Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis (OC) is the most common pregnancy-specific liver disease in the UK, affecting around 5,500 women a year.

The causes of ICP are not yet fully understood, but it is likely to be due to a number of different factors, including:

Hormones

It is thought that the pregnancy hormones (estrogen and progesterone) have an effect on the ability of the liver to transport some chemicals, including bile acids.
It seems that in some women the liver is not able to cope with the rise in the levels of estrogen and progesterone that occurs as pregnancy advances, and the flow of things like bile acids is greatly reduced.
This leads to them building up in the blood and results in the symptoms of ICP.

Genes

ICP is more common in certain populations, including Scandinavians, South Americans and women from South Asia (namely India and Pakistan), and it may also run in families.

This means that there is a genetic element that is associated with ICP although the condition is not caused by one single gene (in contrast with cystic fibrosis, for example), but involves different genetic changes (variants) that increase a woman’s chances of developing it. Researchers have identified some genetic changes that have a large effect on the risk of getting ICP and some that have a small effect; this adds another layer of complication to understanding how gene variants contribute to ICP. A new study being led by Professor Catherine Williamson’s research group has identified more genetic changes on ICP and the results for this will be published soon (2019).
It’s possible that the genetic changes are passed down by the father as well as the mother, so if you’re trying to find out who else in your family may have had the condition you need to ask both your parents (if that’s possible) about their own family history.

Environment

ICP is more common in the winter months in some countries. There has been very little research conducted into the possible reasons for this variation, and at present it can’t be fully explained. Some theories include that the cause of ICP could be linked to:
sunlight and vitamin D levels, as research studies have shown that supplementation with vitamin D can improve cholestasis in animals;
diet, as people often have a tendency to eat fattier foods in the winter.

Why do we worry about ICP?

Although ICP is not generally harmful for the mother-to-be it is associated with fetal distress in labour, premature labour (spontaneous and induced) and stillbirth.

How do I know if I have ICP?

The most common symptom of ICP is itching. Many women do itch in pregnancy, but the itch in ICP is typically noticed on the hands, feet, arms and legs, although it can also be generalised. It usually begins in the third trimester of pregnancy (28 weeks onwards), but some women can itch earlier than this and ICP has been diagnosed as early as 8 weeks. Women often report that it is more noticeable at night, and it can range from mild itching to being so severe that it causes loss of sleep. Until recently the direct cause of this itch was thought to be raised bile acids but recent research links it to two substances in the maternal blood called lysophosphatidic acid (LPA) and sulfated progesterone metabolites.

Other symptoms of the condition can include:

  • Dark urine
  • Pale stools
  • Jaundice (although this is not common)

How is the condition diagnosed?

The diagnosis of ICP is made by excluding other causes of the itch, so screening is likely to include blood tests to check for auto-immune hepatitis, hepatitis C and other conditions such as PBC (primary biliary cholangitis). Other blood tests will also check how well your liver is coping with the condition (liver function test and clotting studies) and how elevated your bile acid levels are. It is bile acids that are thought to be associated with risk to the baby, as they are known to cross the placenta and there has been a small amount of research to suggest that they may affect the baby’s heart.

What treatment might I receive?

Doctors in the UK tend to treat the condition with a drug called UDCA (ursodeoxycholic acid). However, there had been no evidence that this drug actually works until the results of a trial called PITCHES were published in The Lancet in August 2019. The results showed that the drug is not effective for most women although there is still some speculation by researchers that it may help some women who have very severe ICP (bile acids >100 µmol/L). Further research on this is needed.

You may also be given aqueous cream with menthol (to help soothe your skin) and piriton tablets, the side-effects of which might be to help you sleep a little better at night. Some experts have also started to add the drug, rifampicin, to treat women who have very severe ICP but this drug should only be prescribed in conjunction with a clinician ho has specialist knowledge of using the drug.

Your baby may have to be delivered early:

  • In the past some researchers believed that delivering the baby early (around 37–38 weeks) reduced the risk of stillbirth. However, there was not enough evidence to support this until new research (a meta-analysis) was published in February 2019 by Ovadia et al. The meta-analysis showed that provided women’s bile acids remain >100µmol/L the risk of stillbirth from ICP alone (if you have additional complications such as gestational diabetes or pre-eclampsia this will change when your baby is likely to be born) is the same risk as that of women with uncomplicated pregnancies. This means that most women should be able to wait until 39 weeks to meet their babies (there were too few numbers in the analysis of women who were over 39 weeks of pregnancies so no conclusion could be drawn about being able to wait until 40 weeks of pregnancy for induction). It is possible that women whose bile acids never rise >40 µmol/L could await spontaneous labour but this may need further research.
  • However, what this research also shows is that some women whose bile acids remain >100 µmol/L may need to have their pregnancies induced from 34-35 weeks of pregnancy onward as the risk of stillbirth increases after this point (and from 35 weeks of pregnancy) so it is important that their pregnancies are carefully managed. It also means that bile acid tests will be crucial for monitoring ICP pregnancies.

