Jenny Chambers, Founder and CEO, ICP Support
PITCH – Pregnancy Intervention Trial in Cholestasis
The current drug treatment used by doctors for the treatment of intrahepatic cholestasis of pregnancy (ICP) is called ursodeoxycholic acid (UDCA or urso). It was introduced into the UK in 1992 and grew in popularity with health professionals because it appeared to help reduce the level of itching that women with ICP suffer from. Some researchers also believed that taking urso in an ICP pregnancy might help to protect some unborn babies from the risk of stillbirth.
However, urso had never been properly tested on women with ICP to see if it really did help with itch and/or reducing the adverse outcomes associated with ICP, such as spontaneous premature birth, fetal distress or stillbirth. To do this, a clinical trial was needed to compare what happens to women with ICP who take urso with what happens to women with ICP who simply take a dummy (harmless) drug, called a placebo.
The first trial that aimed to test this was called PITCH, and was conducted in the UK in 2009. In trials, large numbers of participants are needed if results are to be meaningful (significant), so one of PITCH’s aims was to establish whether women with ICP would agree to take part; if successful, this would lead to a much larger trial for which funding would still be needed. This first phase was successful and 125 women took part, but towards the end of the trial it was clear that the next ‘bigger numbers’ phase was not going to be funded. This was disappointing to the researchers, who nevertheless made the decision to analyse the results that they had obtained.
PITCH showed that urso did appear to reduce the itch that women with ICP experience, but it was a relatively small reduction and when compared to a survey that women and doctors took part in about itching, it wasn’t enough of a reduction to be considered meaningful to the participants in that survey. It also reduced the incidence of meconium staining (where a baby poos inside the womb). The researchers had also tried to show what would happen if women waited for their babies to be born spontaneously rather than being induced at around 37–38 weeks of pregnancy (something that was common in ICP pregnancies at that time), but they didn’t manage to recruit enough women to this part of the trial and the results weren’t significant; it was also clear that any future trials that tried to test this would also fail to recruit enough women.
Because of the small numbers of women recruited to PITCH, the researchers were not able to show that urso was a drug that should or should not be used, so they continued to try to secure funding for the bigger trial. This took a few years, but they were eventually successful and in 2015 the follow-on trial, PITCHES, was launched.
If you would like to see the full results of the trial click here. Otherwise we have posted the main findings of the trial below.
The question asked by the trial was:
“If a woman has ICP, what are the effects on the baby if she is treated with ursodeoxycholic acid (or placebo)?”
What did they do?
Between December 2015 and September 2018, researchers recruited 605 pregnant women with ICP. Half of the women received urso and half a placebo (a ‘dummy’ tablet that contained no active ingredients).
During the trial they also:
Collected blood test results
Measured the women’s level of itching
Recorded information about the births
Collected blood samples from some women to use for future research
What did they find?
Researchers found that urso is not a drug that helps women with ICP. It did not reduce stillbirths or the chances of a baby needing to be admitted to a neonatal unit. It did not show any meaningful improvement in itch for most women, nor did it reduce the woman’s bile acid levels.
What does this mean for women with ICP?
It means that most women don’t need to take urso, because it won’t help their itching or protect their baby from stillbirth. Further research is needed to identify whether there may still be a group of women who would benefit from taking urso, and whether other drugs could reduce the itch in women with ICP or prevent their babies from being stillborn.
As someone who has taken urso and who also works in a research group investigating the condition, I (along with my research colleagues) had already suspected for some time that urso was not a wonder drug. But I felt that it was very important to help prove or disprove this suspicion so that women with ICP had the right treatment – which is why I agreed to be an Investigator for both the PITCH and PITCHES trials.
Nonetheless, suspecting something and seeing it proven are two very different things! I had so desperately wanted urso to have some benefits. It does of course – some women are helped by urso in that their itch improves a little and it does help reduce inflammation in the liver. But clinically, this doesn’t really mean very much. Urso doesn’t reduce the itch so much that it’s going to bring very much relief (although I appreciate that when you are itching you may feel that any reduction is worth it) and there is no evidence that your liver is going to fail in ICP, so a reduction in alanine transaminase (ALT) which is what rises when the liver is inflamed, doesn’t really mean very much either.
The trial wasn’t designed to show whether or not urso can prevent stillbirth – it’s virtually impossible to have a large enough trial to do this (which is why the main outcome of this trial was a mixture of outcomes that researchers called a ‘composite’ outcome), but it did show that stillbirth happened in both the group of women who took the drug and in the group of women who took the placebo (dummy) drug, meaning that the drug is unlikely to be protective for unborn babies whose mums have ICP.
The results have caused much debate amongst the trial Investigators, with some of us feeling (hoping?) that there may still be a group of women with severe disease who may benefit from taking urso (most likely to be those women whose bile acid levels are over 100 µmol/L). We think this because there are some researchers whose work has shown that it may have a positive impact on the placenta, and Professor Catherine Williamson’s work (here and here) has shown that it may protect the baby’s heart. But all this work has been laboratory based and needs to be proven in pregnant women. We have no evidence that it is harmful to take urso, but equally it would be wrong of me to give you false reassurance that, for those of you with very severe ICP, taking the drug will protect your baby.
The positive news is that we know from earlier work by Ovadia et al that the majority of women with ICP can be reassured about the safety of their babies because if bile acid levels remain below 100 µmol/L, the risk of stillbirth is no different than for those women with uncomplicated pregnancies.
We also know that researchers are currently working hard to identify drugs that can be more effective than urso, so that the awful itch that is experienced by women can be eradicated (or at least reduced to a much more tolerable level). A new trial, called TURRIFIC and headed by Professor Bill Hague in Adelaide, is currently under way in Australia to evaluate the efficacy of rifampicin. This will also involve two UK hospitals. ICP Support is a collaborator on this study. Professor Catherine Williamson is also having discussions with other companies that have drugs that may help treat ICP and I hope that the results of PITCHES will show them how badly their involvement is needed.
In the meantime, bile acid testing seems to be the most effective way of assessing stillbirth risk in ICP, and ICP Support will continue to urge all hospitals to provide frequent testing with results that come back quickly. We will also work hard to continue to raise money to fund research.
If you have been affected by anything I have written please do email me (email@example.com) or ring our supportline.