Rifampicin in the treatment of severe intrahepatic cholestasis of pregnancy

doi:10.1016/j.ejogrb.2015.03.020

European Journal of Obstetrics & Gynecology and Reproductive Biology

Volume 189, June 2015, Pages 59-63

https://doi.org/10.1016/j.ejogrb.2015.03.020 Get rights and content

Abstract

Objective

To describe the use of combined ursodeoxycholic acid (UDCA) and rifampicin treatment in intrahepatic cholestasis of pregnancy (ICP).

Study design

A questionnaire survey of 27 women with 28 affected pregnancies identified via the UK and International Obstetric Medicine forum. The clinical case notes of women with ICP treated with combined UDCA and rifampicin therapy were reviewed, and data regarding maternal and perinatal outcomes extracted.

Results

Serum bile acids remained high whilst taking UDCA as monotherapy. In 14 pregnancies (54%) serum bile acids decreased following the introduction of rifampicin. In 10 pregnancies (38%), there was a 50% reduction in serum bile acids. There were no adverse effects reported with either drug.

Conclusions

This is the first report of the use of rifampicin in ICP. The data suggest that combined treatment with UDCA and rifampicin is an effective way of treating women with severe ICP who do not respond to treatment with UDCA alone.

Introduction

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease, associated with an increased risk of adverse fetal outcomes, including preterm delivery, meconium staining of the amniotic fluid and stillbirth [1], [2]. It is characterised by maternal pruritus and elevated transaminases and serum bile acids. The most sensitive and specific biochemical marker for the diagnosis and monitoring of ICP is the concentration of serum bile acids. Recent studies have shown an increased risk of adverse perinatal outcomes in women with severe ICP (i.e. in those with serum bile acids >40 μmol/L) [1], [2]. ICP is commonly treated with ursodeoxycholic acid (UDCA), which has been shown to improve pruritus and serum biochemistry, including serum bile acid levels [3], [4], [5]. The mechanisms of action of UDCA are not fully understood, but are proposed to include improved bile acid transport and detoxification [6]. Evidence from in vitro studies of the developing fetal heart and the placenta suggest that UDCA may also have a direct protective effect on the fetal compartment in ICP [7]. However, not all women treated with UDCA have a biochemical response or an improvement in symptoms.

Rifampicin has been used in the treatment of several cholestatic liver diseases. In primary biliary cirrhosis it has been shown to reduce bilirubin, enhance hepatic efflux of organic anions, including serum bile acids, and improve pruritus. The mechanisms of its action in such diseases are complementary to those of UDCA, and include enhanced bile acid detoxification and elimination [6]. Combination therapy with rifampicin and UDCA might therefore be more effective than UDCA treatment alone, but there have been no reports of the use of rifampicin in ICP. The aim of this study was to evaluate the impact of the addition of rifampicin to UDCA in the treatment of ICP.

Section snippets

Materials and methods

Women diagnosed with ICP and treated with a combination of ursodeoxycholic acid (UDCA) and rifampicin were identified via the UK and international Obstetric Medicine Discussion Forum, an online organisation for obstetricians and physicians with a specialist interest in Obstetric Medicine. Between 2009 and 2012 consultants with an interest in maternal medicine were asked to submit the details of any woman in their care with severe ICP treated with these drugs. ICP was diagnosed in women

Results

Twenty-eight ICP pregnancies treated with both UDCA and rifampicin were identified in twenty-seven women (one woman had two pregnancies during the study period). Two pregnancies were excluded from subsequent analysis as rifampicin had been started before UDCA, based on the woman's previous history of severe ICP responding to rifampicin (see Table 1 and supplementary Figure 1). Of the remaining 26 pregnancies, two (8%) were twin gestations. 14 (54%) of the women had a previous history of ICP,

Comment

This is the first report of the use of combined UDCA and rifampicin treatment in ICP. This study shows that rifampicin may be a useful adjunct to treatment in pregnant women with increasing serum bile acids despite maximal UDCA therapy. Following the addition of rifampicin, over half of women had some improvement in bile acids, and in 38% of women there was a reduction of greater than 50%. There were no adverse effects reported from either treatment and there were no stillbirths.

This study is

Conflict of interest

The authors have no conflict of interest to declare.

Role of funding source

This study was supported by the National Institute for Health Research (NIHR) Biomedical Research Centres based at Kings College London (grant number: guysbrc-2012-1) and Imperial College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health NIHR or the Department of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Acknowledgements

Paul Seed for help with statistical analysis.

