Efficacy of Ursodeoxycholic Acid in Treating Intrahepatic Cholestasis of Pregnancy: A Meta-analysis

doi:10.1053/j.gastro.2012.08.004

Gastroenterology

Volume 143, Issue 6, December 2012, Pages 1492-1501

https://doi.org/10.1053/j.gastro.2012.08.004 Get rights and content

Background & Aims

We performed a meta-analysis to evaluate the effects of ursodeoxycholic acid (UDCA) on pruritus, liver test results, and outcomes of babies born to women with intrahepatic cholestasis of pregnancy (ICP).

Methods

We performed a systematic review of 9 published, randomized controlled trials (3 double blinded) that compared the effects of UDCA to other drugs, placebo, or no specific treatment (controls) in patients with ICP. We analyzed data from 454 patients: 207 received only UDCA, 70 received only placebo, 42 received cholestyramine, 36 received dexamethasone for 1 week and then placebo for 2 weeks, 65 received S-adenosyl-methionine, and 34 received no specific treatment. To achieve consistency among end points, a standard questionnaire was sent to all corresponding authors. For each end point, we performed pooled analysis that compared the effects of UDCA with those of all controls and UDCA with those of placebos.

Results

In pooled analyses that compared UDCA with all controls, UDCA was associated with total resolution of pruritus (odds ratio [OR], 0.23; 95% confidence interval [CI], 0.07–0.74; P < .01), reduced pruritis (OR, 0.27; 95% CI, 0.13–0.55; P < .0001), normalization of serum levels of alanine aminotransferase (ALT) (OR, 0.23; 95% CI, 0.10–0.50; P < .001), decreased serum level of ALT (OR, 0.24; 95% CI, 0.11–0.52; P < .0001), reduced serum levels of bile acids (OR, 0.37; 95% CI, 0.19–0.75; P < .001), fewer premature births (OR, 0.44; 95% CI, 0.24–0.79; P < .01), reduced fetal distress (OR, 0.46; 95% CI, 0.25–0.86; P < .01), less frequent respiratory distress syndrome (OR, 0.30; 95% CI, 0.12–0.74; P < .01), and fewer neonates in the intensive care unit (OR, 0.49; 95% CI, 0.25–0.98; P = .046). In pooled analyses that compared the effects of UDCA with placebo, UDCA reduced pruritus (OR, 0.21; 95% CI, 0.07–0.62; P < .01), normalized (OR, 0.18; 95% CI, 0.06–0.52; P < .001) or decreased serum levels of ALT (OR, 0.12; 95% CI, 0.05–0.31; P < .0001), and reduced serum levels of bile acids (OR, 0.30; 95% CI, 0.12–0.73; P < .01).

Conclusions

Based on a meta-analysis, UDCA is effective in reducing pruritus and improving liver test results in patients with ICP; UDCA therapy might also benefit fetal outcomes.

Section snippets

Patients and Methods

Meta-analyses were conducted according to a predetermined protocol following the recommendations of Sacks et al¹⁵ but were limited to English language randomized controlled trials (RCTs). To collect data for the meta-analyses, a standardized questionnaire was sent to the corresponding author of each of the selected RCTs.

Studied Population

Nine RCTs including 489 patients with ICP were selected and analyzed.18, 19, 20, 21, 22, 23, 24, 25, 26 Out of the 489 patients, 35 patients who received an association of UDCA and S-adenosyl-methionine were excluded from the meta-analysis. Out of the remaining 454 patients, 207 received UDCA alone, 70 received the placebo alone, 42 received cholestyramine, 36 received dexamethasone for 1 week and then placebo for 2 weeks, 65 received S-adenosyl-methionine, and 34 received no treatment. We sent

Discussion

Although UDCA appears as the most efficient treatment of ICP, the evidence of its benefit on pruritus is still debated, and the only previous meta-analysis failed to provide significant results.²⁷ Moreover, the role of UDCA in preventing severe fetal outcome has never been demonstrated.²⁸ In the previously published systematic review on this topic led by Burrows et al (update available on www.cochrane.org), the authors concluded that “inconsistent and inadequate reporting of results precluded

Acknowledgments

The authors thank Adam Smith for reviewing the English text.

