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DOI: 10.1055/a-2483-5910
Adverse Outcomes Associated with Progressive Intrahepatic Cholestasis of Pregnancy
Funding M.R.S. is supported by NIH T32 HD007203-42 grant. Otherwise, no funding sources were utilized for this study.

Abstract
Objective
This study aimed to assess the association between increasing bile acid levels in pregnancies with cholestasis and adverse outcomes.
Study Design
This is a retrospective cohort study of singleton, non-anomalous gestations complicated by cholestasis delivered at a single academic medical center from 2005 to 2019. We compared rates of adverse outcomes in pregnancies complicated by mild cholestasis (initial total bile acid [TBA] <40 μmol/L and peak TBA <40 μmol/L), progressive cholestasis (initial TBA <40 μmol/L and peak TBA ≥40 μmol/L), and severe cholestasis (initial TBA ≥40 μmol/L). Our primary outcome was a composite adverse outcome including spontaneous preterm labor and delivery, umbilical artery pH <7.20, 5-minute Apgar <7, cesarean delivery for nonreassuring fetal heart rate tracing, meconium-stained amniotic fluid, and neonatal intensive care unit (NICU) admission. Analyses were performed using mild cholestasis as the base comparator and a second analysis using severe cholestasis as the base comparator.
Results
Of the 1,182 pregnancies complicated by cholestasis, 732 (61.9%) had mild cholestasis, 78 (6.6%) had progressive cholestasis, and 372 (31.5%) had severe cholestasis. After adjusting for confounders including gestational age at diagnosis and using mild cholestasis as the base comparator, both progressive and severe cholestasis were associated with the composite adverse outcome (progressive intrahepatic cholestasis of pregnancy [ICP], OR = 1.70; 95% CI: 1.04–2.78 and severe ICP, OR = 1.60; 95% CI: 1.24–2.06). When using progressive cholestasis as the base comparator, there were no statistically significant differences in the primary or secondary outcomes between progressive cholestasis and severe cholestasis.
Conclusion
This study highlights the significance of monitoring peak bile acid levels and that some cases of cholestasis may progress in pregnancy and the adverse associations are better reflected by the peak TBA level and not the cholestasis severity at initial diagnosis.
Key Points
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Outcomes with worsening cholestasis severity (progressive) are unknown.
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Retrospective study comparing mild to progressive to severe cholestasis.
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Progressive cholestasis outcomes are more similar to severe cholestasis.
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Clinical utility of trending bile acids warrants further study.
Keywords
bile acids - cholestasis severity - hepatobiliary disease - intrahepatic cholestasis - preterm birthPublication History
Received: 23 September 2024
Accepted: 22 November 2024
Accepted Manuscript online:
26 November 2024
Article published online:
24 December 2024
© 2024. Thieme. All rights reserved.
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References
- 1 Pataia V, Dixon PH, Williamson C. Pregnancy and bile acid disorders. Am J Physiol Gastrointest Liver Physiol 2017; 313 (01) G1-G6
- 2 Bacq Y, Sapey T, Bréchot MC, Pierre F, Fignon A, Dubois F. Intrahepatic cholestasis of pregnancy: a French prospective study. Hepatology 1997; 26 (02) 358-364
- 3 Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol 2009; 15 (17) 2049-2066
- 4 Lee RH, Goodwin TM, Greenspoon J, Incerpi M. The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. J Perinatol 2006; 26 (09) 527-532
- 5 Reyes H, Gonzalez MC, Ribalta J. et al. Prevalence of intrahepatic cholestasis of pregnancy in Chile. Ann Intern Med 1978; 88 (04) 487-493
