Intrahepatic Cholestasis of Pregnancy (ICP) 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. Its main symptom is itching, and the condition is associated with spontaneous premature birth, fetal distress and, in severe cases, stillbirth. The causes of ICP are not yet fully understood, so if you have ICP it is important to know that it is not as a result of anything that you have done. Causes of ICP Hormones Both pregnancy hormones, estrogen and progesterone, have been cited in ICP, and research has shown that the breakdown products of the pregnancy hormone, progesterone, (called sulphated progesterone sulphated metabolites) are known to be higher in women who have ICP. The result of these high levels have an effect on the ability of the liver to transport some chemicals, including bile acids. The flow of bile is reduced leading to the bile acids building up in the blood, which in turn leads to the symptoms women experience in ICP. Genes ICP is more common in certain populations, including Scandinavians, South Americans and women from South Asia (namely India and Pakistan), or whose family origins are India or Pakistan. It has also been found in families which means that there is a genetic element associated with ICP. However, 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 are due to be published soon (2021). 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 - research studies have shown that supplementation with vitamin D can improve cholestasis in animals diet - 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 (both spontaneous and induced) and, in severe cases, stillbirth. How do I know if I have ICP? The most common symptom of ICP is itching. Itching in pregnancy is common (around 20% of women will itch during pregnancy), but the itch in ICP is typically noticeable on the hands, feet, arms and legs, although it can occur anywhere on the body. 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 their itching is more noticeable at night, and it can range from mild itching to being so severe that it can cause loss of sleep and some women have reported feeling suicidal. 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 or ‘floaty’ stools (steatorrhea) Jaundice (although this is not common) Right upper quadrant pain (RUQ) – increasing reports of this symptom have emerged recently as potentially being associated with ICP and needs further research How is the condition diagnosed? The diagnosis of ICP is typically 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 primary biliary cholangitis (PBC). 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. Bile acids are important to test because they are associated with the risk of stillbirth. It is also important that you do not fast for this test, even if you are told to do so. This is because risk is assessed on peak bile acid levels and if you fast, your bile acids will be their lowest. What treatment might I receive? Doctors in the UK tend to treat the condition with a drug called UDCA (ursodeoxycholic acid). However, there has been no evidence that this drug actually worked 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). More recently research from Ovadia et al, 2021 showed that urso can actually reduce the risk of spontaneous premature birth, particularly in those women whose bile acids are >40 µmol/L so you may want to discuss with your doctor whether it may still be worth trying the drug especially as PITCHES also showed that it is safe to take. You may be given aqueous cream with menthol (to help cool and soothe your skin). Anti-histamine tablets (such as piriton) are often given as the side-effects include drowsiness which might help you to sleep 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 who has specialist knowledge of using the medication. If you are prescribed rifampicin, be aware that it will turn your urine an orange-red colour! This is perfectly safe albeit it a little alarming the first time you see it happen. 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 is the same risk as that of women with uncomplicated pregnancies. This means that most women should be able to wait until 38-39 weeks to meet their babies. There were too few numbers of women in the analysis who had their babies beyond 39 weeks, so no conclusion could be drawn about being able to wait until 40 weeks of pregnancy for induction. It is probably reasonable to assume that women whose bile acids never rise >40 µmol/L could await spontaneous labour, but this may need further research and you should discuss your options with your doctor. If you have additional complications such as gestational diabetes or pre-eclampsia this may change the timing of when your baby needs to be born. However, what this research also showed was that some women whose bile acids remain >100 µmol/L will need to have their pregnancies induced from 34-35 weeks of pregnancy onward as the risk of stillbirth increases from 35 weeks of pregnancy, so it is important that these pregnancies are carefully managed. It also means that regularly having non-fasting bile acid tests, with results returned within 48 hours, is crucial for monitoring ICP pregnancies. Vitamin K If one of your clotting tests is abnormal, you should be advised to have water soluble 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 or ‘floaty’ 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. How do I cope with the itch? As well as the treatments that doctor may offer you, you can help the itch if you: Keep as cool as you can – use a fan in the evenings if the weather is hot Turn the temperature down in the house a little if it’s winter Freeze a plastic bottle of water, wrap in a thin cloth to avoid ice burns and place this on affected areas of your skin to cool down Don’t wear clothes that have fibres which will make you itch Don’t lay in bed and scratch, it can just make you feel worse. Get up, make a drink, turn the television on or listen to music to try and distract yourself 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 should 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, but if they don’t resolve you may need to be referred to a liver specialist. Will I get ICP in any future pregnancy? You have a high chance of developing the condition again in another pregnancy; research quotes this risk as being between 60% and 90% Can I pass ICP 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. Further information and support ICP Support https://www.facebook.com/icpsupport 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.2826 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 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 Lancet2019; 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 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. 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. 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