References (38)

H. Reyes et al.
Prevalence of intrahepatic cholestasis of pregnancy in La Paz, Bolivia
J Chronic Dis
(1979)
F. Lammert et al.
Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management
J Hepatol
(2000)
L. Sentilhes et al.
La Cholestase Intrahépatique Gravidique
J Gynecol Obstet Biol Reprod (Paris)
(2008)
B. Pathak et al.
Cholestasis of pregnancy
Obstet Gynecol Clin North Am
(2010)
R. DerSimonian et al.
Meta-analysis in clinical trials
Control Clin Trials
(1986)
A. Diaferia et al.
Ursodeoxycholic acid therapy in pregnant women with cholestasis
Int J Gynaecol Obstet
(1996)
J. Palma et al.
Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized, double-blind study controlled with placebo
J Hepatol
(1997)
A. Floreani et al.
S-adenosylmethionine versus ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy: preliminary results of a controlled trial
Eur J Obstet Gynecol Reprod Biol
(1996)
J. Kondrackiene et al.
Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy
Gastroenterology
(2005)
G. Paumgartner et al.
Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited
Hepatology
(2002)

M.A. Serrano et al.

Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta

J Hepatol

(1998)

T. Laatikainen et al.

Maternal serum bile acid levels and fetal distress in cholestasis of pregnancy

Int J Gynaecol Obstet

(1984)

Y. Bacq et al.

Intrahepatic cholestasis of pregnancy: a French prospective study

Hepatology

(1997)

H. Reyes

Review: intrahepatic cholestasisA puzzling disorder of pregnancy

J Gastroenterol Hepatol

(1997)

V. Geenes et al.

Intrahepatic cholestasis of pregnancy

World J Gastroenterol

(2009)

H. Reyes et al.

Prevalence of intrahepatic cholestasis of pregnancy in Chile

Ann Intern Med

(1978)

R.H. Lee et al.

The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population

J Perinatol

(2006)

Obstetric cholestasis

RCOG

(2011)

M.M. Saleh et al.

Consensus on the management of obstetric cholestasis: National UK survey

BJOG

(2007)

Cited by (199)

