Methods
This is a secondary analysis of the PITCHES study, a parallel-group, double-blind, multicentre, randomised placebo-controlled trial with individual randomisation to UDCA or placebo using a 1:1 allocation ratio. The original primary analysis was published in August 2019.6 A prespecified statistical analysis plan was written for this secondary analysis (Appendix S1).
Women were eligible to enrol in the trial if they had a diagnosis of intrahepatic cholestasis of pregnancy, characterised by pruritus and an increase in serum bile acid concentration above the upper limit of normal in their local laboratory. Additional inclusion criteria included: being between 20 weeks and 0 days, and 40 weeks and 6 days of pregnancy on the day of randomisation, a singleton or twin pregnancy, no known lethal fetal anomaly, aged 18 years or over, and able to give written informed consent. Participants were randomly allocated to receive UDCA or placebo using a 1:1 ratio, using a minimisation algorithm. Trial participants, clinical care providers, outcome assessors and data analysis were all masked to allocation. The placebo and UDCA tablets looked identical. A starting dose of two tablets a day was recommended (equivalent to a UDCA dose of 500 mg twice a day in the UDCA group). This dose could be increased or decreased by one tablet a day every 3–14 days up to a maximum of 4 tablets a day, at a clinician’s discretion. It was recommended that treatment should continue from enrolment until the infant’s birth.
The primary outcome was a composite of perinatal death (defined as in-utero fetal death after randomisation or known neonatal death up to 7 days after birth), 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. Secondary maternal outcomes were collected on all women at clinical visits between randomisation and delivery. These included serum bile acid concentration (µmol/L) and itch severity (measured as the worst episode of itch over the past 24 hours in mm on a 0 to 100 mm visual analogue scale, where 100 mm was the worst itch). Secondary perinatal outcomes were collected on case-note review after infant discharge. Full details about the original trial can be found in the protocol and primary analysis.6,7