Intrahepatic Cholestasis of Pregnancy

Intrahepatic Cholestasis of Pregnancy (ICP) is also known as Obstetric Cholestasis (OC) and is the most common pregnancy-specific liver disease in the UK, affecting around 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 and South Americans, and it may also run in families.
These observations raise the possibility of a genetic cause for the disease.
ICP 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. However, a new study being led by Professor Catherine Williamson’s research group hopes to identify all the genetic changes involved in ICP.
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). Although this drug is not licensed for use in pregnancy, there is good evidence that it can help improve itching and reduce the abnormal bile acid levels. It has been used in the UK since 1991 and has been taken by thousands of women. 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:

  • Some researchers believe that delivering the baby early (around 37–38 weeks) reduces the risk of stillbirth. This is because stillbirth (in ICP) tends to occur in the last few weeks of pregnancy. The reason it happens so late in pregnancy is unclear, although it may be linked to all the changes that take place in the woman as her body prepares for labour, together with the impact that the bile acids have. Further research is needed to establish this.
  • There has been research to suggest that if the bile acid levels come down to normal or under 40 µmol/L, the pregnancy could be allowed to progress as normal, permitting spontaneous labour to occur. However, in the absence of large trials to prove that this is safe (and researchers still also have to prove that bile acids have been the cause of stillbirth), many doctors are continuing to deliver the baby by 37–38 weeks.
  • A more recent study suggests that some babies may need to be born earlier than 37 weeks if the ICP is very severe (severe ICP is defined by researchers as bile acid levels being greater than 40 µmol/L and very severe would suggest bile acids over 100 µmol/L), but this is anecdotal (not scientifically proven) so please discuss this with your own doctor).

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

  • 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