Gradual dosing of ursodeoxycholic acid in mothers with intrahepatic cholestasis of pregnancy may improve composite neonatal outcome
2024, Annals of Hepatology
Intrahepatic cholestasis of pregnancy (ICP) is often accompanied by fetal and maternal complications.
Retrospective review of the clinical course of women with ICP and their neonates treated at our medical center over a 10-year period. Special attention was paid to the maternal and neonatal response to 2 different modes of ursodeoxycholic acid (UDCA) administration.
Neonates of mothers with high total bile acid levels had a poorer composite neonatal outcome. Twenty-seven women who presented at an advanced stage of their pregnancies did not receive UDCA. UDCA was administered in 2 modes: either a full dose at admission (76 women) or a gradually increasing dose until the desired dosage was reached (25 women). The mean gestational age at delivery for the 94 neonates that were exposed to full UDCA dose was the lowest (36±2.3 weeks for the full dose, 37±1.4 weeks for the 30 neonates from the gradually increasing dose, 38±1.6 weeks for the 29 neonates from the no treatment group, p<0.001). The group of neonates that were exposed to full UDCA dose had the highest rate of unfavorable composite neonatal outcome (53% for full dose, 30% for gradually increasing dose, 24% for the no treatment group, p=0.006).
Compared to the administration of a full UDCA dose, the administration of a gradually increasing dose of UDCA may be associated with a greater gestational age at delivery and fewer events of unfavorable composite neonatal outcomes. These novel findings should be retested prospectively in a large cohort of patients.
Maternal liver-related symptoms during pregnancy in primary sclerosing cholangitis
2024, JHEP Reports
Although worsening liver-related symptoms during pregnancy can occur in primary sclerosing cholangitis (PSC), there are insufficient data to effectively counsel patients on their pre-conception risk and no clear recommendations on monitoring and management during pregnancy. We aimed to describe maternal liver-related symptoms in pregnancy, both before and after PSC diagnosis, and explore factors associated with worsening symptoms and liver-related outcomes.
We conducted a multicentre retrospective observational study of females with PSC and known pregnancy with live birth, via the International PSC Study Group. We included 450 patients from 12 European centres. Data included clinical variables, liver-related symptoms (pruritus and/or cholangitis) during pregnancy, and liver biochemistry. A composite primary endpoint of transplant-free survival from time of PSC diagnosis was used.
There were 266 pregnancies in 178 patients following PSC diagnosis. Worsening liver-related symptoms were reported in 66/228 (28.9%) pregnancies; they had a reduced transplant-free survival (p = 0.03), which retained significance on multivariate analysis (hazard ratio 3.02, 95% CI 1.24-7.35; p = 0.02).
Abnormal biochemistry and/or liver-related symptoms (pruritus and/or cholangitis) were noted during pregnancy before PSC diagnosis in 21/167 (12.6%) patients. They had a reduced transplant-free survival from pregnancy (p = 0.01), which did not retain significance in a multivariable model (hazard ratio 1.10, 95% CI 0.43-2.85; p = 0.84).
Liver-related symptoms are frequently encountered during pregnancies before the diagnosis of PSC, and pregnancy may expose the pre-clinical phase of PSC in some patients. Worsening liver-related symptoms were seen in a third of our cohort with known PSC during pregnancy; and this subgroup had a poorer prognosis, which may be related to more advanced liver disease at time of pregnancy and/or a more severe disease phenotype.
Patients with PSC can develop worsening of their liver-related symptoms during pregnancy; however, risk factors for this and the long-term implications are not known. We identified that there is a significant risk of these symptoms in pregnancy, both before and after PSC has been diagnosed, particularly in patients with elevated alkaline phosphatase. Furthermore, our findings suggest that worsening symptoms during pregnancy may be associated with adverse long-term clinical outcomes of liver transplantation and death in patients with known PSC. This may be related to the presence of more advanced liver disease at time of pregnancy. This information can be used to counsel patients with PSC before conception and identify patients who need close follow-up after delivery.
Intrahepatic cholestasis of pregnancy is associated with increased risk of hepatobiliary disease and adverse fetal outcomes: A systematic review and meta-analysis
2023, iLIVER
The aim of this study was to review the literature and perform a meta-analysis to clarify the association between intrahepatic cholestasis of pregnancy and risks of long-term maternal hepatobiliary disease as well as adverse fetal outcomes including preterm birth, meconium-stained amniotic fluid, and stillbirth.
This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive literature search was performed using Cochrane, Embase, and PubMed databases to identify observational or cohort studies comparing pregnant women with intrahepatic cholestasis of pregnancy (ICP) to pregnant women without ICP. Data from the included studies were analyzed using the Review Manager 5.4.1 software.
The meta-analysis showed a significant association between ICP and the risk of hepatobiliary diseases (pooled risk ratio [RR]: 2.81, 95% confidence interval [CI]: 2.66–2.97, p < 0.00001), hepatitis C (HC): a significant association between ICP and risk of HC (pooled RR: 4.02, 95% CI: 3.12–5.19, p < 0.00001), meconium-stained amniotic fluid (MSAF): ICP was significantly associated with an increased risk of MSAF (pooled RR: 1.91, 95% CI: 1.65–2.21, p < 0.00001), and preterm birth: the meta-analysis demonstrated a significant association between ICP and preterm birth (pooled RR: 2.11, 95% CI: 2.01–2.21, p < 0.00001).
