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

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; Tharni Vasavan; Lucy C Chappell; Catherine Williamson

doi:10.1016/S2468-1253(21)00074-1

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

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 GrymowiczBerrin 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, Tharni Vasavan, Lucy C Chappell, Catherine Williamson

Women & Children's Health

Research output: Contribution to journal › Article › peer-review

74 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	547-558
Number of pages	12
Journal	The Lancet Gastroenterology & Hepatology
Volume	6
Issue number	7
Early online date	26 Apr 2021
DOIs	https://doi.org/10.1016/S2468-1253(21)00074-1
Publication status	Published - Jul 2021

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10.1016/S2468-1253(21)00074-1

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Ovadia, C., Sajous, J., Seed, P. T., Patel, K., Williamson, N. J., Attilakos, G., Azzaroli, F., Bacq, Y., Batsry, L., Broom, K., Brun-Furrer, R., Bull, L., Chambers, J., Cui, Y., Ding, M., Dixon, P. H., Estiú, M. C., Gardiner, F. W., Geenes, V., ... Williamson, C. (2021). Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis. The Lancet Gastroenterology & Hepatology, 6(7), 547-558. https://doi.org/10.1016/S2468-1253(21)00074-1

@article{3b8a33c4d9264bb19a1835c76411d542,

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

abstract = "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.",

author = "Caroline Ovadia and Jenna Sajous and Seed, {Paul T} and Kajol Patel and Williamson, {Nicholas J} and George Attilakos and Francesco Azzaroli and Yannick Bacq and Linoy Batsry and Kelsey Broom and Romana Brun-Furrer and Laura Bull and Jenny Chambers and Yue Cui and Min Ding and Dixon, {Peter H} and Esti{\'u}, {Maria C} and Gardiner, {Fergus W} and Victoria Geenes and Monika Grymowicz and Berrin G{\"u}naydin and Hague, {William M} and Christian Haslinger and Yayi Hu and Ugo Indraccolo and Alexander Juusela and Kane, {Stefan C} and Ayse Kebapcilar and Levent Kebapcilar and Katherine Kohari and Jūratė Kondrackienė and Koster, {Maria P H} and Lee, {Richard H} and Xiaohua Liu and Anna Locatelli and Macias, {Rocio I R} and Riza Madazli and Agata Majewska and Kasia Maksym and Marathe, {Jessica A} and Adam Morton and Oudijk, {Martijn A} and Deniz {\"O}ztekin and Peek, {Michael J} and Shennan, {Andrew H} and Tribe, {Rachel M} and Valeria Tripodi and Tharni Vasavan and Chappell, {Lucy C} and Catherine Williamson",

note = "Funding Information: This study was funded by Tommy's (registered charity number 1060508), the Wellcome Trust (092993/Z/10/Z), ICP Support, and the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' National Health Service Foundation Trust and King's College London (IS-BRC-1215–20006). CW is supported by a NIHR Senior Investigator Award. PTS is partly funded by NIHR Collaboration for Leadership in Applied Health Research and Care South London. The views expressed in this Article are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health. We thank Ge Han for translating Chinese language manuscripts. Publisher Copyright: {\textcopyright} 2021 The Authors(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = jul,

doi = "10.1016/S2468-1253(21)00074-1",

language = "English",

volume = "6",

pages = "547--558",

journal = "The Lancet Gastroenterology & Hepatology",

issn = "2468-1253",

publisher = "Elsevier",

number = "7",

}

Ovadia, C , Sajous, J , Seed, PT, Patel, K, Williamson, NJ, Attilakos, G, Azzaroli, F, Bacq, Y, Batsry, L, Broom, K, Brun-Furrer, R, Bull, L, Chambers, J, Cui, Y, Ding, M, Dixon, PH, Estiú, MC, Gardiner, FW, Geenes, V, Grymowicz, M, Günaydin, B, Hague, WM, Haslinger, C, Hu, Y, Indraccolo, U, Juusela, A, Kane, SC, Kebapcilar, A, Kebapcilar, L, Kohari, K, Kondrackienė, J, Koster, MPH, Lee, RH, Liu, X, Locatelli, A, Macias, RIR, Madazli, R, Majewska, A, Maksym, K, Marathe, JA, Morton, A, Oudijk, MA, Öztekin, D, Peek, MJ, Shennan, AH , Tribe, RM, Tripodi, V, Vasavan, T , Chappell, LC & Williamson, C 2021, 'Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis', The Lancet Gastroenterology & Hepatology, vol. 6, no. 7, pp. 547-558. https://doi.org/10.1016/S2468-1253(21)00074-1

TY - JOUR

T1 - Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy

T2 - a systematic review and individual participant data meta-analysis

AU - Ovadia, Caroline

AU - Sajous, Jenna

AU - Seed, Paul T

AU - Patel, Kajol

AU - Williamson, Nicholas J

AU - Attilakos, George

AU - Azzaroli, Francesco

AU - Bacq, Yannick

AU - Batsry, Linoy

AU - Broom, Kelsey

AU - Brun-Furrer, Romana

AU - Bull, Laura

AU - Chambers, Jenny

AU - Cui, Yue

AU - Ding, Min

AU - Dixon, Peter H

AU - Estiú, Maria C

AU - Gardiner, Fergus W

AU - Geenes, Victoria

AU - Grymowicz, Monika

AU - Günaydin, Berrin

AU - Hague, William M

AU - Haslinger, Christian

AU - Hu, Yayi

AU - Indraccolo, Ugo

AU - Juusela, Alexander

AU - Kane, Stefan C

AU - Kebapcilar, Ayse

AU - Kebapcilar, Levent

AU - Kohari, Katherine

AU - Kondrackienė, Jūratė

AU - Koster, Maria P H

AU - Lee, Richard H

AU - Liu, Xiaohua

AU - Locatelli, Anna

AU - Macias, Rocio I R

AU - Madazli, Riza

AU - Majewska, Agata

AU - Maksym, Kasia

AU - Marathe, Jessica A

AU - Morton, Adam

AU - Oudijk, Martijn A

AU - Öztekin, Deniz

AU - Peek, Michael J

AU - Shennan, Andrew H

AU - Tribe, Rachel M

AU - Tripodi, Valeria

AU - Vasavan, Tharni

AU - Chappell, Lucy C

AU - Williamson, Catherine

N1 - Funding Information: This study was funded by Tommy's (registered charity number 1060508), the Wellcome Trust (092993/Z/10/Z), ICP Support, and the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' National Health Service Foundation Trust and King's College London (IS-BRC-1215–20006). CW is supported by a NIHR Senior Investigator Award. PTS is partly funded by NIHR Collaboration for Leadership in Applied Health Research and Care South London. The views expressed in this Article are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health. We thank Ge Han for translating Chinese language manuscripts. Publisher Copyright: © 2021 The Authors(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/7

Y1 - 2021/7

N2 - 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.

AB - 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.

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DO - 10.1016/S2468-1253(21)00074-1

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SN - 2468-1253

VL - 6

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JO - The Lancet Gastroenterology & Hepatology

JF - The Lancet Gastroenterology & Hepatology

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ER -

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

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