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Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial

BMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e3799 (Published 13 June 2012) Cite this as: BMJ 2012;344:e3799
  1. Lucy C Chappell, clinical senior lecturer in maternal and fetal medicine1,
  2. Vinita Gurung, specialist trainee in obstetrics and gynaecology2,
  3. Paul T Seed, senior lecturer in medical statistics1,
  4. Jenny Chambers, clinical trial coordinator3,
  5. Catherine Williamson, professor of obstetric medicine3,
  6. James G Thornton, professor of obstetrics and gynaecology4
  7. on behalf of the PITCH Study Consortium
  1. 1Women’s Health Academic Centre, King’s Health Partners, UK
  2. 2Birmingham City Hospital, Birmingham, UK
  3. 3Department of Surgery and Cancer, Imperial College London, UK
  4. 4Nottingham Clinical Trials Unit, Nottingham Health Science Partners, Queen’s Medical Centre, Nottingham NG7 2UH, UK
  1. Correspondence to: J G Thornton jim.thornton{at}nottingham.ac.uk
  • Accepted 17 April 2012

Abstract

Objectives To test whether ursodeoxycholic acid reduces pruritus in women with intrahepatic cholestasis of pregnancy, whether early term delivery does not increase the incidence of caesarean section, and the feasibility of recruiting women with intrahepatic cholestasis of pregnancy to trials of these interventions.

Design First phase of a semifactorial randomised controlled trial.

Setting Nine consultant led maternity units, United Kingdom.

Participants 125 women with intrahepatic cholestasis of pregnancy (pruritus and raised levels of serum bile acids) or pruritus and raised alanine transaminase levels (>100 IU/L) recruited after 24 weeks’ gestation and followed until delivery. 56 women were randomised to ursodeoxycholic acid, 55 to placebo, 30 to early term delivery, and 32 to expectant management.

Interventions Ursodeoxycholic acid 500 mg twice daily or placebo increased as necessary for symptomatic or biochemical improvement until delivery; early term delivery (induction or delivery started between 37+0 and 37+6) or expectant management (spontaneous labour awaited until 40 weeks’ gestation or caesarean section undertaken by normal obstetric guidelines, usually after 39 weeks’ gestation).

Main outcome measures The primary outcome for ursodeoxycholic acid was maternal itch (arithmetic mean of measures (100 mm visual analogue scale) of worst itch in past 24 hours) and for the timing of delivery was caesarean section. Secondary outcomes were other maternal and perinatal outcomes and recruitment rates.

Results Ursodeoxycholic acid reduced itching by −16 mm (95% confidence interval −27 mm to −6 mm), less than the 30 mm difference prespecified by clinicians and women as clinically meaningful. 32% (14/44) of women randomised to ursodeoxycholic acid experienced a reduction in worst itching by at least 30 mm compared with 16% (6/37) randomised to placebo. The difference of 16% (95% confidence interval −3 to 34); this would represent a number needed to treat of 6, but it failed to reach significance. Early term delivery did not increase caesarean sections (7/30 (23%) in the early term delivery group versus 11/32 (33%) in the expectant management group (relative risk 0.70, 95% confidence interval 0.31 to 1.57). No serious harms were noted in either trial. 22% (73/325) of eligible women participated in the drug trial and 19% (39/209) in the timing of delivery trial; both groups had a similar spectrum of disease severity to non-participants.

Conclusions Ursodeoxycholic acid significantly reduces pruritus, but the size of the benefit may be too small for most doctors to recommend it, or for most women to want to take it. Women are, however, likely to differ in whether they consider the benefit to be worthwhile. Planned early term delivery seems not to increase incidence of caesarean section, although a small increase cannot be excluded. A trial to test whether ursodeoxycholic acid reduces adverse perinatal outcomes would have to be large, but is feasible. A trial to test the effect of early term delivery on adverse fetal outcomes would have to be significantly larger and may not be feasible.

Trial registration Current Controlled Trials ISRCTN37730443.

Footnotes

  • We thank the women who participated; the obstetricians and midwives who referred women to the researchers; Professor William Hague for suggesting the PITCH acronym; and Dr Falk Pharma for supplying the ursodeoxycholic acid and placebo capsules for the trial.

  • Contributors: LCC and VG contributed equally and are joint first authors. JGT was chief investigator and LCC and CW were principal investigators for the study and contributed to all stages. VG was the clinical research fellow and trial coordinator for the study. PTS undertook all statistical analyses. JC was involved from the design of the study through execution to interpretation, and facilitated the online survey of women with obstetric cholestasis. LCC drafted the manuscript. All authors contributed to revisions and approved the final draft. JGT is guarantor. All authors had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis.

  • Funding: This study was funded by the research for patient benefit programme of the National Institute for Health Research (NIHR). LCC is funded by a Department of Health-NHS clinical senior lecturer award. VG was funded by Nottingham University Hospitals NHS Trust and the NIHR research for patient benefit programme. PTS is funded by Tommy’s Charity. CW is funded by the Biomedical Research Centre at Imperial College Healthcare NHS Trust. The sponsor was the University of Nottingham. The sponsor played no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that: LCC is funded by a Department of Health-NHS clinical senior lecturer award, VG was funded by Nottingham University Hospitals NHS Trust and NIHR research for patient benefit programme, PTS is funded by Tommy’s Charity, and CW is funded by the Biomedical Research Centre at Imperial College Healthcare NHS Trust; JC is the founder of Obstetric Cholestasis Support UK, a support group for women and families affected by obstetric cholestasis; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: This trial was approved by the Berkshire Research Ethics Committee (reference No 08/H0505/7).

  • Data sharing: An anonymised dataset is available from the corresponding author (jim.thornton{at}nottingham.ac.uk) on request. Participants did not give explicit informed consent for data sharing but the data available are anonymised and the risk of identification is low.

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