Intrahepatic cholestasis of pregnancy



Intrahepatic cholestasis of pregnancy is a liver disease unique to pregnancy that is characterised by pruritus and elevated bile acids.

Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-associated liver disease. It is characterised by pruritus (i.e. itching), elevated bile acids, and variable elevations in liver function tests (e.g. ALT/AST). It is due to cholestasis (i.e. decreased bile flow) and classically occurs in the late second or third trimester.

ICP is important to recognise because it is associated with an increased risk of fetal demise and stillbirth, particularly when the bile acid concentration is ≥ 100 micromol/L.

Pregnancy-associated liver disease

ICP is the most common pregnancy-associated liver disease.

Pregnancy-associated liver disease refers to a unique set of disorders that affect the liver during pregnancy. Some are common and usually have a mild presentation (e.g. ICP). Others are severe and can be life-threatening for both mother and fetus (e.g. acute fatty liver of pregnancy)

Pregnancy-associated liver diseases include:

  • Intrahepatic cholestasis of pregnancy (ICP)
  • HELLP syndrome (haemolytic anaemia, elevated liver function tests, low platelets)
  • Acute fatty liver of pregnancy (AFLP)
  • Liver dysfunction in pre-eclampsia
  • Liver dysfunction in hyperemesis gravidarum


ICP is a common disorder in pregnancy but the incidence varies worldwide.

The incidence of ICP varies by geographical location. The incidence across Europe ranges from 0.5-1.5%. The highest incidence is in Scandinavia. In some countries, ICP is more common in the winter months for unknown reasons (e.g. Sweden).

ICP is more common in multiple pregnancies (I.e. twins, triplets) and patients with a past history of ICP have an increased risk in subsequent pregnancies.

Aetiology & pathophysiology

The exact cause of ICP remains unknown.

ICP is a pregnancy-related liver disorder meaning it occurs during pregnancy, most commonly in the late second or third trimester. The exact cause is unknown by is likely due to a combination of genetic susceptibility, hormonal and environmental factors.

  • Genetics: a genetic basis is proposed by a high recurrence rate, increased risk in first-degree relatives and high rate in certain ethnic groups. ABCB4 has been identified as an at-risk gene (encodes a canalicular phospholipid translocator)
  • Hormones: oestrogen is suspected to play a significant role in ICP. Oestrogen is highest during the second half of pregnancy when ICP occurs and oestrogen is known to cause cholestasis. Excess administration of progesterone may also contribute to ICP in pregnancy.
  • Environment: geographical and seasonal variation indicate an environmental role, but the exact mechanisms are unclear.

There is a small association between ICP and underlying liver disease (e.g. NAFLD) that may be revealed during pregnancy and contribute to the development of ICP.

Clinical features

The cardinal feature of ICP is pruritus, which may precedes abnormalities in bile acids and liver function tests.


Usually, symptoms begin in the late second or third trimester.

  • Pruritus: usually starts and predominates in soles and palms. It is worse at night. Ranges from mild to severe.
  • Right upper quadrant pain
  • Nausea
  • Anorexia
  • Steatorrhoea: excess fat in faeces (pale, oily, difficult to flush)

NOTE: pruritus affects up to one-quarter of pregnancies. Of these, ICP represents a small proportion.


There may be evidence of scratch marks and excoriation. Jaundice can occur.

  • Scratch marks
  • Excoriation
  • Jaundice (up to 25%): 1-4 weeks after pruritus onset

Primary skin lesions or stigmata of chronic liver disease warrant consideration of an alternative diagnosis

Diagnosis & investigations

The diagnosis of ICP is usually made on the presence of pruritus and elevated bile acids in pregnancy.

Many diseases can cause pruritus or abnormal liver function tests in pregnancy. A formal diagnosis is based on the history, clinical examination, and laboratory investigations to ensure an alternative diagnosis is excluded and to demonstrate the elevated levels of bile acids. Pruritus may precede biochemical abnormalities, so tests should be repeated if suspected.

Bile acids

Serum bile acids should be measures in all suspected ICP cases. Seen in > 90% of affected pregnancies. If initially normal, important to check weekly unless empirical treatment was started.

