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

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 We also included two unpublished cohort studies.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.Caroline Ovadia, Jenna Sajous, Paul T Seed, Kajol Patel, Nicholas J Williamson, George Attilakos, Francesco Azzaroli, Yannick Bacq, Linoy Batsry, Kelsey Broom, Romana Brun-Furrer, Laura Bull, Jenny Chambers, Yue Cui, Min Ding, Peter H Dixon, Maria C Estiú, Fergus W Gardiner, Victoria Geenes, Monika Grymowicz, Berrin Günaydin, William M Hague, Christian Haslinger, Yayi Hu, Ugo Indraccolo, Alexander Juusela, Stefan C Kane, Ayse Kebapcilar, Levent Kebapcilar, Katherine Kohari, Jūratė Kondrackienė, Maria P H Koster, Richard H Lee, Xiaohua Liu, Anna Locatelli, Rocio I R Macias, Riza Madazli, Agata Majewska, Kasia Maksym, Jessica A Marathe, Adam Morton, Martijn A Oudijk, Deniz Öztekin, Michael J Peek, Andrew H Shennan, Rachel M Tribe, Valeria Tripodi, Naciye Türk Özterlemez, Tharni Vasavan, L F Audris Wong, Yoav Yinon, Qianwen Zhang, Keren Zloto, Hanns-Ulrich Marschall, Jim Thornton, Lucy C Chappell, Catherine Williamso

Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers

__Background__ Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth. __Methods__ We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and populationbased studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134. __Findings__ We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·91%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0·32%) of 163947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73–2·89]

Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease, characterized by maternal pruritus and raised serum bile acids. Our objectives were to describe the epidemiology and pregnancy complications associated with severe ICP and to test the hypothesis that adverse perinatal outcomes are increased in these women. A prospective population-based case-control study with national coverage was undertaken using the UK Obstetric Surveillance System (UKOSS). Control data for comparison were obtained from women with healthy pregnancy outcome through UKOSS (n = 2,232), St Mary's Maternity Information System (n = 554,319), and Office for National Statistics (n = 668,195). The main outcome measures investigated were preterm delivery, stillbirth, and neonatal unit admission. In all, 713 confirmed cases of severe ICP were identified, giving an estimated incidence of 9.2 per 10,000 maternities. Women with severe ICP and a singleton pregnancy (n = 669) had increased risks of preterm delivery (164/664; 25% versus 144/2200; 6.5%; adjusted odds ratio [OR] 5.39, 95% confidence interval [CI] 4.17 to 6.98), neonatal unit admission (80/654; 12% versus 123/2192; 5.6%; adjusted OR 2.68, 95% CI 1.97 to 3.65), and stillbirth (10/664; 1.5% versus 11/2205; 0.5%; adjusted OR 2.58, 95% CI 1.03 to 6.49) compared to controls. Seven of 10 stillbirths in ICP cases were associated with coexisting pregnancy complications. These differences remained significant against national data. Risks of preterm delivery, meconium-stained amniotic fluid, and stillbirth rose with increasing maternal serum bile acid concentrations.In the largest prospective cohort study in severe ICP to date, we demonstrate significant increased risks of adverse perinatal outcomes, including stillbirth. Our findings support the case for close antenatal monitoring of pregnancies affected by severe ICP

A placental phenotype for intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy specific liver disease associated with significant risk of fetal complications. It is hypothesised that the risk of adverse fetal outcomes relates to the toxic effects of bile acids, the levels of which are increased in both maternal and fetal serum. Human and rodent studies have shown that transplacental transfer of bile acids is impaired in ICP. Furthermore, the morphology of placentas from the rodent model of ICP is markedly abnormal, and is associated with increased expression of apoptotic markers and oxidative stress. Using placental tissue from ICP cases and normal pregnancies and cultured placental explant fragments we investigated the histological and molecular effects of cholestasis. We also examined the influence of ursodeoxycholic acid (UDCA) administration on these parameters. Here we report that ICP is associated with several morphological abnormalities of the placenta, including an increase in the number of syncytial knots, and that these can be reproduced in an in vitro (explant) model exposed to the bile acids taurocholic acid and taurochenodoexycholic acid. Furthermore, we demonstrate that ursodeoxycholic acid, a drug commonly used in the management of ICP, has a protective effect on placental tissue both in vivo and in vitro