Background:

Intrahepatic cholestasis of pregnancy, characterised by maternal pruritus and raised serum bile acid concentrations, is associated with increased rates of stillbirth, preterm birth and neonatal unit admission. Ursodeoxycholic acid is widely used as a treatment, but without an adequate evidence base.

Objective:

We aimed to evaluate whether or not ursodeoxycholic acid reduces adverse perinatal outcomes in affected women.

Design:

Multicentre, masked, randomised, placebo-controlled, two-arm, parallel-group trial.

Setting:

Thirty-three UK maternity units.

Participants:

Women with intrahepatic cholestasis of pregnancy aged ≥ 18 years, between 20⁺⁰ and 40⁺⁶ weeks’ gestation with a singleton or twin pregnancy and no known lethal fetal anomaly.

Interventions:

Women were randomly assigned (1 : 1 allocation ratio) to take ursodeoxycholic acid tablets or matched placebo tablets, at an equivalent dose of 1000 mg daily, titrated as needed.

Main outcome measures:

The primary outcome was a composite of perinatal death (in utero fetal death after randomisation or known neonatal death up to 7 days) or preterm delivery (< 37 weeks’ gestation) or neonatal unit admission for at least 4 hours (from birth until hospital discharge). Each infant was counted once within this composite. Analyses were by intention to treat.

Results:

Between 23 December 2015 and 7 August 2018, 605 women were randomised, with 305 women allocated to the ursodeoxycholic acid arm and 300 women to the placebo arm. There was no evidence of a significant difference in the incidence of the primary outcome between the groups: 23.0% (74 out of 322 infants) in the ursodeoxycholic acid group compared with 26.7% (85 out of 318 infants) in the placebo group; adjusted risk ratio 0.85 (95% confidence interval 0.62 to 1.15). There was no evidence of a significant difference in total costs (maternal, infant and the cost of ursodeoxycholic acid) between the two trial groups. There were two serious adverse events in the ursodeoxycholic acid group and six in the placebo group.

Limitations:

Limitations include a primary outcome event rate in the control group that was lower than that estimated for the sample size calculation, but the lack of evidence of effect in all analyses suggests that it is unlikely that the trial had insufficient power.

Conclusions:

In this clinical trial of ursodeoxycholic acid in women with intrahepatic cholestasis of pregnancy, there is no evidence that it is effective in reducing a composite of adverse perinatal outcomes.

Future work:

Future research should aim to elucidate the aetiology and pathophysiology of adverse perinatal outcomes, particularly stillbirth, in women with intrahepatic cholestasis of pregnancy to assist the development of an effective preventative treatment. Further exploratory analyses may identify groups of women who might respond to ursodeoxycholic acid treatment.

Trial registration:

Current Controlled Trials ISRCTN91918806.

Funding:

This project was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 9. See the NIHR Journals Library website for further project information.

Article history

The research reported in this issue of the journal was funded by the EME programme as project number 12/164/16. The contractual start date was in March 2015. The final report began editorial review in May 2019 and was accepted for publication in March 2020. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The EME editors and production house have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the final report document. However, they do not accept liability for damages or losses arising from material published in this report.