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

Abstract

Summary 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 We also included two unpublished cohort studies.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 consideri...

The impact of assisted reproductive technology in twin pregnancies complicated by intrahepatic cholestasis: a five-year retrospective study

“…Another multicenter prospective RCT found that compared with placebo, UDCA could not reduce the incidence of stillbirth, preterm delivery, neonatal hospitalization, and other adverse outcomes in patients with ICP, suggesting that the routine usage of UDCA for women with mild ICP should be reassessed [ 13 ]. The latest meta-analysis including a total of 34 studies by Ovadia and colleagues shows that the stillbirth rate is approximately 0.7% in ICP patients who underwent UDCA, concluding that UDCA has no significant effect on the prevalence of stillbirth, but it has the opposite result of a lower still-birth rate (0.2%) when considering only randomized controlled trials [ 14 ]. Our study only included women who had taken UDCA when diagnosed with ICP, almost 82% of them plus taking SAMe, and 64% triply using cholestyramine, but subgroup analysis showed no differences in serum TBA levels and stillbirth rate.…”

“…Even though medication helps improve laboratory abnormalities, it is still uncertain whether it could reduce adverse perinatal outcomes [ 13 , 14 ], so someone begins to question aggressive UDCA usage for women with mild TBA levels [ 15 , 16 ] or try to find more predictable indicators for adverse perinatal outcomes in ICP [ 11 ]. The varied incidence of ICP is 0.3%–5.6% among pregnant women, but it could be 20.9% ~ 24.6% during twin pregnancies because ART has been widely applied in infertile women [ 17 – 19 ].…”

Intrahepatic Cholestasis of Pregnancy

“…1 is based on the RCOG Green-top Guideline No. 43 from 2011 which is continually updated according to the most recent findings (see also Mitchell et al, 2021 78 and Ovadia et al 2021 79 ). When this article went to press, the RCOG had not yet updated its recommendations.…”

“…In zwei weiteren Metaanalysen konnte ebenfalls eine Verringerung der Frühgeburtsrate beschrieben werden 65 , 79 .…”

“…1 basiert auf der RCOG Green-top Guideline No. 43. aus dem Jahr 2011 und wird fortlaufend entsprechend den aktuellen Erkenntnissen angepasst, siehe auch dazu Mitchell et al, 2021 78 und Ovadia et al 2021 79 . Bei Drucklegung dieses Artikels hat die RCOG die Empfehlungen überarbeitet.…”