When I was diagnosed with intrahepatic cholestasis of pregnancy in 1991, there was nothing written about management of the condition in any institutional guidelines and most health professionals had not heard of it. It was sheer luck (although, following two stillbirths, I didn't feel quite so lucky at the time) that I was finally diagnosed by an obstetrician who had an interest in the condition and who worked with a hepatologist with an interest in intrahepatic cholestasis of pregnancy. Both were keen to conduct research into the disease, so during my final pregnancy I agreed to donate the samples they wanted as well as taking a new medication for the condition.
Intrahepatic cholestasis of pregnancy is the most common pregnancy-specific liver disease affecting around 5500 women a year in the UK (0.7%) (Abedin et al, 1999). There is a geographical spread to incidence of the condition; women whose family birth origins are South American, South Asian and Scandinavian are more likely to be affected (Ovadia and Williamson, 2016). Intrahepatic cholestasis of pregnancy is caused through a combination of genetics, hormones and environmental factors. Its main symptom, pruritus, can be so distressing for women that some have reported feeling suicidal (Chambers, 2021). Other symptoms include dark urine, steatorrhea and right upper quadrant pain (ICP Support, 2022). It is associated with fetal distress, spontaneous premature birth and, in severe cases, stillbirth (Ovadia et al, 2019). Diagnosis is made through liver bloods tests and more specifically, non-fasting bile acid tests.
ICP Support (2021), the charity, grew from an information and support line started in 1991. One of the charity's main aims is the promotion and support of research. My earlier experiences with research had left me fascinated by the etiology of intrahepatic cholestasis of pregnancy, and I was keen for the charity to work with researchers to help improve treatment and management of the condition. I was further motivated to do this because I was told by doctors that they would only start to take intrahepatic cholestasis of pregnancy seriously when there was evidence to ‘prove’ that it was not a benign condition (as many of them believed).
This led to another lucky meeting in 1997 with Professor Catherine Williamson. Catherine was training to be an obstetric physician at Imperial College London and had made intrahepatic cholestasis of pregnancy her research focus. Working with Catherine has taught me how long research takes. Recruitment for one of the studies that ICP Support was involved in began in November 2011, but it was only in 2021 that the outcomes were published (Mitchell et al, 2021). The study identified that the threshold level for bile acids (which diagnose intrahepatic cholestasis of pregnancy) had been set too low and could mean that many women were being needlessly worried. It also highlighted the importance of not fasting for bile acid tests, as this can result in the diagnosis being missed.
As a result of working with Catherine, ICP Support has been able to embed research into the way it functions and help its beneficiaries. Public and patient involvement is now essential in all research applications and the charity can:
- Advise researchers on the feasibility of proposed studies, including asking people affected by the condition for their views through focus groups and surveys
- Review participant information sheets and other relevant documentation
- Act as a conduit for recruitment. Catherine applies for ethical approval to advertise her research through the charity, and the charity can act as a filter for recruiting people to the studies
- Disseminate the results of that research via the charity's website and social media platforms
- Promote and fund research.
ICP Support has been instrumental in helping to recruit to studies. For me, the greatest achievement is the charity's involvement with a study that is still running today (ICP Support, 2022) and which has led to many publications, including a meta-analysis published in The Lancet in 2019 (Ovadia et al, 2019). The data from this study helped to identify the threshold at which the risk of stillbirth occurs in intrahepatic cholestasis of pregnancy. This is hugely important for health professionals because it means that they can reassure 90% of women with intrahepatic cholestasis of pregnancy about the safety of their baby.
ICP Support also supports research into identifying new medications to treat intrahepatic cholestasis of pregnancy. Currently, there is no medication that will provide a clinically meaningful improvement in both bile acid concentrations and pruritus (Chappell et al, 2019), and although the current choice of drug to treat intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, has its place (Ovadia et al, 2021), it is clear that a new drug is needed that can effectively reduce both bile acids and the often debilitating itch that comes with intrahepatic cholestasis of pregnancy.
One such medication, volixibat, is being evaluated in the OHANA trial, initiated by the US-based company Mirum, and which is being supported by the charity (ClinicalTrials.gov, 2021). The hope is that volixibat will reduce bile acid concentrations in women with intrahepatic cholestasis of pregnancy as well as improve pruritus. In a recent survey about pruritus in intrahepatic cholestasis of pregnancy conducted by Mirum Pharmaceuticals (2021) and ICP Support in 2021, the median worst itch reported by women for their most recent intrahepatic cholestasis of pregnancy pregnancy was 9 (0 for ‘no itch’, 10 for ‘worst itch you can possibly imagine’).
Much has changed since I was first diagnosed with intrahepatic cholestasis of pregnancy. Research has identified that there is longer term impact from having the condition; some women are more likely to develop liver disease and need to be extra vigilant about the future health of their livers (Wikström Shemer et al, 2015). This means that more research is needed to follow these women beyond pregnancy.
On the other hand, it has now been shown that women can wait a little longer for induction, thereby reducing the rate of preterm iatrogenic inductions (Ovadia et al, 2019). Research has also identified some of the genetic variants associated with the condition (Dixon et al, 2017). This means that the daughters of women with intrahepatic cholestasis of pregnancy could eventually be screened to establish the likelihood of them developing intrahepatic cholestasis of pregnancy should they decide to have children, and that their sons could be screened to see how likely they are to pass a genetic variant down through their family.
There is no doubt that women want more research to take place. In an online discussion between women who have had intrahepatic cholestasis of pregnancy and researchers held in October 2021, women suggested the following areas for research:
- The psychological impact
- The longer term impact
- The effect of diet and nutrition
- Overlapping conditions (such as gestational diabetes)
- Cyclical itch
- Faster diagnosis.
Whatever pathways the research takes, when I hand over the reins of running the charity to someone else (in a few years' time) I will leave knowing that thousands of women have been helped by the research and that thousands more will continue to benefit. I may be stepping away from the charity but I will not be stepping away from the research; I intend to be involved in it for as long as is possible.