ICP demonstrated statistically significant associations with increased risks of hepatobiliary disease, HC, MSAF, and preterm birth.
Intrahepatic cholestasis of pregnancy: French College of Obstetricians and Gynecologists guidelines for clinical practice
2023, Gynecologie Obstetrique Fertilite et Senologie
Déterminer les stratégies permettant de réduire la morbidité maternelle et périnatale associée à la cholestase gravidique.
Méthodologie GRADE avec questions formulées sous le format PICO (Patients, Intervention, Comparison, Outcome) et critères de jugement définis a priori et classifiés selon leur importance. Recherche bibliographique extensive : Medline, Cochrane, EMBASE, Google Scholar. Analyse de la qualité de la preuve (élevée, modérée, basse, très basse) et formulation d’une recommandation : (i) forte ou (ii) faible ou (iii) absence de recommandation. Deux tours de relectures de type Delphi avec des relecteurs extérieurs ont été utilisés pour retenir les recommandations faisant consensus.
Parmi les 14 recommandations (issues de 12 questions PICO et d’une question sur la définition hors format PICO), 14 (100 %) ont fait l’objet d’un accord. Les données de la littérature n’ont pas permis d’émettre de recommandation pour deux questions. La cholestase gravidique est définie par la survenue d’un prurit évocateur (palmoplantaire, nocturne) associé à une anomalie biologique : élévation des acides biliaires > 10 μmol/L ou augmentation des alanines aminotransférases (ALAT) supérieurs à 2N après élimination des diagnostics différentiels. En l’absence de symptômes évocateurs d’un diagnostic différentiel, il est recommandé de ne pas réaliser de bilan complémentaire biologique ou échographique. Chez des femmes présentant une cholestase gravidique, il est recommandé d’administrer de l’acide ursodésoxycholique afin de réduire l’intensité du prurit maternel, d’améliorer le bilan biologique (acides biliaires totaux et ALAT) et de réduire la prématurité totale (Recommandations fortes. Qualité de la preuve modérée). Il est recommandé de ne pas administrer de la S-adénosyl-L-méthionine, de la dexaméthasone, de la gomme de guar ou du charbon activé dans le but de réduire l’intensité du prurit maternel (Recommandation forte. Qualité de la preuve basse) et les données de la littérature sont insuffisantes en nombre et en qualité pour émettre une recommandation quant à l’administration d’anti-histaminiques (Absence de recommandation. Qualité de la preuve basse). Il est recommandé de ne pas utiliser la rifampicine (Recommandation faible. Qualité de la preuve très basse) ni d’avoir recours à des échanges plasmatiques (Recommandation forte. Qualité de la preuve très basse) pour réduire le prurit maternel et la morbidité périnatale. Il est recommandé une surveillance biologique des acides biliaires et des transaminases, sans qu’une fréquence puisse être déterminée, pour réduire la morbi-mortalité périnatale (mort fœtale in utero [MFIU], prématurité) (Recommandation faible. Qualité de la preuve basse). Les données de la littérature sont insuffisantes en nombre et qualité pour émettre une recommandation quant à l’intérêt d’une surveillance par rythme cardiaque fœtal ou par échographie obstétricale pour réduire la morbidité périnatale (Absence de recommandation). Il est recommandé d’induire la naissance en cas de concentration d’acides biliaires ≥ 100 μmol/L à partir de 36 SA pour réduire la morbidité périnatale, en particulier la MFIU. En cas de concentration d’acides biliaires < 100 μmol/L, il est recommandé d’informer de la possibilité d’induire la naissance entre 37⁺⁰ –39⁺⁶ SA pour réduire la morbidité périnatale (Recommandation forte. Qualité de la preuve basse). Il est recommandé de contrôler la normalisation du bilan hépatique après l’accouchement avant de prescrire une contraception œstroprogestative idéalement faiblement dosée en œstrogènes (risque de récidive du prurit et de la cytolyse) (Recommandation faible. Qualité de la preuve très basse).
Même si la qualité de la preuve des études concernant la cholestase gravidique reste faible, il y a un fort consensus en France sur la façon de prendre en charge les femmes ayant une cholestase gravidique. Le traitement de référence de la cholestase gravidique est l’acide ursodésoxycholique.
To identify strategies for reducing neonatal and maternal morbidity associated with intrahepatic cholestasis pregnancy (ICP).
The quality of evidence of the literature was assessed following the GRADE methodology with questions formulated in the PICO format (Patients, Intervention, Comparison, Outcome) and outcomes defined a priori and classified according to their importance. An extensive bibliographic search was performed on PubMed, Cochrane, EMBASE and Google Scholar databases. The quality of the evidence was assessed (high, moderate, low, very low) and a (i) strong or (ii) weak recommendations or (iii) no recommendation were formulated. The recommendations were reviewed in two rounds with external reviewers (Delphi survey) to select the consensus recommendations.
