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Meta-Analysis
. 2020 Jul 27;7(7):CD000493.
doi: 10.1002/14651858.CD000493.pub3.

Pharmacological interventions for treating intrahepatic cholestasis of pregnancy

Kate F Walker  1 , Lucy C Chappell  2 , William M Hague  3   4 , Philippa Middleton  5 , Jim G Thornton  1
Affiliations
Meta-Analysis

Pharmacological interventions for treating intrahepatic cholestasis of pregnancy

Kate F Walker et al. Cochrane Database Syst Rev. .

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.

PubMed Disclaimer

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.

Figures

1
1
Study flow diagram
2
2
3
3
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: UDCA versus placebo, Outcome 1: Mean of worst itching scores over preceding 24 hours between randomisation and delivery
1.2
1.2. Analysis
Comparison 1: UDCA versus placebo, Outcome 2: Pruritus improvement
1.3
1.3. Analysis
Comparison 1: UDCA versus placebo, Outcome 3: Mean of average itching scores over preceding 24 hours between randomisation and delivery
1.4
1.4. Analysis
Comparison 1: UDCA versus placebo, Outcome 4: Stillbirth
1.5
1.5. Analysis
Comparison 1: UDCA versus placebo, Outcome 5: Fetal distress/asphyxial event
1.6
1.6. Analysis
Comparison 1: UDCA versus placebo, Outcome 6: Subgroup analysis ‐ fetal distress/asphyxial events
1.7
1.7. Analysis
Comparison 1: UDCA versus placebo, Outcome 7: Change in bile acid concentration, µmol/L
1.8
1.8. Analysis
Comparison 1: UDCA versus placebo, Outcome 8: ALT, IU/L
1.9
1.9. Analysis
Comparison 1: UDCA versus placebo, Outcome 9: ALT reduction, IU/L
1.10
1.10. Analysis
Comparison 1: UDCA versus placebo, Outcome 10: Caesarean section
1.11
1.11. Analysis
Comparison 1: UDCA versus placebo, Outcome 11: Postpartum haemorrhage
1.12
1.12. Analysis
Comparison 1: UDCA versus placebo, Outcome 12: Adverse effects of medication
1.13
1.13. Analysis
Comparison 1: UDCA versus placebo, Outcome 13: Meconium‐stained liquor
1.14
1.14. Analysis
Comparison 1: UDCA versus placebo, Outcome 14: Mean gestational age at birth (weeks)
1.15
1.15. Analysis
Comparison 1: UDCA versus placebo, Outcome 15: Spontaneous birth at less than 37 weeks
1.16
1.16. Analysis
Comparison 1: UDCA versus placebo, Outcome 16: Total preterm birth at less than 37 weeks
1.17
1.17. Analysis
Comparison 1: UDCA versus placebo, Outcome 17: Admission to neonatal intensive care unit
2.1
2.1. Analysis
Comparison 2: SAMe versus placebo, Outcome 1: Stillbirth/neonatal death
2.2
2.2. Analysis
Comparison 2: SAMe versus placebo, Outcome 2: Bile acid reduction, µmol/L
2.3
2.3. Analysis
Comparison 2: SAMe versus placebo, Outcome 3: ALT reduction, IU/L
2.4
2.4. Analysis
Comparison 2: SAMe versus placebo, Outcome 4: Caesarean section
2.5
2.5. Analysis
Comparison 2: SAMe versus placebo, Outcome 5: Spontaneous birth at less than 37 weeks
2.6
2.6. Analysis
Comparison 2: SAMe versus placebo, Outcome 6: Total preterm birth at less than 37 weeks
3.1
3.1. Analysis
Comparison 3: Guar gum versus placebo, Outcome 1: Pruritus improvement
3.2
3.2. Analysis
Comparison 3: Guar gum versus placebo, Outcome 2: Total bile acids (µmol/L)
3.3
3.3. Analysis
Comparison 3: Guar gum versus placebo, Outcome 3: ALT, U/L
3.4
3.4. Analysis
Comparison 3: Guar gum versus placebo, Outcome 4: Adverse effects of medication
3.5
3.5. Analysis
Comparison 3: Guar gum versus placebo, Outcome 5: Mean gestational age at birth
4.1
4.1. Analysis
Comparison 4: Activated charcoal versus no treatment, Outcome 1: Pruritus improvement
4.2
4.2. Analysis
Comparison 4: Activated charcoal versus no treatment, Outcome 2: Bile acids after 8 days treatment, µmol/L
4.3
4.3. Analysis
Comparison 4: Activated charcoal versus no treatment, Outcome 3: ALT after 8 days treatment, U/L
4.4
4.4. Analysis
