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Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses

Ovadia, Caroline; Seed, Paul T.; Sklavounos, Alexandros; Geenes, Victoria; Di Illio, Chiara; Chambers, Jenny; Kohari, Katherine; Bacq, Yannick; Bozkurt, Nuray; Brun-Furrer, Romana; Bull, Laura; Estiú, Maria C.; Grymowicz, Monika; Gunaydin, Berrin; Hague, William M.; Haslinger, Christian; Hu, Yayi; Kawakita, Tetsuya; Kebapcilar, Ayse G.; Kebapcilar, Levent; Kondrackienė, Jūratė; Koster, Maria P.H.; Kowalska-Kańka, Aneta; Kupčinskas, Limas; Lee, Richard H.; Locatelli, Anna; Macias, Rocio I.R.; Marschall, Hanns-Ulrich; Oudijk, Martijn A.; Raz, Yael; Rimon, Eli; Shan, Dan; Shao, Yong; Tribe, Rachel; Tripodi, Valeria; Yayla Abide, Cigdem; Yenidede, Ilter; Thornton, Jim G.; Chappell, Lucy C.; Williamson, Catherine


Caroline Ovadia

Paul T. Seed

Alexandros Sklavounos

Victoria Geenes

Chiara Di Illio

Jenny Chambers

Katherine Kohari

Yannick Bacq

Nuray Bozkurt

Romana Brun-Furrer

Laura Bull

Maria C. Estiú

Monika Grymowicz

Berrin Gunaydin

William M. Hague

Christian Haslinger

Yayi Hu

Tetsuya Kawakita

Ayse G. Kebapcilar

Levent Kebapcilar

Jūratė Kondrackienė

Maria P.H. Koster

Aneta Kowalska-Kańka

Limas Kupčinskas

Richard H. Lee

Anna Locatelli

Rocio I.R. Macias

Hanns-Ulrich Marschall

Martijn A. Oudijk

Yael Raz

Eli Rimon

Dan Shan

Yong Shao

Rachel Tribe

Valeria Tripodi

Cigdem Yayla Abide

Ilter Yenidede

Jim G. Thornton

Lucy C. Chappell

Catherine Williamson


Jim Thornton


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.

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 population-based 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.

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 165 136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·83%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0·32%) of 163 947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73–2·89]; I2=59·8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0·83 [95% CI 0·74–0·92]), but not alanine aminotransferase (ROC AUC 0·46 [0·35–0·57]). For singleton pregnancies, the prevalence of stillbirth was three (0·13%; 95% CI 0·02–0·38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 μmol/L versus four (0·28%; 0·08–0·72) of 1412 cases with total bile acids of 40–99 μmol/L (hazard ratio [HR] 2·35 [95% CI 0·52–10·50]; p=0·26), and versus 18 (3·44%; 2·05–5·37) of 524 cases for bile acids of 100 μmol/L or more (HR 30·50 [8·83–105·30]; p


Ovadia, C., Seed, P. T., Sklavounos, A., Geenes, V., Di Illio, C., Chambers, J., …Williamson, C. (2019). Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses. Lancet, 393(10174), 899-909.

Journal Article Type Article
Acceptance Date Feb 14, 2019
Online Publication Date Feb 14, 2019
Publication Date Mar 8, 2019
Deposit Date Feb 27, 2019
Publicly Available Date Feb 28, 2019
Journal The Lancet
Print ISSN 0140-6736
Electronic ISSN 1474-547X
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 393
Issue 10174
Pages 899-909
Public URL
Publisher URL


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