The information - obstetric cholestasis
Obstetricians Dr Victoria Geenes and Professor Catherine Williamson use PUNs and DENs to offer an evidence-based lowdown on obstetric cholestasis.
The patient’s unmet needs (PUNs)
A 25-year-old woman, 34 weeks into her first pregnancy, attends in distress. ‘It’s this itching, doctor,’ she says. ‘It’s driving me mad.’ The symptom started suddenly a few days ago and is affecting her whole body, particularly her palms and soles. She has no other specific symptoms and is on no medication. On examination, you note multiple scratch marks, but no rash or jaundice. ‘I’ve read that this can be something to do with the liver,’ she says. ‘Will it hurt my baby? And is there anything you can give me?’
The doctor’s educational needs (DENs)
What are the possible causes of itching in pregnancy?
Itching in pregnancy is common and is often attributed to stretching of the skin. However, significant pruritus in the absence of a rash is less common and warrants further investigation. There are a number of causes of pruritus in pregnancy, including obstetric cholestasis (OC), dermatological conditions, infestation (such as scabies), viral or bacterial infections, allergic reactions and drug eruptions. Pregnancy-specific skin conditions that result in pruritus include polymorphic eruption of pregnancy, atopic eruption of pregnancy, pemphigoid gestationis, prurigo of pregnancy, pruritic folliculitis and pruritus gravidarum. Other pregnancy-specific disorders, such as acute fatty liver of pregnancy (AFLP), HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) and pre-eclampsia with elevated liver enzymes may present with cholestasis symptoms.
What helps distinguish obstetric cholestasis from these other causes?
OC (also known as intrahepatic cholestasis of pregnancy) can be distinguished by the history and biochemical abnormalities.1 OC typically presents at around 30 weeks’ gestation, although it has been reported in the first trimester. Classically, women report itching of the hands and feet, which is worst at night, but this is variable and the itching may affect any body part. Unlike pregnancy-specific dermatoses, there is no rash, although there may be scratch marks.
OC is characterised by raised serum bile acids and liver transaminases. Bilirubin may be raised, but is more typically normal, and 10% of women are jaundiced. There may be a family history of itching during pregnancy. Other causes of itching and liver dysfunction should be excluded.
What are the risks to mother and foetus?
The main risks relate to foetal outcomes. The largest prospective study of severe OC (serum bile acid levels greater than 40μmol/l) to date reported that there are increased rates of spontaneous and iatrogenic preterm delivery, admission to the neonatal unit and stillbirth.2 This study reported high rates of meconium staining of amniotic fluid, which tended to occur at earlier gestations than in
a healthy pregnancy. These findings are supported by several other smaller prospective studies as well as a large number of retrospective studies.3
With regard to the mothers, if the woman reports steatorrhoea, there is potentially an increased risk of postpartum haemorrhage, but this remains largely theoretical and there are very few reports of postpartum haemorrhage associated with OC.
As the symptoms and biochemical abnormalities of OC resolve following delivery (typically within two to eight weeks), it has historically been considered a benign condition for the mother. However, it is essential to repeat LFTs and serum bile acid levels at eight to 12 weeks postpartum, and to consider alternative diagnoses if abnormalities persist. There are only a few long-term follow-up studies, but there is evidence that these women have an increased risk of gallstones, non-alcoholic cirrhosis and pancreatitis, hepatitis C and autoimmune hepatitis in later life.4
What blood tests should the GP arrange? Are straightforward LFTs adequate, or should bile acids be measured too?
The most sensitive and specific test is the serum bile acid level, which is raised to make the diagnosis of OC. Most units in the UK use an upper limit of 14μmol/l. The transaminase levels, ALT and AST, are also often elevated and can be used to support the diagnosis. Bilirubin may be raised in approximately 10% of women. Alkaline phosphatase is produced in large quantities by the placenta during pregnancy and is therefore of limited use. The clotting profile should be checked in women who report steatorrhoea, as there is a theoretical risk of vitamin K malabsorption and a prolonged prothrombin time. Additional tests that may prove useful are hepatitis C serology, anti-mitochondrial and anti-smooth muscle antibodies, as OC may be the presenting feature of these disorders.4
Following diagnosis, women should be referred to the obstetric teams for discussions regarding the timing of delivery. Ideally, this should take place within a week, especially if diagnosis is made at around 37 weeks’ gestation. It is recommended that serum bile acids and LFTs are monitored weekly following the diagnosis.