Of the 14 questions (from 12 PICO questions and one definition question outside the PICO format), there was agreement between the working group and the external reviewers on 14 (100%). The level of evidence of the literature was insufficient to provide a recommendation on two questions. ICP is defined by the occurrence of suggestive pruritus (palmoplantar, nocturnal) associated with a total bile acid level > 10 μmol/L or an alanine transaminase level above 2N after ruling out differential diagnoses. In the absence of suggestive symptoms of a differential diagnosis, it is recommended not to carry out additional biological or ultrasound tests. In women with CIP, ursodeoxycholic acid is recommended to reduce the intensity of maternal pruritus (Strong recommendation. Quality of the evidence moderate) and to decrease the level of total bile acids and alanine transaminases. (Strong recommendation. Quality of the evidence moderate). S-adenosyl-methionine, dexamethasone, guar gum or activated charcoal should not be used to reduce the intensity of maternal pruritus (Strong recommendation. Quality of evidence low), and there is insufficient data to recommend the use of antihistamines (No recommendation. Quality of evidence low). Rifampicin (Weak recommendation. Very low quality of evidence) or plasma exchange (Strong recommendation. Very low quality of evidence) should not be used to reduce maternal pruritus and perinatal morbidity. Serum monitoring of bile acids is recommended to reduce perinatal morbidity and mortality (stillbirth, prematurity) (Low recommendation. Quality of the evidence low). The level of evidence is insufficient to determine whether fetal heart rate or fetal ultrasound monitoring are useful to reduce perinatal morbidity (No recommendation). Birth is recommended when bile acid level is above 99 μmol/L from 36 weeks gestation to reduce perinatal morbidity, in particular stillbirth. When bile acid level is above 99 μmol/L is below 100 μmol/L, women should be informed that induction of labor could be considered 37 and 39 weeks gestation to reduce perinatal morbidity. (Strong recommendation. Quality of evidence low). In postpartum, total bile acids and alanine transaminases level should be checked and normalized before prescribing estrogen-progestin contraception, ideally with a low estrogen dose (risk of recurrence of pruritus and cytolysis) (Low recommendation. Quality of evidence very low).
Although the quality of evidence regarding ICP gestational cholestasis remains low, there is a strong consensus in France, as shown by our Delphi study, on how to manage women with ICP. The reference first-line treatment is ursodeoxycholic acid.
Risk of stillbirth in United States patients with diagnosed intrahepatic cholestasis of pregnancy
2023, American Journal of Obstetrics and Gynecology
Intrahepatic cholestasis of pregnancy is associated with a 4- to 10-fold increase in the risk of stillbirth in the absence of intervention, leading to recommendations for antenatal assessment, ursodiol use, and often preterm or early term delivery.
This study aimed to determine whether current management strategies for intrahepatic cholestasis of pregnancy mitigate the elevated risk of stillbirth at a population level.
This was a retrospective cohort study using the 2015–2020 National Readmissions Database, an administrative database developed by the United States Agency for Healthcare Research and Quality. Our study identified delivery hospitalizations, gestational age at delivery, occurrence of intrahepatic cholestasis of pregnancy and stillbirth, and comorbid conditions using the International Classification of Diseases diagnosis and procedure codes. Moreover, this study compared the timing of delivery and stillbirth rates of pregnant patients with intrahepatic cholestasis of pregnancy vs those without intrahepatic cholestasis of pregnancy at the time of delivery hospitalization.
This study identified a cohort of 9,987,705 delivery hospitalizations in the National Readmissions Database, corresponding to a weighted national estimate of 18,609,207 births. Of these births, 152,040 (0.8%) were noted to have an intrahepatic cholestasis of pregnancy diagnosis. Patients with an intrahepatic cholestasis of pregnancy diagnosis were older, with small differences in comorbidities, such as a higher rate of gestational diabetes mellitus, than patients without an intrahepatic cholestasis of pregnancy diagnosis at delivery hospitalization. The overall rates of stillbirth were lower among those with intrahepatic cholestasis of pregnancy than among those without intrahepatic cholestasis of pregnancy (252 vs 386 per 100,000 deliveries; risk difference, 133 fewer per 100,000 deliveries; 95% confidence interval, 98–170), a finding that persisted after adjustment for insurance status, socioeconomic factors, and comorbid conditions (risk difference, 160 fewer stillbirths per 100,000 deliveries; 95% confidence interval, 127–194). Furthermore, although patients with intrahepatic cholestasis of pregnancy were more likely to deliver before term than those without intrahepatic cholestasis of pregnancy (30.1% vs 9.3%; P<.001), increased rates of stillbirth were not noted at any point after stratification of the cohort by gestational age at delivery.
Patients with intrahepatic cholestasis of pregnancy diagnosis codes delivered earlier than those without intrahepatic cholestasis of pregnancy diagnosis codes, but the percentage of births affected by stillbirth was lower, even when stratifying for gestational age at birth. These results may provide reassurance to patients receiving an intrahepatic cholestasis of pregnancy diagnosis that current management does mitigate stillbirth risk in intrahepatic cholestasis of pregnancy.
EASL Clinical Practice Guidelines on the management of liver diseases in pregnancy
2023, Journal of Hepatology
Liver diseases in pregnancy comprise both gestational liver disorders and acute and chronic hepatic disorders occurring coincidentally in pregnancy. Whether related to pregnancy or pre-existing, liver diseases in pregnancy are associated with a significant risk of maternal and fetal morbidity and mortality. Thus, the European Association for the Study of Liver Disease invited a panel of experts to develop clinical practice guidelines aimed at providing recommendations, based on the best available evidence, for the management of liver disease in pregnancy for hepatologists, gastroenterologists, obstetric physicians, general physicians, obstetricians, specialists in training and other healthcare professionals who provide care for this patient population.

