Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis,The Lancet Gastroenterology & Hepatology

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Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis
The Lancet Gastroenterology & Hepatology ( IF 35.7 ) Pub Date : 2021-04-27 , DOI: 10.1016/s2468-1253(21)00074-1
Caroline Ovadia ₁ , Jenna Sajous ₁ , Paul T Seed ₁ , Kajol Patel ₁ , Nicholas J Williamson ₁ , George Attilakos ₂ , Francesco Azzaroli ₃ , Yannick Bacq ₄ , Linoy Batsry ₅ , Kelsey Broom ₆ , Romana Brun-Furrer ₇ , Laura Bull ₈ , Jenny Chambers ₉ , Yue Cui ₁₀ , Min Ding ₁₀ , Peter H Dixon ₁ , Maria C Estiú ₁₁ , Fergus W Gardiner ₁₂ , Victoria Geenes ₁ , Monika Grymowicz ₁₃ , Berrin Günaydin ₁₄ , William M Hague ₁₅ , Christian Haslinger ₇ , Yayi Hu ₁₆ , Ugo Indraccolo ₁₇ , Alexander Juusela ₁₈ , Stefan C Kane ₁₉ , Ayse Kebapcilar ₂₀ , Levent Kebapcilar ₂₁ , Katherine Kohari ₂₂ , Jūratė Kondrackienė ₂₃ , Maria P H Koster ₂₄ , Richard H Lee ₂₅ , Xiaohua Liu ₂₆ , Anna Locatelli ₂₇ , Rocio I R Macias ₂₈ , Riza Madazli ₂₉ , Agata Majewska ₃₀ , Kasia Maksym ₂ , Jessica A Marathe ₃₁ , Adam Morton ₃₂ , Martijn A Oudijk ₃₃ , Deniz Öztekin ₃₄ , Michael J Peek ₃₅ , Andrew H Shennan ₁ , Rachel M Tribe ₁ , Valeria Tripodi ₃₆ , Naciye Türk Özterlemez ₁₄ , Tharni Vasavan ₁ , L F Audris Wong ₃₇ , Yoav Yinon ₅ , Qianwen Zhang ₁₆ , Keren Zloto ₅ , Hanns-Ulrich Marschall ₃₈ , Jim Thornton ₃₉ , Lucy C Chappell ₁ , Catherine Williamson ₁

Affiliation

Department of Women and Children's Health, King's College London, London, UK.
Department of Obstetrics and Gynaecology, University College London Hospitals NHS Foundation Trust, London, UK.
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
Department of Hepatology and Gastroenterology, University Hospital of Tours, Tours, France.
Department of Obstetrics and Gynecology, Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Bendigo Healthcare Group, Bendigo, VIC, Australia.
Department of Obstetrics, University Hospital Zurich, Zurich, Switzerland.
Department of Medicine and Institute for Human Genetics, University of California, San Francisco, CA, USA.
Women's Health Research Centre, Imperial College London, London, UK.
School of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Ramón Sardá Mother's and Children's Hospital, Buenos Aires, Argentina.
Royal Flying Doctor Service, Barton, ACT, Australia.
Department of Gynecological Endocrinology, Medical University of Warsaw, Warsaw, Poland.
Department of Anesthesiology and Reanimation, Gazi University School of Medicine, Ankara, Turkey.
Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.
Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China.
Maternal-Infantile Department, Complex Operative Unit of Obstetrics and Gynecology Alto Tevere Hospital of Città di Castello, Città di Castello, Italy.
Newark Beth Israel Medical Center, Newark, NJ, USA.
Department of Maternal-Fetal Medicine, Royal Women's Hospital, Parkville, VIC, Australia; Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC, Australia.
Department of Gynecology and Obstetrics, Selcuk University, Konya, Turkey.
Department of Internal Medicine, Selcuk University, Konya, Turkey.
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Center Rotterdam, Netherlands.
Department of Obstetrics and Gynecology, Keck School of Medicine University of Southern California, Los Angeles, CA, USA.
Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Obstetrics and Gynecology, University of Milano-Bicocca, Monza, Italy.
Department 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.
Department of Obstetrics and Gynecology, Istanbul University, Cerrahpaşa, Istanbul, Turkey.
First Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland.
Department of Cardiology, Royal Adelaide Hospital, Adelaide, SA, Australia.
Department of Obstetric Medicine, Mater Health Services Public Hospital, Brisbane, QLD, Australia.
Department of Obstetrics, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands.
Department of Obstetrics and Gynecology, İzmir Bakircay University, İzmir, Turkey.
ANU Medical School, College of Health and Medicine, The Australian National University, Canberra, ACT, Australia.
Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
Department of Women's and Newborn, Gold Coast University Hospital, Southport, QLD, Australia.
Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, Nottingham, UK.