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Intrahepatic cholestasis of pregnancy: French College of Obstetricians and Gynecologists guidelines for clinical practice
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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.
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Some previous studies supported that rifampicin was an effective treatment for benign intrahepatic cholestasis. However, the efficacy and safety of rifampicin remain unclear. Therefore, this study aimed to evaluate its efficacy and safety on benign intrahepatic cholestasis.
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A total of 17 rifampicin-treated patients were enrolled in the study from January 2019 to January 2021. Among them, 14 patients (82%) improved, with significantly decreased TBIL, DBIL, and TBA levels after 3 weeks of treatment (all P < 0.05), whereas the remaining 3 had no improvement. Moreover, GGT levels of the former were significantly lower than those of the latter (34 (12–227) U/L vs. 244 (76–293) U/L, P = 0.023) at baseline. No severe adverse effect was observed during treatment.
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Citation Excerpt :
UDCA also reduces meconium-stained amniotic fluid.73,79,80 Rifampicin, when used in combination with UDCA treatment, can cause a reduction in pruritus and serum bile acid concentration.80 Rifampicin has been shown to improve cholestatic pruritus in nonpregnant individuals.81
The liver disorders unique to pregnancy include hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, acute fatty liver of pregnancy, and preeclampsia-associated hepatic impairment, specifically hemolysis, elevated liver enzymes, and low platelet count syndrome (HELLP). Their importance lies in the significant maternal and fetal/neonatal morbidity and mortality. Expeditious diagnosis and clinical evaluation is critical to ensure timely, appropriate care and minimize risks to the pregnant woman and her fetus/baby. A multidisciplinary approach is essential, including midwives, maternal-fetal-medicine specialists, anesthetists, neonatologists, and hepatologists.
Approach to the patient with cholestasis and jaundice syndrome. Joint AMH, AMG, and AMEG scientific position statement
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El término colestasis se refiere a la retención de ácidos biliares ya sea dentro del hepatocito o en los ductos biliares de cualquier calibre. Por laboratorio, se define por la elevación de fosfatasa alcalina arriba de 1.67 veces su valor normal. Las enfermedades colestásicas pueden asociarse a un proceso inflamatorio de la glándula hepática que provoca destrucción de los hepatocitos (hepatitis), a ictericia (coloración amarillenta de piel y mucosas asociada a elevación en niveles séricos de bilirrubinas) o ambas, aunque estos tres conceptos no deben considerarse sinónimos. Los padecimientos colestásicos pueden clasificarse como intra o extrahepáticos dependiendo de su etiología, y esto es importante para elegir los estudios diagnósticos adecuados y la terapéutica indicada en cada uno de los casos. Una historia clínica completa, aunada a exploración física exhaustiva y estudios iniciales básicos como el ultrasonido hepático y las pruebas de funcionamiento del hígado, pueden ayudar al clínico a decidir el camino a seguir al enfrentarse al paciente con colestasis. La Asociación Mexicana de Hepatología, la Asociación Mexicana de Gastroenterología y la Asociación Mexicana de Endoscopia Gastrointestinal decidieron trabajar en el primer posicionamiento científico mexicano sobre este tema.
The term cholestasis refers to bile acid retention, whether within the hepatocyte or in the bile ducts of any caliber. Biochemically, it is defined by a level of alkaline phosphatase that is 1.67-times higher than the upper limit of normal. Cholestatic diseases can be associated with an inflammatory process of the liver that destroys hepatocytes (hepatitis), with jaundice (yellowing of the skin and mucus membranes, associated with elevated serum bilirubin levels), or with both, albeit the three concepts should not be considered synonymous. Cholestatic diseases can be classified as intrahepatic or extrahepatic, depending on their etiology. Knowing the cause of the condition is important for choosing the adequate diagnostic studies and appropriate treatment in each case. A complete medical history, together with a thorough physical examination and basic initial studies, such as liver ultrasound and liver function tests, aid the clinician in deciding which path to follow, when managing the patient with cholestasis. In a joint effort, the Asociación Mexicana de Hepatología (AMH), the Asociación Mexicana de Gastroenterología (AMG) and the Asociación Mexicana de Endoscopia Gastrointestinal (AMEG) developed the first Mexican scientific position statement on said theme.
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Rifampicin in the treatment of severe intrahepatic cholestasis of pregnancy

Abstract

Objective

Study design

Results

Conclusions

Introduction

Section snippets

Materials and methods

Results

Comment

Conflict of interest

Role of funding source

Acknowledgements

Gastroenterology

Placenta

Lancet

Gastroenterology

Gastroenterology

Gastroenterology

Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study

Hepatology