Ursodeoxycholic acid for intrahepatic cholestasis in pregnancy
Authors: Hanns-Ulrich Marschall
Journal: The Lancet (2019)

Intrahepatic cholestasis of pregnancy is the most common pregnancy-specific liver disease, with a global incidence of between 0·2% and 2·0%. Intrahepatic cholestasis of pregnancy is characterised by otherwise unexplained pruritus, typically starting in the late second or third trimester of pregnancy, increased serum bile acid concentration or transaminase concentration, or both, and spontaneous relief of symptoms and normalisation of biochemical abnormalities post partum.1Lammert F Marschall HU Glantz A Matern S Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management.J Hepatol. 2000; 33: 1012-1021Summary Full Text Full Text PDF PubMed Scopus (356) Google Scholar, 2Geenes V Williamson C Intrahepatic cholestasis of pregnancy.World J Gastroenterol. 2009; 15: 2049-2066Crossref PubMed Scopus (408) Google Scholar Intrahepatic cholestasis of pregnancy is associated with adverse pregnancy outcomes, including fetal distress, meconium-stained amniotic fluid, spontaneous and iatrogenic preterm birth, neonatal unit admission, and stillbirth.1Lammert F Marschall HU Glantz A Matern S Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management.J Hepatol. 2000; 33: 1012-1021Summary Full Text Full Text PDF PubMed Scopus (356) Google Scholar, 2Geenes V Williamson C Intrahepatic cholestasis of pregnancy.World J Gastroenterol. 2009; 15: 2049-2066Crossref PubMed Scopus (408) Google Scholar The risk of non-lethal adverse pregnancy outcomes in intrahepatic cholestasis of pregnancy increases with serum bile acid concentrations of 40 μmol/L or more,3Glantz A Marschall HU Mattsson LA Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates.Hepatology. 2004; 40: 467-474Crossref PubMed Scopus (568) Google Scholar and risk of stillbirth increases with serum bile acid concentrations of 100 μmol/L or more.4Ovadia 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: 899-909Summary Full Text Full Text PDF PubMed Scopus (207) Google Scholar Several treatments to relieve maternal itch have been tested, of which only ursodeoxycholic acid has been widely implemented, although the clinical benefit was found to be small.5Chappell LC Gurung V Seed PT Chambers J Williamson C Thornton JG Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial.BMJ. 2012; 344e3799Crossref PubMed Scopus (123) Google Scholar Ursodeoxycholic acid was also advocated to protect the fetus from pregnancy complications, although evidence for this was absent.6Gurung V Middleton P Milan SJ Hague W Thornton JG Interventions for treating cholestasis in pregnancy.Cochrane Database Syst Rev. 2013; 6CD000493PubMed Google Scholar, 7Shen Y Zhou J Zhang S et al.Is it necessary to perform the pharmacological interventions for intrahepatic cholestasis of pregnancy? A Bayesian network meta-analysis.Clin Drug Investig. 2019; 39: 15-26Crossref PubMed Scopus (13) Google Scholar In The Lancet, Lucy Chappell and colleagues8Chappell LC Bell JL Smith A et al.Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial.Lancet. 2019; (published online Aug 1.)http://dx.doi.org/10.1016/S0140-6736(19)31270-XSummary Full Text Full Text PDF Scopus (134) Google Scholar present the results of the PITCHES trial, a multicentre, randomised, placebo-controlled trial of ursodeoxycholic acid in women with intrahepatic cholestasis of pregnancy, defined by otherwise unexplained pruritis and serum bile acid concentrations of 10–14 μmol/L or more (dependent on local laboratory reference ranges) after gestational week 20. 605 women were randomly allocated to receive either 1000 mg daily ursodeoxycholic acid (n=305) or matching placebo (n=300) and were followed up until maternal and infant discharge. Chappell and colleagues found no statistically significant difference between treatment groups in the primary outcome measure, which was a composite of perinatal (intrauterine or neonatal) death, preterm delivery (<37 gestational weeks), or neonatal unit admission for at least 4 h. An improvement in maternal itch score was found in women who received ursodeoxycholic acid compared with the placebo group, but the effect was small and of questionable clinical significance. The data presented by Chappell and colleagues, which were also supported by the most recent Cochrane review,6Gurung V Middleton P Milan SJ Hague W