View all citing articles on Scopus

: This article has an accompanying continuing medical education activity on page e13. Learning Objective: Upon completion of the CME activity, successful learners will be able to prescribe a medical treatment for intrahepatic cholestasis of pregnancy (ICP).

: Conflicts of interest The authors disclose no conflicts.

View full text

Original ResearchClinical—LiverEfficacy of Ursodeoxycholic Acid in Treating Intrahepatic Cholestasis of Pregnancy: A Meta-analysis

Background & Aims

Methods

Results

Conclusions

Section snippets

Patients and Methods

Studied Population

Discussion

Acknowledgments

J Chronic Dis

J Hepatol

J Gynecol Obstet Biol Reprod (Paris)

Obstet Gynecol Clin North Am

Control Clin Trials

Int J Gynaecol Obstet

J Hepatol

Eur J Obstet Gynecol Reprod Biol

Gastroenterology

Hepatology

J Hepatol

Int J Gynaecol Obstet

Intrahepatic cholestasis of pregnancy: a French prospective study

Hepatology

Review: intrahepatic cholestasisA puzzling disorder of pregnancy

J Gastroenterol Hepatol

Intrahepatic cholestasis of pregnancy

World J Gastroenterol

Prevalence of intrahepatic cholestasis of pregnancy in Chile

Ann Intern Med

The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population

J Perinatol

Obstetric cholestasis

RCOG

Consensus on the management of obstetric cholestasis: National UK survey

BJOG

Original Research
Clinical—Liver
Efficacy of Ursodeoxycholic Acid in Treating Intrahepatic Cholestasis of Pregnancy: A Meta-analysis