The primary bile acids measured are cholic and chenodeoxycholic acid. Severe cholestasis is generally defined as bile acids > 40 micromol/L but the exact cut-off is variable and depends on the local laboratory normal values.

Liver function tests

Patients with ICP may have deranged liver function tests.

  • AST/ALT: elevated ~60%. Levels should be unaffected by pregnancy. Values usually minimally elevated (i.e. < x2 ULN).
  • ALP: may be elevated but it is raised in pregnancy anyway due to the expression of a placental isoenzyme (an enzyme with identical structure/function).
  • Bilirubin: elevated in up to 25%. Rarely > 100 umol/L.

Extremely high levels of AST/ALT or bilirubin should warrant investigation for an alternative diagnosis.


A liver ultrasound is commonly completed in patients with deranged liver function tests to exclude an alternative diagnosis. There are no structural defects (e.g. biliary dilatation, mass lesion) associated with ICP.

Fetal complications

The most significant risk of ICP to the fetus is stillbirth.

In ICP, high maternal bile acids may cross the placenta and accumulate in the amniotic fluid and fetus. This can lead to fetal demise. This usually presents as a sudden deterioration rather than a slow deterioration meaning growth restriction and oligohydramnios are not features.

Fetal effects of ICP:

  • Stillbirth: unclear mechanism
  • Spontaneous preterm labour
  • Iatrogenic preterm labour
  • Meconium-stained amniotic fluid
  • Neonatal respiratory distress syndrome
  • Need for neonatal ICU admission

The risk of serious fetal effects correlates with a higher degree of maternal bile acids. Levels ≥ 100 micromol/L is associated with a significantly increased risk of stillbirth at any point during pregnancy. Rates of stillbirth increase with gestational age.


The principal treatment of ICP is ursodeoxycholic acid (UDCA) although this does not seem to improve fetal outcomes.

The management of ICP aims to improve symptoms of pruritus in patients and reduce fetal perinatal morbidity and mortality.

Maternal management

All patients with ICP should be offered UDCA to reduce symptoms and to improve liver function tests and bile acids. UDCA can be started empirically for pruritus or initiated once bile acids/LFTs become abnormal. An improvement is usually seen in 1-2 weeks of therapy.

Once initiated, weekly blood can be assessed to determine the level of bile acids. However, UDCA does not seem to affect fetal/neonatal outcomes. Several additional agents can be used for refractory cases including glutathione precursor S-adenosyl-methionine, cholestyramine, or rifampicin.

Pregnancy management

Patients usually have frequent blood tests and monitoring during the antepartum period once ICP is diagnosed, but the value of fetal monitoring is unclear especially as fetal demise is suspected to be a sudden event.

The key to pregnancy management is the timing of delivery. This needs to balance the risk of stillbirth with increasing gestational age versus the increased perinatal risk with earlier delivery. In general, delivery before 37+0/40 should be avoided if bile acids are not elevated.

The Royal College of Obstetricians and Gynaecologists released guidelines in 2011 (reviewed in 2014) that set out principles on the timing of delivery. This details that patients should be informed that the case for early intervention (i.e. induction of labour at > 37+0 weeks) may be stronger in those with more severe bile acid levels and patients should be informed regarding the increased risk of perinatal morbidity with early intervention.

The American College of Obstetricians and Gynaecologists and authors of Uptodate generally recommend active management (i.e. induction of labour) based on bile acid levels.

  • Bile acids ≥ 100 micromol/L: consider delivery at 36 weeks gestations. Certain situations may warrant even earlier delivery (e.g. excruciating/unremitting maternal pruritus)
  • Bile acids < 100 micromol/L: consider delivery at 36-39+0 weeks gestation. Consider delivery at diagnosis if diagnosed >39+0 weeks.

No special requirements are needed during labor, but continuous fetal monitoring should be used (e.g. cardiotocograph - CTG).


Pruritus associated with ICP should resolve rapidly within a few days after delivery.

Following delivery, pruritus and liver function abnormalities should improve rapidly. Patients can still breastfeed and UDCA is usually stopped on the day of delivery (low levels may be detected in breastmilk but not expected to have adverse effects). If LFTs do not improve, patients should be referred to hepatology to investigate for underlying liver disease.

Importantly, ICP will recur in 60-70% of pregnancies, but the clinical course is highly variable.

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