Thornton JG Interventions for treating cholestasis in pregnancy.Cochrane Database Syst Rev. 2013; 6CD000493PubMed Google Scholar suggest that we should reconsider the widespread use of ursodeoxycholic acid in intrahepatic cholestasis of pregnancy. However, this reconsideration might be difficult to pursue; the use of ursodeoxycholic acid in intrahepatic cholestasis of pregnancy has become very popular without formal approval. Pruritus might improve after commencement of treatment with ursodeoxycholic acid and the treatment is considered to be safe; however, the findings of Chappell and colleagues show that a similar effect can also occur with placebo. The strengths of the PITCHES trial are its well controlled design, the careful statistical evaluation, and the large sample size, with a sample size calculated from published data. However, because the observed event rate in the control group was lower than expected, the difference in the incidence of the composite primary outcome between ursodeoxycholic acid and placebo groups (4%) was much smaller than anticipated. Because there was no difference in the primary outcome between patients presenting with serum bile acid concentrations above and below 40 μmol/L (a measure of disease severity), a significant benefit of UDCA would be unlikely to have been observed in a larger study population. Whether or not patients presenting with bile acid concentrations higher than 100 μmol/L with increased stillbirth risk4Ovadia 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: 899-909Summary Full Text Full Text PDF PubMed Scopus (207) Google Scholar could benefit from treatment with ursodeoxycholic acid will remain an open question because studies evaluating it would demand sample sizes that are not feasible. The composite primary outcome in the PITCHES trial included preterm birth. Although the UK guidelines recommend offering delivery from 37 weeks' gestation, iatrogenic preterm birth is common in intrahepatic cholestasis of pregnancy.9Royal College of Obstetricians and GynaecologistsObstetric cholestasis: green-top guideline no. 43. Royal College of Obstetricians and Gynaecologists, London2011Google Scholar Delivery is typically indicated to prevent stillbirth; however, Ovadia and colleagues4Ovadia 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: 899-909Summary Full Text Full Text PDF PubMed Scopus (207) Google Scholar recently found that women with bile acid concentrations of less than 100 μmol/L are at no higher risk of stillbirth than the general population. Therefore, iatrogenic preterm birth might be avoidable for most women with intrahepatic cholestasis of pregnancy. Given that the prevalence of spontaneous onset of labour was higher among women taking placebo than among those taking ursodeoxycholic acid, changes in antenatal care, such as reduced use of ursodeoxycholic acid and iatrogenic preterm delivery, might lead to a higher proportion of spontaneous preterm births. The pragmatic approach of the PITCHES trial is both a strength and a limitation. Diagnosis of intrahepatic cholestasis of pregnancy was exclusively based on itch and elevated serum bile acid concentration, which facilitated the recruitment of a large number of participants. However, these criteria do not strictly follow the definition of intrahepatic cholestasis of pregnancy, which is a diagnosis of exclusion of other liver diseases presenting with the same symptom and biomarker (eg, chronic hepatitis C virus infection or primary biliary cholangitis) and disappearance of pruritus and normalisation of elevated liver tests post partum. Thus, some women with underlying chronic liver disease might have erroneously been included in the PITCHES trial. Nevertheless, these conditions are rare, so the observed outcomes are unlikely to have been affected. I report grants and non-financial support from Intercept, and non-financial support from Albireo, outside the area of work commented on here. I have a continuous collaboration with Catherine Williamson, one of the Article authors. I am grateful to Catherine Ovadia for her input on an earlier version of this Comment. Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trialTreatment with ursodeoxycholic acid does not reduce adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. Therefore, its routine use for this condition should be reconsidered. Full-Text PDF Open Access