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