Comparison 4: Activated charcoal versus no treatment, Outcome 4: Mean gestational age at birth
5.1
5.1. Analysis
Comparison 5: Dexamethasone versus placebo, Outcome 1: Stillbirths
5.2
5.2. Analysis
Comparison 5: Dexamethasone versus placebo, Outcome 2: Fetal distress/asphyxial event
5.3
5.3. Analysis
Comparison 5: Dexamethasone versus placebo, Outcome 3: Subgroup analysis ‐ fetal distress/asphyxial event
5.4
5.4. Analysis
Comparison 5: Dexamethasone versus placebo, Outcome 4: Meconium‐stained liquor
5.5
5.5. Analysis
Comparison 5: Dexamethasone versus placebo, Outcome 5: Spontaneous birth at less than 37 weeks
5.6
5.6. Analysis
Comparison 5: Dexamethasone versus placebo, Outcome 6: Total preterm births at less than 37 weeks
6.1
6.1. Analysis
Comparison 6: UDCA versus SAMe, Outcome 1: Pruritus improvement
6.2
6.2. Analysis
Comparison 6: UDCA versus SAMe, Outcome 2: Mean pruritus score one week post treatment
6.3
6.3. Analysis
Comparison 6: UDCA versus SAMe, Outcome 3: Mean pruritus score two weeks post treatment
6.4
6.4. Analysis
Comparison 6: UDCA versus SAMe, Outcome 4: Fetal distress/asphyxial events
6.5
6.5. Analysis
Comparison 6: UDCA versus SAMe, Outcome 5: Bile acids, µmol/L
6.6
6.6. Analysis
Comparison 6: UDCA versus SAMe, Outcome 6: ALT, µkatl/L
6.7
6.7. Analysis
Comparison 6: UDCA versus SAMe, Outcome 7: Caesarean section
6.8
6.8. Analysis
Comparison 6: UDCA versus SAMe, Outcome 8: Meconium‐stained liquor
6.9
6.9. Analysis
Comparison 6: UDCA versus SAMe, Outcome 9: Mean gestational age at birth
6.10
6.10. Analysis
Comparison 6: UDCA versus SAMe, Outcome 10: Spontaneous birth at less than 37 weeks
6.11
6.11. Analysis
Comparison 6: UDCA versus SAMe, Outcome 11: Total preterm birth at less than 37 weeks
6.12
6.12. Analysis
Comparison 6: UDCA versus SAMe, Outcome 12: Admission to neonatal intensive care unit
7.1
7.1. Analysis
Comparison 7: UDCA versus dexamethasone, Outcome 1: Fetal distress/asphyxial events
7.2
7.2. Analysis
Comparison 7: UDCA versus dexamethasone, Outcome 2: Adverse effects of medication
7.3
7.3. Analysis
Comparison 7: UDCA versus dexamethasone, Outcome 3: Meconium‐stained liquor
7.4
7.4. Analysis
Comparison 7: UDCA versus dexamethasone, Outcome 4: Spontaneous birth at less than 37 weeks
7.5
7.5. Analysis
Comparison 7: UDCA versus dexamethasone, Outcome 5: Total preterm birth at less than 37 weeks
8.1
8.1. Analysis
Comparison 8: UDCA versus cholestyramine, Outcome 1: Pruritus score (> 50% reduction after 14 days treatment)
8.2
8.2. Analysis
Comparison 8: UDCA versus cholestyramine, Outcome 2: Fetal distress/asphyxial event
8.3
8.3. Analysis
Comparison 8: UDCA versus cholestyramine, Outcome 3: Bile acids, µmol/L
8.4
8.4. Analysis
Comparison 8: UDCA versus cholestyramine, Outcome 4: ALT, U/L
8.5
8.5. Analysis
Comparison 8: UDCA versus cholestyramine, Outcome 5: Caesarean section
8.6
8.6. Analysis
Comparison 8: UDCA versus cholestyramine, Outcome 6: Adverse effects of medication
8.7
8.7. Analysis
Comparison 8: UDCA versus cholestyramine, Outcome 7: Mean gestational age at birth
8.8
8.8. Analysis
Comparison 8: UDCA versus cholestyramine, Outcome 8: Total preterm birth at less than 37 weeks
9.1
9.1. Analysis
Comparison 9: UDCA + SAMe versus placebo, Outcome 1: Bile acid reduction at 20 days, µmol/L
10.1
10.1. Analysis
Comparison 10: UDCA + SAMe versus SAMe, Outcome 1: Pruritus improvement
10.2
10.2. Analysis
Comparison 10: UDCA + SAMe versus SAMe, Outcome 2: Stillbirths/neonatal deaths
10.3
10.3. Analysis
Comparison 10: UDCA + SAMe versus SAMe, Outcome 3: Fetal distress/asphyxial event
10.4
10.4. Analysis
Comparison 10: UDCA + SAMe versus SAMe, Outcome 4: Bile acids, µmol/L
10.5
10.5. Analysis
Comparison 10: UDCA + SAMe versus SAMe, Outcome 5: ALT, µkatl/L
10.6
10.6. Analysis
