosyl-l-methionine in the treatment of gestational cholestasis. BJOG Int J Obstetr Gynaecol. 2004;111(1):17–21.CrossRefGoogle Scholar
  48. 48.
    Glantz A, Marschall HU, Lammert F, Mattsson LA. Intrahepatic cholestasis of pregnancy: a randomized controlled trial comparing dexamethasone and ursodeoxycholic acid. Hepatology. 2005;42(6):1399–405.CrossRefGoogle Scholar
  49. 49.
    Binder T, Salaj P, Zima T, Vítek L. Randomized prospective comparative study of ursodeoxycholic acid and S-adenosyl-L-methionine in the treatment of intrahepatic cholestasis of pregnancy. J Perinat Med. 2006;34(5):383–91.CrossRefGoogle Scholar
  50. 50.
    Liu Y, Qiao F, Liu H, Liu D. Ursodeoxycholic acid in the treatment of intraheptic cholestasis of pregnancy. J Huazhong Univ Sci Technol (Med Sci). 2006;26(3):350.CrossRefGoogle Scholar
  51. 51.
    Chappell LC, Gurung V, Seed PT, Chambers J, Williamson C, Thornton JG. Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial. BMJ. 2012;13(344):e3799.CrossRefGoogle Scholar
  52. 52.
    Joutsiniemi T, Timonen S, Leino R, Palo P, Ekblad U. Ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy: a randomized controlled trial. Arch Gynecol Obstet. 2014;289(3):541.CrossRefGoogle Scholar
  53. 53.
    Obstetriciansgynecologists ACO. ACOG committee opinion no. 560: Medically indicated late-preterm and early-term deliveries. Obstetr Gynecol. 2013;121(4):908–10.Google Scholar
  54. 54.
    Henderson CE, Shah RR, Gottimukkala S, Ferreira KK, Hamaoui A, Mercado R. Primum non nocere: how active management became modus operandi for intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol. 2014;211(3):189–96.CrossRefGoogle Scholar
  55. 55.
    Ofliver EAF. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51(4):237–67.Google Scholar
  56. 56.
    Kong X, Kong Y, Zhang F, Wang T, Yan J. Evaluating the effectiveness and safety of ursodeoxycholic acid in treatment of intrahepatic cholestasis of pregnancy: a meta-analysis (a prisma-compliant study). Medicine. 2016;95(40):e4949.CrossRefGoogle Scholar
  57. 57.
    Chappell LC, Chambers J, Thornton JG, Williamson C. Does ursodeoxycholic acid improve perinatal outcomes in women with intrahepatic cholestasis of pregnancy? BMJ. 2018;360:k104.CrossRefGoogle Scholar
  58. 58.
    Arthur C, Mahomed K. Intrahepatic cholestasis of pregnancy: diagnosis and management; a survey of Royal Australian and New Zealand College of Obstetrics and Gynaecology fellows. Aust N Z J Obstet Gynaecol. 2014;54(3):263.CrossRefGoogle Scholar
  59. 59.
    Azzaroli F, Turco L, Lisotti A, Calvanese C, Mazzella G. The pharmacological management of intrahepatic cholestasis of pregnancy. Curr Clin Pharmacol. 2011;6(1):12.CrossRefGoogle Scholar
  60. 60.
    Almasio P, Bortolini M, Pagliaro L, Coltorti M. Role of S-adenosyl-L-methionine in the treatment of intrahepatic cholestasis. Drugs. 1990;40(3):111–23.CrossRefGoogle Scholar
  61. 61.
    Crowther MJ, Riley RD, Staessen JA, Wang J, Francois G, Lambert PC. Individual patient data meta-analysis of survival data using Poisson regression models. BMC Med Res Methodol. 2012;12(1):34.CrossRefGoogle Scholar
  62. 62.
    Pjetursson BE, Thoma D, Jung R, Zwahlen M, Zembic A. A systematic review of the survival and complication rates of implant-supported fixed dental prostheses (FDPs) after a mean observation period of at least 5 years. Clin Oral Implants Res. 2012;23(Suppl 6):22–38.CrossRefGoogle Scholar
  63. 63.
    Friede T, Röver C, Wandel S, Neuenschwander B. Meta-analysis of few small studies in orphan diseases. Res Synthesis Methods. 2016;8(1):79–91.CrossRefGoogle Scholar
  64. 64.
    Golder S, Loke YK, Bland M. Meta-analyses of adverse effects data derived from randomised controlled trials as compared to observational studies: methodological overview. Plos Med. 2011;8(5):e1001026.CrossRefGoogle Scholar
  65. 65.
    Schünemann HJ, Tugwell P, Reeves BC, Akl EA, Santesso N, Spencer FA, et al. Non-randomized studies as a source of complementary, sequential or replacement evidence for randomized controlled trials in systematic reviews on the effects of interventions. Res Synth Methods. 2013;4(1):49–62.CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Epidemiology and Medical Statistics, School of Public HealthNantong UniversityNantongChina
  2. 2.Center for Liver Diseases, Nantong Third People’s HospitalNantong UniversityNantongChina
  3. 3.Department of Obstetrics and GynecologyAffiliated Hospital of Nantong UniversityNantongChina

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