Vitamin K

If one of your clotting tests is abnormal, you should be advised to have Vitamin K which helps to correct the clotting problem. Specialists in the condition will also prescribe vitamin K if the mother-to-be has pale stools (steatorrhea). It is however, the policy of some hospitals to give Vitamin K to all women with ICP regardless of their clotting results even though there is no research to endorse this practice. It’s worth discussing this with your own doctor if you have any concerns.

Do I need tests after birth?

Yes, your GP will want to make sure that all your blood tests have come back to normal, so they will repeat the liver function test and check your bile acid levels around 6–12 weeks after you have had your baby. Sometimes blood results can take a little longer to go back to normal and if they don’t resolve you may need to be referred to a liver specialist.

Will I get ICP in any future pregnancy?

You do have a high chance of developing the condition again; research quotes this risk as being between 60% and 90%

Can I pass it on?

Researchers are currently investigating how this condition is passed down through families. To date, several genetic changes (variants) have been identified that are implicated in the condition. Further work is continuing to identify more. If you have a girl she will have around a 12% risk of developing ICP if she has children. If you have a boy he may pass the genetic inheritance on to his children.

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References

  • Chappell LC, Bell JL, Smith A, Linsell L, Juszczak E, Dixon PH, Chambers J, Hunter R, Dorling J, Williamson C, Thornton JG. Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial. The Lancet 2019; https://doi.org/10.1016/S0140-6736(19)31270-X
  • Ovadia C, Seed PT, Sklavounos A, Geenes V, Di Illio C, Chambers J et al.
    Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta- analyses. The Lancet 2019; DOI: http://dx.doi.org/10.1016/S0140-6736(18)31877-4.
    PDF
  • Abu-Hayyeh S, Ovadia C, Lieu T, Jensen DD, Chambers J, Dixon PH, Lovgren-Sandblom A, Bolier R, Tolenaars D, Kremer AE, Syngelaki A, Noori M, Williams D, Marin JJG, Monte MJ, Nicolaides KH, Beuers U, Oude-Elferink R, Seed PT, Chappell L, Marschall H-U, Bunnett NW, Williamson C Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum.Hepatology2015; doi: 10.1002/hep.28265
  • Andreas E. Kremer et al. (2010) Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology, Volume 139, Pages 1008–1018.
  • Arrese M, Reyes H. Intrahepatic cholestasis of pregnancy: a past and present riddle. Ann Hepatol 2006; 5: 202-205
  • Dixon PH, Williamson C. The molecular genetics of intrahepatic cholestasis of pregnancy. Obstet Med 2008; 1: 65-71
  • Geenes V, Chappell LC, Seed PT, Steer PJ, Knight, M, Williamson C: Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study.Hepatology2014; First published online 26 February 2014; DOI: 10.1002/hep.26617
  • Geenes V, Chambers J, Khurana R, Wikström Shemer E, Sia W, Mandair D, Elias E, Marschall H-U, Hague W, Williamson C (2015) Rifampicin in the treatment of severe intrahepatic cholestasis of pregnancy.European Journal of Obstetrics & Gynecology and Reproductive Biology, Volume 189. pages 59–63
  • Williamson, C, Geenes, V. Intrahepatic Cholestasis of Pregnancy. Obstet Gynecol 2014;124:120–33
  • Glantz A, Marschall HU, Lammert F, Mattsson LA Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology 2004, Volume 40, Issue 2:467-474
  • Reid R, Ivey KJ, Rencoret RH, Storey B. Fetal complications of obstetric cholestasis. Br Med J 1976; 1: 870-872
  • Walker IA, Nelson-Piercy C, Williamson C. Role of bile acid measurement in pregnancy. Ann Clin Biochem 2002; 39: 105-113
  • RCOG Greentop Guideline 43 April 2011 Being revised 2016
  • Walker IA, Nelson-Piercy C, Williamson C. Role of bile acid measurement in pregnancy. Ann Clin Biochem 2002; 39: 105-113
  • Williamson, C, Geenes, V. Intrahepatic Cholestasis of Pregnancy. Obstet Gynecol 2014;124:120–33