- 6 Brouwers L, Koster MPH, Page-Christiaens GC. et al. Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acid levels. Am J Obstet Gynecol 2015; 212 (01) 100.e1-100.e7
- 7 Kawakita T, Parikh LI, Ramsey PS. et al. Predictors of adverse neonatal outcomes in intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol 2015; 213 (04) 570.e1-570.e8
- 8 Rioseco AJ, Ivankovic MB, Manzur A. et al. Intrahepatic cholestasis of pregnancy: a retrospective case-control study of perinatal outcome. Am J Obstet Gynecol 1994; 170 (03) 890-895
- 9 Ovadia C, Seed PT, Sklavounos A. et al. Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses. Lancet 2019; 393 (10174): 899-909
- 10 Sarker M, Zamudio AR, DeBolt C, Ferrara L. Beyond stillbirth: association of intrahepatic cholestasis of pregnancy severity and adverse outcomes. Am J Obstet Gynecol 2022; 227 (03) 517
- 11 Sarker M, Getrajdman C, Warren L, Ferrara L. Severe fat-soluble vitamin deficiency suspected secondary to intrahepatic cholestasis of pregnancy: a case report. Case Rep Womens Health 2022; 35: e00430
- 12 Sarker MR, Warren L, Getrajdman C, Ferrara L. Severe cholestasis-associated coagulopathy diagnosed by routine screening: a case report. AJOG Glob Rep 2023; 3 (03) 100235
- 13 Mahle AC, Morris BD, Frazer Z, Novak C. Severe vitamin deficiencies in pregnancy complicated by progressive familial intrahepatic cholestasis. BMJ Case Rep 2021; 14 (03) 240248
- 14 Di Mascio D, Quist-Nelson J, Riegel M. et al. Perinatal death by bile acid levels in intrahepatic cholestasis of pregnancy: a systematic review. J Matern Fetal Neonatal Med 2021; 34 (21) 3614-3622
- 15 Cui D, Zhong Y, Zhang L, Du H. Bile acid levels and risk of adverse perinatal outcomes in intrahepatic cholestasis of pregnancy: a meta-analysis. J Obstet Gynaecol Res 2017; 43 (09) 1411-1420
- 16 Bicocca MJ, Sperling JD, Chauhan SP. Intrahepatic cholestasis of pregnancy: Review of six national and regional guidelines. Eur J Obstet Gynecol Reprod Biol 2018; 231: 180-187
- 17 Society for Maternal-Fetal Medicine (SMFM). Lee RH, Greenberg M, Metz T, Pettker CM. Society for Maternal-Fetal Medicine Consult Series #53: Intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol 2021; 224: B2-B9
- 18 Kawakita T, Parikh LI, Ramsey PS. et al. Predictors of adverse neonatal outcomes in intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol 2015; 213 (04) 570.e1-570.e8
- 19 Girling J, Knight CL, Chappell L. Royal College of Obstetricians and Gynaecologists. Intrahepatic cholestasis of pregnancy: Green-top Guideline No. 43 June 2022. BJOG 2022; 129 (13) e95-e114
- 20 Sarker MR, Debolt CA, Canfield D, Ferrara L. History of cholestasis is not associated with worsening outcomes in subsequent pregnancy with cholestasis. Am J Perinatol 2024; 41 (14) 1924-1929
- 21 Fleminger J, Seed PT, Smith A. et al. Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a secondary analysis of the PITCHES trial. BJOG 2021; 128 (06) 1066-1075
- 22 Chappell LC, Bell JL, Smith A. et al; PITCHES study group. Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial. Lancet 2019; 394 (10201): 849-860
- 23 Tamzali I, Pirics ML, Bicocca M, Burwick RM. Reconsidering absolute diagnostic thresholds in intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol 2022; 227 (05) 784-786
- 24 Mitchell AL, Ovadia C, Syngelaki A. et al. Re-evaluating diagnostic thresholds for intrahepatic cholestasis of pregnancy: case-control and cohort study. BJOG 2021; 128 (10) 1635-1644
- 25 Huri M, Seravalli V, Lippi C. et al. Intrahepatic cholestasis of pregnancy - Time to redefine the reference range of total serum bile acids: A cross-sectional study. BJOG 2022; 129 (11) 1887-1896
- 26 Smith DD, Kiefer MK, Lee AJ. et al. Effect of fasting on total bile acid levels in pregnancy. Obstet Gynecol 2020; 136 (06) 1204-1210