Ursodeoxycholic acid versus placebo, and early delivery versus expectant management, in women with obstetric cholestasis: Two semi-factorial randomised clinical trials.

Background: To test the hypotheses that ursodeoxycholic acid reduces maternal itching in women with obstetric cholestasis, that early delivery does not increase caesarean section rates and to test the feasibility of recruiting women with obstetric cholestasis to trials of these interventions. Methods: Semi-factorial double blind randomised controlled trial of two interventions in women with obstetric cholestasis. Nine consultant-led maternity units in the UK. Participants 125 women with obstetric cholestasis (pruritus and raised maternal serum bile acids or raised alanine transaminase >100 IU/L) recruited after 24 weeks' gestation and followed until delivery. Interventions (i) Ursodeoxycholic acid 500 mg twice a day or placebo increased as necessary for symptomatic or biochemical improvement until delivery. (ii) Early delivery (induction or delivery commenced between 37 + 0 and 37 + 6) or to expectant management (where spontaneous labour was awaited or caesarean section undertaken according to normal obstetric guidelines, usually after 39 weeks' gestation). For the ursodeoxycholic acid comparison, the primary outcome was maternal itch, measured as the arithmetic mean of all post-randomisation measures of worst itch in the previous 24 h assessed on a 100 mm visual analogue scale. For the timing of delivery comparison, primary outcome was caesarean section. Other maternal and perinatal outcomes were collected as secondary outcome measures, as were recruitment rates to the trial. Results: Ursodeoxycholic acid reduced itching by -16 mm (95% CI - 27 mm to - 5.9 mm). This reduction was less than the 30 mm difference pre-specified by clinicians and women as clinically meaningful. Early delivery did not increase Caesarean sections: 7/30 (23%) in the early delivery group vs. 11/32 (33%) in the expectant management group (relative risk 0.7 [95% CI 0.31-1.6]). Twenty-two percent (73/331) of eligible women participated in the UDCA trial and 18% (39/214) of those eligible participated in the timing of delivery trial, and both groups had a similar spectrum of disease severity to non-participants. Conclusion: Ursodeoxycholic acid reduces itching but not by an amount sufficient for most women or obstetricians who were consulted (n = 200)to judge the benefit worthwhile. Planned early delivery appears not to increase incidence of Caesarean section although a small increase has not been excluded. A trial to test the hypothesis that ursodeoxycholic acid reduces important adverse perinatal outcomes would have to be large, but is feasible. A trial to test the effect of early delivery on adverse fetal outcomes would have to be significantly larger and may not be feasible.