Background

Ursodeoxycholic 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.

Methods

In 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.

Findings

The 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).

Interpretation

Ursodeoxycholic 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.

Funding

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

中文翻译：

熊去氧胆酸在妊娠期肝内胆汁淤积症中的应用：系统评价和个体参与者数据荟萃分析

背景

熊去氧胆酸通常用于治疗妊娠期肝内胆汁淤积症，但其最大的试验发现对复合结局（死产、早产和新生儿病房入院）的益处微乎其微。我们旨在检查熊去氧胆酸是否会影响特定的不良围产期结局。

方法

在这项系统评价和个体参与者数据元分析中，我们无语言限制地搜索了 PubMed、Web of Science、Embase、MEDLINE、CINAHL、Global Health、MIDIRS 和 Cochrane，以获取从数据库开始到 2020 年 1 月 1 日之间发表的相关文章，使用涉及妊娠肝内胆汁淤积症、熊去氧胆酸和围产期结局的搜索词。符合条件的研究有 30 名或更多研究参与者，并报告了至少一名患有妊娠期肝内胆汁淤积症和胆汁酸浓度为 40 μmol/L 或更高的个体。我们还纳入了两项未发表的队列研究。个体参与者数据是从选定研究的作者那里收集的。主要结果是死产的发生率，我们预计没有足够的数据来达到统计功效。所以，我们将死产和早产的复合作为主要的次要结局。使用多水平建模和调整胆汁酸浓度、产次和多胎妊娠进行混合效应荟萃分析。对所有研究和不同亚组进行了个体参与者数据分析，这些分析是通过将分析限制在仅随机对照试验、仅单胎妊娠或仅双臂研究而产生的。本研究在 PROSPERO 注册，CRD42019131495。它们是通过将分析限制在仅随机对照试验、仅单胎妊娠或仅双臂研究而产生的。本研究在 PROSPERO 注册，CRD42019131495。它们是通过将分析限制在仅随机对照试验、仅单胎妊娠或仅双臂研究而产生的。本研究在 PROSPERO 注册，CRD42019131495。

发现

我们联系了符合我们纳入标准的 85 项研究的作者。荟萃分析纳入了来自 34 项研究的 6974 名女性的个体参与者数据，其中 4726 人（67·8%）服用了熊去氧胆酸。在接受熊去氧胆酸治疗的妊娠期肝内胆汁淤积症女性中，5097 名胎儿中有 35 名（0·7%）发生死产，在未接受熊去氧胆酸治疗的妊娠期肝内胆汁淤积症女性中，2038 名胎儿中有 12 名（0·6%）发生死产（调整后）优势比 [aOR] 1·04, 95% CI 0·35–3·07；p=0·95)。仅考虑随机对照试验时，熊去氧胆酸治疗对死产发生率也没有影响（aOR 0·29，95% CI 0·04-2·42；p=0·25）。在所有研究中，熊去氧胆酸治疗对复合结局的发生率没有影响（aOR 1·28, 95% CI 0·86–1·91；p=0·22），