Comparison 10: UDCA + SAMe versus SAMe, Outcome 6: Caesarean section
10.7
10.7. Analysis
Comparison 10: UDCA + SAMe versus SAMe, Outcome 7: Postpartum haemorrhage
10.8
10.8. Analysis
Comparison 10: UDCA + SAMe versus SAMe, Outcome 8: Meconium‐stained liquor
10.9
10.9. Analysis
Comparison 10: UDCA + SAMe versus SAMe, Outcome 9: Spontaneous birth at less than 37 weeks
10.10
10.10. Analysis
Comparison 10: UDCA + SAMe versus SAMe, Outcome 10: Total preterm birth at less than 37 weeks
10.11
10.11. Analysis
Comparison 10: UDCA + SAMe versus SAMe, Outcome 11: Admission to neonatal intensive care unit
11.1
11.1. Analysis
Comparison 11: UDCA + SAMe versus UDCA, Outcome 1: Pruritus improvement
11.2
11.2. Analysis
Comparison 11: UDCA + SAMe versus UDCA, Outcome 2: Mean pruritus score post treatment
11.3
11.3. Analysis
Comparison 11: UDCA + SAMe versus UDCA, Outcome 3: Stillbirths/neonatal deaths
11.4
11.4. Analysis
Comparison 11: UDCA + SAMe versus UDCA, Outcome 4: Fetal distress/asphyxial event
11.5
11.5. Analysis
Comparison 11: UDCA + SAMe versus UDCA, Outcome 5: Bile acids, µmol/L
11.6
11.6. Analysis
Comparison 11: UDCA + SAMe versus UDCA, Outcome 6: ALT, µkatl/L
11.7
11.7. Analysis
Comparison 11: UDCA + SAMe versus UDCA, Outcome 7: Reduction in ALT (IU/L) after treatment
11.8
11.8. Analysis
Comparison 11: UDCA + SAMe versus UDCA, Outcome 8: Caesarean section
11.9
11.9. Analysis
Comparison 11: UDCA + SAMe versus UDCA, Outcome 9: Postpartum haemorrhage
11.10
11.10. Analysis
Comparison 11: UDCA + SAMe versus UDCA, Outcome 10: Meconium‐stained liquor
11.11
11.11. Analysis
Comparison 11: UDCA + SAMe versus UDCA, Outcome 11: Spontaneous birth at less than 37 weeks
11.12
11.12. Analysis
Comparison 11: UDCA + SAMe versus UDCA, Outcome 12: Total preterm births at less than 37 weeks
11.13
11.13. Analysis
Comparison 11: UDCA + SAMe versus UDCA, Outcome 13: Admission to neonatal intensive care unit
12.1
12.1. Analysis
Comparison 12: UDCA + Salvia versus UDCA, Outcome 1: Reduction in pruritus from moderate/severe to mild (0‐4 scale)
12.2
12.2. Analysis
Comparison 12: UDCA + Salvia versus UDCA, Outcome 2: Reduction in ALT (IU/L) after treatment
12.3
12.3. Analysis
Comparison 12: UDCA + Salvia versus UDCA, Outcome 3: Meconium‐stained liquor
12.4
12.4. Analysis
Comparison 12: UDCA + Salvia versus UDCA, Outcome 4: Fetal distress
13.1
13.1. Analysis
Comparison 13: YCHD versus SAMe, Outcome 1: Degree of pruritus after treatment
13.2
13.2. Analysis
Comparison 13: YCHD versus SAMe, Outcome 2: Stillbirths/neonatal deaths
13.3
13.3. Analysis
Comparison 13: YCHD versus SAMe, Outcome 3: Fetal distress/asphyxial event
13.4
13.4. Analysis
Comparison 13: YCHD versus SAMe, Outcome 4: Bile salt (CGA) concentration
13.5
13.5. Analysis
Comparison 13: YCHD versus SAMe, Outcome 5: ALT
13.6
13.6. Analysis
Comparison 13: YCHD versus SAMe, Outcome 6: Caesarean section
13.7
13.7. Analysis
Comparison 13: YCHD versus SAMe, Outcome 7: Meconium‐stained liquor
13.8
13.8. Analysis
Comparison 13: YCHD versus SAMe, Outcome 8: Mean gestational age at birth
14.1
14.1. Analysis
Comparison 14: Danxioling versus Yiganling, Outcome 1: Pruritus
14.2
14.2. Analysis
Comparison 14: Danxioling versus Yiganling, Outcome 2: Stillbirths/neonatal deaths
14.3
14.3. Analysis
Comparison 14: Danxioling versus Yiganling, Outcome 3: Bile acid concentration (CGA)
14.4
14.4. Analysis
Comparison 14: Danxioling versus Yiganling, Outcome 4: ALT
14.5
14.5. Analysis
Comparison 14: Danxioling versus Yiganling, Outcome 5: Caesarean section
14.6
14.6. Analysis
Comparison 14: Danxioling versus Yiganling, Outcome 6: Meconium‐stained liquor
14.7
14.7. Analysis
Comparison 14: Danxioling versus Yiganling, Outcome 7: Spontaneous birth at less than 37 weeks
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References

