Evidence map›Paper›PMID 33915090›Full record

SynthesisThe lancet. Gastroenterology & hepatology2021

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis.

Caroline Ovadia, Jenna Sajous, Paul T Seed, Kajol Patel, Nicholas J Williamson, George Attilakos, Francesco Azzaroli, Yannick Bacq, Linoy Batsry, Kelsey Broom and 47 more

Open access · hybridAbstract readMeta-AnalysisSystematic Review
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in The lancet. Gastroenterology & hepatology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers, 4 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
78citing papers in PubMed, 4 pooled it
8.9field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

78 citing papers in PubMed, 4 syntheses or guidelines pooled it, 142 citations in OpenAlex.

  1. FIGO guideline on liver disease and pregnancy.International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics · 2025
    Guideline
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  13. Liver Conditions Specific to Pregnancy: Optimizing Management and Outcomes.The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology · 2026
    Review
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18 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

57 authors at 20 institutions in 15 countries.

Caroline OvadiaDepartment of Women and Children's Health, King's College London, London, UK.
Jenna SajousDepartment of Women and Children's Health, King's College London, London, UK.
Paul T SeedDepartment of Women and Children's Health, King's College London, London, UK.
Kajol PatelDepartment of Women and Children's Health, King's College London, London, UK.
Nicholas J WilliamsonDepartment of Women and Children's Health, King's College London, London, UK.
George AttilakosDepartment of Obstetrics and Gynaecology, University College London Hospitals NHS Foundation Trust, London, UK.
Francesco AzzaroliDepartment of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
Yannick BacqDepartment of Hepatology and Gastroenterology, University Hospital of Tours, Tours, France.
Linoy BatsryDepartment of Obstetrics and Gynecology, Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Kelsey BroomBendigo Healthcare Group, Bendigo, VIC, Australia.
Romana Brun-FurrerDepartment of Obstetrics, University Hospital Zurich, Zurich, Switzerland.
Laura BullDepartment of Medicine and Institute for Human Genetics, University of California, San Francisco, CA, USA.
Jenny ChambersWomen's Health Research Centre, Imperial College London, London, UK.
Yue CuiSchool of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Min DingSchool of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Peter H DixonDepartment of Women and Children's Health, King's College London, London, UK.
Maria C EstiúRamón Sardá Mother's and Children's Hospital, Buenos Aires, Argentina.
Fergus W GardinerRoyal Flying Doctor Service, Barton, ACT, Australia.
Victoria GeenesDepartment of Women and Children's Health, King's College London, London, UK.
Monika GrymowiczDepartment of Gynecological Endocrinology, Medical University of Warsaw, Warsaw, Poland.
Berrin GünaydinDepartment of Anesthesiology and Reanimation, Gazi University School of Medicine, Ankara, Turkey.
William M HagueRobinson Research Institute, University of Adelaide, Adelaide, SA, Australia.
Christian HaslingerDepartment of Obstetrics, University Hospital Zurich, Zurich, Switzerland.
Yayi HuDepartment of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China.
Ugo IndraccoloMaternal-Infantile Department, Complex Operative Unit of Obstetrics and Gynecology Alto Tevere Hospital of Città di Castello, Città di Castello, Italy.
Alexander JuuselaNewark Beth Israel Medical Center, Newark, NJ, USA.
Stefan C KaneDepartment of Maternal-Fetal Medicine, Royal Women's Hospital, Parkville, VIC, Australia; Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC, Australia.
Ayse KebapcilarDepartment of Gynecology and Obstetrics, Selcuk University, Konya, Turkey.
Levent KebapcilarDepartment of Internal Medicine, Selcuk University, Konya, Turkey.
Katherine KohariDepartment of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
Jūratė KondrackienėDepartment of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
Maria P H KosterDepartment of Obstetrics and Gynaecology, Erasmus MC, University Medical Center Rotterdam, Netherlands.
