Pharmacological interventions for treating intrahepatic cholestasis of pregnancy

Kate F Walker, Lucy C Chappell, William M Hague, Philippa Middleton, Jim G Thornton, Kate F Walker, Lucy C Chappell, William M Hague, Philippa Middleton, Jim G Thornton

Abstract

Background: Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that can develop in pregnancy. It occurs when there is a build-up of bile acids in the maternal blood. It has been linked to adverse maternal and fetal/neonatal outcomes. As the pathophysiology is poorly understood, therapies have been largely empiric. As ICP is an uncommon condition (incidence less than 2% a year), many trials have been small. Synthesis, including recent larger trials, will provide more evidence to guide clinical practice. This review is an update of a review first published in 2001 and last updated in 2013.

Objectives: To assess the effects of pharmacological interventions to treat women with intrahepatic cholestasis of pregnancy, on maternal, fetal and neonatal outcomes.

Search methods: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (13 December 2019), and reference lists of retrieved studies.

Selection criteria: Randomised or quasi-randomised controlled trials, including cluster-randomised trials and trials published in abstract form only, that compared any drug with placebo or no treatment, or two drug intervention strategies, for women with a clinical diagnosis of intrahepatic cholestasis of pregnancy.

Data collection and analysis: The review authors independently assessed trials for eligibility and risks of bias. We independently extracted data and checked these for accuracy. We assessed the certainty of the evidence using the GRADE approach.

Main results: We included 26 trials involving 2007 women. They were mostly at unclear to high risk of bias. They assessed nine different pharmacological interventions, resulting in 14 different comparisons. We judged two placebo-controlled trials of ursodeoxycholic acid (UDCA) in 715 women to be at low risk of bias. The ten different pharmacological interventions were: agents believed to detoxify bile acids (UCDA) and S-adenosylmethionine (SAMe); agents used to bind bile acids in the intestine (activated charcoal, guar gum, cholestyramine); Chinese herbal medicines (yinchenghao decoction (YCHD), salvia, Yiganling and Danxioling pill (DXLP)), and agents aimed to reduce bile acid production (dexamethasone) Compared with placebo, UDCA probably results in a small improvement in pruritus score measured on a 100 mm visual analogue scale (VAS) (mean difference (MD) -7.64 points, 95% confidence interval (CI) -9.69 to -5.60 points; 2 trials, 715 women; GRADE moderate certainty), where a score of zero indicates no itch and a score of 100 indicates severe itching. The evidence for fetal distress and stillbirth were uncertain, due to serious limitations in study design and imprecision (risk ratio (RR) 0.70, 95% CI 0.35 to 1.40; 6 trials, 944 women; RR 0.33, 95% CI 0.08 to 1.37; 6 trials, 955 women; GRADE very low certainty). We found very few differences for the other comparisons included in this review. There is insufficient evidence to indicate if SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, Salvia, Yinchenghao decoction, Danxioling and Yiganling, or Yiganling alone or in combination are effective in treating women with intrahepatic cholestasis of pregnancy.

Authors' conclusions: When compared with placebo, UDCA administered to women with ICP probably shows a reduction in pruritus. However the size of the effect is small and for most pregnant women and clinicians, the reduction may fall below the minimum clinically worthwhile effect. The evidence was unclear for other adverse fetal outcomes, due to very low-certainty evidence. There is insufficient evidence to indicate that SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, YCHD, DXLP, Salvia, Yiganling alone or in combination are effective in treating women with cholestasis of pregnancy. There are no trials of the efficacy of topical emollients. Further high-quality trials of other interventions are needed in order to identify effective treatments for maternal itching and preventing adverse perinatal outcomes. It would also be helpful to identify those women who are mostly likely to respond to UDCA (for example, whether bile acid concentrations affect how women with ICP respond to treatment with UDCA).

Trial registration: ClinicalTrials.gov NCT01965054 NCT01226823 NCT03056274.

Conflict of interest statement

Kate F Walker: none known.

Philippa Middleton is an investigator on the TURRIFIC study. Recruitment to this trial has now started. Assessment, data extraction and data entry for this study in any future review will not be performed by William M Hague or Philippa Middleton, Lucy Chappell or Jim G Thornton.

William M Hague: I am the lead CI for the TURRIFIC trial (Trial of URsodeoxycholic acid vs RIFampicin in the treatment of severe early onset Intrahepatic Cholestasis of Pregnancy, funded by the MRFF, which will impact on the later versions of the Systematic Review. Recruitment to this trial has now started. Assessment, data extraction and data entry for this study in any future review will not be performed by William M Hague, Philippa Middleton, Lucy Chappell or Jim G Thornton.

Lucy C Chappell: is an author of the Chappell 2012 and Chappell 2019 trials. Assessment, data extraction and data entry for Chappell 2012 were conducted by Philippa Middleton and a previous author, Stephen Milan. Assessment, data extraction and data entry for Chappell 2019 were conducted by Kate Walker and Philippa Middleton. Lucy Chappell is also an investigator on the TURRIFIC study. Assessment, data extraction and data entry for this study in any future review will not be performed by William M Hague, Philippa Middleton, Lucy Chappell or Jim G Thornton.

Jim G Thornton: is an author of the Chappell 2012 and Chappell 2019 trials. Assessment, data extraction and data entry for Chappell 2012 were conducted by Philippa Middleton and a previous author, Stephen Milan. Assessment, data extraction and data entry for Chappell 2019 were conducted by Kate Walker and Philippa Middleton. Jim G Thornton is also an investigator on the TURRIFIC study. Assessment, data extraction and data entry for this study in any future review will not be performed by William M Hague, Philippa Middleton, Lucy Chappell or Jim G Thornton.