What is the management both in terms of the pregnancy and in terms of symptoms?
Management aims to alleviate symptoms, correct biochemical abnormalities and reduce the risk of adverse outcomes. Increased monitoring with regular CTGs is often recommended, but it should be noted that a normal CTG is not predictive of subsequent compromise, and there are several case reports of normal movements and CTG recordings in the hours preceding death. Many units advocate elective preterm or late-term delivery to help reduce the risk of late stillbirth in OC, based on evidence showing a clustering of stillbirths around 37-38 weeks’ gestation. As there is no evidence to support or refute this, clinicians must make an individual judgment.2,5
Ursodeoxycholic acid (UDCA) is commonly used to treat OC and improves symptoms and biochemistry in the majority of cases.3,6,7 Two recent studies with relatively small numbers suggest that UDCA treatment may improve perinatal outcomes, but the results of
a definitive, well-powered study are awaited. Other pharmacological treatments, including S-adenosyl-L-methionine, dexamethasone and cholestyramine, have largely been superseded by UDCA.3 Aqueous cream with 1-2% menthol is a useful topical treatment to relieve pruritus. Chlorpheniramine (piriton) may be given and its sedative effects may aid sleep, but it does not affect the disease process.
What is the likelihood of this recurring? Are there any contraception implications?
There is a high rate of recurrence in future pregnancies.3 But disease severity and perinatal outcomes cannot be predicted by an individual’s history, and recurrence is less likely following a multiple pregnancy. Some women report a recurrence of itching with their menstrual cycle, most commonly in the second half of the cycle and when taking the combined oral contraceptive pill. It is therefore recommended that women use progestogen-only contraception, and have repeat LFTs in the event of a recurrence of symptoms with the combined oral contraceptive pill.
The cause is not fully understood, but it is likely to relate to a genetic susceptibility to the cholestatic effects of reproductive hormones.
OC affects approximately 1% of pregnant women in the UK. It is more common in women of Asian origin.
OC typically presents with pruritus in the third trimester. Classically, this is on the hands and feet, but it may affect any part of the body. It is usually worst at night. OC is diagnosed on the basis of raised serum bile acid levels and elevated liver enzymes. It is associated with an increased risk of adverse perinatal outcomes, including preterm delivery, admission to the neonatal unit and stillbirth.
Women with OC should be referred to the obstetric team to discuss the timing of delivery. They should have regular LFTs, including serum bile acids. UDCA can be used to reduce pruritus and improve liver function.
Symptoms and abnormalities resolve postpartum. OC recurs in up to 90% of subsequent pregnancies, and there is also a risk of a recurrence of symptoms with the menstrual cycle or when taking the combined oral contraceptive pill. There is also an increased risk of hepatobiliary disease later in life.
Dr Victoria Geenes is a clinical research fellow at King’s College London.
Professor Catherine Williamson is a professor of women’s health and consultant obstetric physician at King’s Health Partners, London.
1 Walker I, Chappell L, Williamson C. Rational testing: abnormal liver function tests in pregnancy. BMJ 2013;25:347
2 Geenes V, Chappell LC, Seed PT et al. Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: A prospective population-based case-control study. Hepatology 2014;59:1482-91
3 Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. WJG 2009;15:2049-66
4 Marschall HU, Shemer EW, Ludvigsson JF et al. Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: A population-based cohort study. Hepatology 2013; 58:1385-91
5 RCOG. Obstetric Cholestasis. Green Top Guideline No 43. 2011.
6 Bacq Y, Sentilhes L, Reyes H et al. Efficacy of Ursodeoxycholic Acid in Treating Intrahepatic Cholestasis of Pregnancy: A Meta-analysis. Gastroenterology 2012;143:1492-501
7 Chappell LC, Gurung V, Seed PT et al. Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial. BMJ 2012;344:e3799.