Richard H LeeDepartment of Obstetrics and Gynecology, Keck School of Medicine University of Southern California, Los Angeles, CA, USA.
Xiaohua LiuShanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
Anna LocatelliDepartment of Obstetrics and Gynecology, University of Milano-Bicocca, Monza, Italy.
Rocio I R MaciasDepartment of Physiology and Pharmacology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institute of Biomedical Research of Salamanca, University of Salamanca, Salamanca, Spain.
Riza MadazliDepartment of Obstetrics and Gynecology, Istanbul University, Cerrahpaşa, Istanbul, Turkey.
Agata MajewskaFirst Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland.
Kasia MaksymDepartment of Obstetrics and Gynaecology, University College London Hospitals NHS Foundation Trust, London, UK.
Jessica A MaratheDepartment of Cardiology, Royal Adelaide Hospital, Adelaide, SA, Australia.
Adam MortonDepartment of Obstetric Medicine, Mater Health Services Public Hospital, Brisbane, QLD, Australia.
Martijn A OudijkDepartment of Obstetrics, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands.
Deniz ÖztekinDepartment of Obstetrics and Gynecology, İzmir Bakircay University, İzmir, Turkey.
Michael J PeekANU Medical School, College of Health and Medicine, The Australian National University, Canberra, ACT, Australia.
Andrew H ShennanDepartment of Women and Children's Health, King's College London, London, UK.
Rachel M TribeDepartment of Women and Children's Health, King's College London, London, UK.
Valeria TripodiFacultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
Naciye Türk ÖzterlemezDepartment of Anesthesiology and Reanimation, Gazi University School of Medicine, Ankara, Turkey.
Tharni VasavanDepartment of Women and Children's Health, King's College London, London, UK.
L F Audris WongDepartment of Women's and Newborn, Gold Coast University Hospital, Southport, QLD, Australia.
Yoav YinonDepartment of Obstetrics and Gynecology, Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Qianwen ZhangDepartment of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China.
Keren ZlotoDepartment of Obstetrics and Gynecology, Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Hanns-Ulrich MarschallDepartment of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
Jim ThorntonDivision of Child Health, Obstetrics and Gynaecology, University of Nottingham, Nottingham, UK.
Lucy C ChappellDepartment of Women and Children's Health, King's College London, London, UK.
Catherine WilliamsonDepartment of Women and Children's Health, King's College London, London, UK. Electronic address: catherine.williamson@kcl.ac.uk.
King's College London · GBChongqing Medical University · CNGazi University · TRMedical University of Warsaw · PLSelçuk University · TRSichuan University · CNTel Aviv University · ILUniversity College London · GBUniversity Hospital of Zurich · CHAustralian National University · AUBakırçay ÜniversitesiBendigo Health · AUCentre Hospitalier Universitaire de Tours · FRCittà di Castello Hospital · ITErasmus MC · NLGold Coast Hospital · AUHospital Ramos Mejía · ARImperial College London · GBIstanbul University-Cerrahpaşa · TRLithuanian University of Health Sciences · LT

Funding

Yale Clinical and Translational Science Award (U Component)UL1TR001863 · NCATS · YALE UNIVERSITY · PI John H. Krystal, LUCILA OHNO-MACHADO · 2016 to 2026
$102.9M
Department of HealthNCATS NIH HHS UL1 TR001863Wellcome Trust 092993/Z/10/Z
6 · The paper itself

Abstract

backgroundUrsodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes.

methodsIn this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 μmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495.

findingsThe authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35-3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04-2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86-1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39-0·91; p=0·016).

interpretationUrsodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment.

fundingTommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research.

Indexed as

Cholagogues and CholereticsCholestasis, IntrahepaticFemaleHumansPregnancyPregnancy ComplicationsUrsodeoxycholic AcidCholagogues and CholereticsUrsodeoxycholic Acid

Identifiers

PMID33915090
PMCPMC8192305
OpenAlexW3158941524

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.