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

• Autores: Ovadia, Caroline; Sajous, Jenna; Seed, Paul T.; Patel, Kajol; Williamson, Nicholas J.; Attilakos, George; Azzaroli, Francesco; Bacq, Yannick; Batsry, Linoy; Broom, Kelsey; Brun Furrer, Romana; Bull, Laura; Chambers, Jenny; Cui, Yue; Ding, Min; Dixon, Peter H.; Estiú, Maria C.; Gardiner, Fergus W.; Geenes, Victoria; Grymowicz, Monika; Günaydin, Berrin; Hague, William M; Haslinger, Christian; Hu, Yayi; Indraccolo, Ugo; Juusela, Alexander; Kane, Stefan C; Kebapcilar, Ayse; Kebapcilar, Levent; Tripodi, Valeria Paula
• Año de publicación: 2021
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: URSODEOXYCHOLIC ACID; INTRAHEPATIC CHOLESTASIS OF PREGNANCY; META-ANALYSIS
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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 We also included two unpublished cohort studies.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.
Fil: Ovadia, Caroline. King's College London; Reino Unido
Fil: Sajous, Jenna. King's College London; Reino Unido
Fil: Seed, Paul T.. King's College London; Reino Unido
Fil: Patel, Kajol. King's College London; Reino Unido
Fil: Williamson, Nicholas J.. King's College London; Reino Unido
Fil: Attilakos, George. University College London; Estados Unidos
Fil: Azzaroli, Francesco. Universidad de Bologna; Italia
Fil: Bacq, Yannick. Universite de Tours; Francia
Fil: Batsry, Linoy. Universitat Tel Aviv; Israel
Fil: Broom, Kelsey. Healthcare Group; Australia
Fil: Brun Furrer, Romana. University Hospital Zurich; Suiza
Fil: Bull, Laura. University of California; Estados Unidos
Fil: Chambers, Jenny. Imperial College London; Reino Unido
Fil: Cui, Yue. Chongqing Medical University; China
Fil: Ding, Min. Chongqing Medical University; China
Fil: Dixon, Peter H.. King's College London; Reino Unido
Fil: Estiú, Maria C.. Gobierno de la Ciudad Autonoma de Buenos Aires. Hospital Materno Infantil Ramon Sarda; Argentina
Fil: Gardiner, Fergus W.. Royal Flying Doctor Service; Australia
Fil: Geenes, Victoria. King's College London; Reino Unido
Fil: Grymowicz, Monika. Medical University of Warsaw; Polonia
Fil: Günaydin, Berrin. Gazi University School of Medicine; Turquía
Fil: Hague, William M. University of Adelaide; Australia
Fil: Haslinger, Christian. University Hospital Zurich; Suiza
Fil: Hu, Yayi. Sichuan University; China
Fil: Indraccolo, Ugo. Alto Tevere Hospital of Città di Castello; Italia
Fil: Juusela, Alexander. Newark Beth Israel Medical Center; Estados Unidos
Fil: Kane, Stefan C. Royal Women's Hospital; Australia. University of Melbourne; Australia
Fil: Kebapcilar, Ayse. Selcuk University; Turquía
Fil: Kebapcilar, Levent. Selcuk University; Turquía
Fil: Tripodi, Valeria Paula. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina