Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis.
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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, Kohari Katherine, Kondrackienė Jūratė, Koster Maria P H, Lee Richard H, Liu Xiaohua, Locatelli Anna, Macias Rocio I R, Madazli Riza, Majewska Agata, Maksym Kasia, Marathe Jessica A, Morton Adam, Oudijk Martijn A, Öztekin Deniz, Peek Michael J, Shennan Andrew H, Tribe Rachel M, Tripodi Valeria, Türk Özterlemez Naciye, Vasavan Tharni, Wong L F Audris, Yinon Yoav, Zhang Qianwen, Zloto Keren, Marschall Hanns-Ulrich, Thornton Jim, Chappell Lucy C, Williamson Catherine
Аннотация
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 We also included two unpublished cohort studies.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.