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Binder 2006 {published data only}
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Riikonen 2000 {published data only}
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Roncaglia 2004 {published data only}
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Shi 2002 {published data only}
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Sun 2014 {published data only}
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Wang 2003 {published data only}
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Zhang 2012 {published data only}
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Zhang 2015 {published data only}
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References to studies excluded from this review

Elias 2001 {published data only}
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Gautam 2013 {published data only}
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Jain 2013 {published data only}
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Kohari 2013 {published data only}
    1. Kohari K, NCT01965054. The use of fish oil supplementation in treatment of intrahepatic cholestasis of pregnancy. clinicaltrials.gov/ct2/show/NCT01965054 (first received 18 October 2013).
Liu 1990 {published data only}
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Mazzella 2010 {published data only}
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Shi 2006 {published data only}
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References to studies awaiting assessment

Chen 2019 {published data only}
    1. Chen Y. Ursodeoxycholic acid combined with TCM liquid in the treatment of intrahepatic cholestasis of pregnancy and its effect on blood biochemical indexes and pregnancy outcome. Boletin de Malariologia y Salud Ambiental 2019;59:5.
EUCTR2008‐001323‐64‐IT 2008 {published data only}
    1. EUCTR2008-001323-64-IT. Phase iii double blind placebo controlled randomized study on the efficacy of ursodeoxycholic acid for the treatment of intrahepatic cholestasis of pregnancy - certo_01 2008. www.clinicaltrialsregister.eu/ctr-search/trial/2008-001323-64/IT (first received 10 March 2008). [CENTRAL: CN-01845664]
Liu 2018 {published data only}
    1. Liu H, ChiCTR1800015136. Study on application of Levocarnitine in intrahepatic cholestasis of pregnancy. www.chictr.org.cn/showproj.aspx?proj=25782 (first received 9 March 2018).

References to ongoing studies

Hague 2018 {published data only}
    1. Hague WM, ACTRN12618000332224. A randomised Trial of URsodeoxycholic acid versus RIFampicin in severe early-onset Intrahepatic Cholestasis of pregnancy: the TURRIFIC study, comparing their effectiveness in the reduction of pruritus. www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12618000332224 (first received 4 February 2018).
Shehata 2017 {published data only}
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