PITCHES: Phase III trial in IntrahepaTic CHolestasis of pregnancy (ICP) to evaluate urSodeoxycholic acid (UDCA) in improving perinatal outcomes
Intrahepatic cholestasis of pregnancy (ICP), also called obstetric cholestasis (OC), is the most common liver disorder specific to pregnancy. It presents with maternal pruritus, raised concentrations of serum bile acids and abnormal liver function tests. The maternal symptoms typically resolve postpartum, but affected women have an increased risk of hepatobiliary disease in later life (Marschall et al., 2013). ICP is associated with increased rates of spontaneous and iatrogenic preterm labour, fetal hypoxia, meconium-stained amniotic fluid (Glantz et al., 2004, Chappell et al., 2012, Geenes and Williamson 2009). There are also reports of increased rates of intrauterine death (Fisk et al., 1998, Davies et al., 1995, Williamson et al., 2004), although the incidence is low (Glantz et al., 2004, Geenes et al., 2014). Most clinicians treat ICP with ursodeoxycholic acid (UDCA) (Saleh et al., 2007, Zapata et al., 2005) to improve maternal pruritus and biochemical abnormalities.
However, there are currently no data to support the use of UDCA to improve pregnancy outcome as none of the trials performed to date have been powered to address this question.
This placebo controlled trial aims to evaluate the effect of ursodeoxycholic acid (UDCA) treatment on reduction of perinatal death, preterm delivery and neonatal unit admission in women with ICP, with the goal of establishing the potential benefit to the fetus. Pregnant women are eligible if they have ICP (defined as pruritus together with a raised serum bile acid above the upper limit of normal) between 20+0 and 40+6 in a consultant-led maternity unit and are able to give informed consent. The dose of UDCA is 500mg bd, increased in increments of 500 mg per day every 3-14 days if there is no biochemical or clinical improvement, based on clinical decision, to a maximum of 2 grams per day. The primary outcome measure is the proportion of infants affected by death (in utero fetal death or neonatal death) or preterm delivery (less than 37 weeks' gestation) or neonatal unit (NNU) admission for at least 4 hours. Women are randomised at their first visit and then seen weekly, coincident with routine follow-up within their consultant unit for biochemical monitoring, until delivery.
550 infants of women with ICP (290 per group) are required to have a 90% chance of detecting, as significant at the 5% level, a decrease in the composite primary outcome measure from 40% in the control group to 27% in the treated group. We will recruit 580 women in total; this will allow for the possibility of 5% of infants being lost to follow-up and is a conservative estimate given that some women will have twin pregnancies.
This trial will provide definitive evidence for (or against) a role for UDCA in ameliorating adverse perinatal outcomes. If UDCA is beneficial, once published these results would be highly likely to lead to an immediate change in clinical practice, through individual choice of clinicians and pregnant women with ICP, and through changing national / international guidelines.