What is intrahepatic cholestasis of pregnancy (ICP), its causes, symptoms, management, and follow-up?

Intrahepatic Cholestasis of Pregnancy: Causes, Symptoms, Management, and Follow-up

Intrahepatic cholestasis of pregnancy (ICP) is a reversible liver disorder characterized by pruritus without primary rash and elevated bile acids that requires prompt treatment with ursodeoxycholic acid and careful monitoring with delivery timing based on bile acid levels to prevent adverse fetal outcomes including stillbirth. 1

Definition and Epidemiology

Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, is a pregnancy-specific liver disorder that:

• Affects 0.3-15% of pregnancies (most estimates between 0.3-0.5%) 1
• Occurs more commonly in multiple pregnancies 1
• Typically presents in the second or third trimester 2
• Is reversible with spontaneous resolution within 4-6 weeks after delivery 2

Pathophysiology and Causes

ICP has a multifactorial pathogenesis involving:

1. Genetic factors:

   • Variants in hepatocanalicular transport proteins:
     • ATP-binding cassette (ABC) transporter B4 (phosphatidylcholine floppase)
     • ABC transporter B11 (bile salt export pump)
     • ABC transporter C2 (conjugated organic anion transporter)
     • ATP8B1 (FIC1) 2
   • Mutations in ABCB11 gene can cause early-onset ICP 3

2. Hormonal factors:

   • Higher incidence in twin pregnancies
   • Can be triggered by high-dose oral contraceptives and progesterone 2
   • Increased sensitivity to estrogens and progestogens 4

3. Environmental factors 2

During ICP, there is increased flux of bile acids from mother to fetus, with elevated bile acid levels in amniotic fluid, cord blood, and meconium 2, 5.

Clinical Presentation and Symptoms

The cardinal symptoms and signs include:

• Pruritus (itching):

  • Occurs without primary rash
  • Generalized but predominantly affects palms and soles
  • Typically worse at night
  • May lead to excoriations or prurigo nodularis from scratching 1

• Other symptoms:

  • Rarely, steatorrhea and postpartum hemorrhage due to vitamin K deficiency 2
  • Jaundice in only 10-15% of cases 2, 1

Diagnosis

Diagnosis is based on:

1. Clinical presentation:

   • Unexplained pruritus without primary rash 1

2. Laboratory findings:

   • Elevated serum bile acid levels (≥10 μmol/L) - most sensitive indicator 1
   • Elevated liver enzymes (ALT, AST) in most cases 1
   • Mild jaundice with moderately elevated conjugated bilirubin in 10-15% of cases 2, 1

3. Exclusion of other causes of pruritus and liver dysfunction 1

A liver biopsy is generally not warranted 2.

Risk Stratification

Risk stratification based on bile acid levels:

• >10 μmol/L: Diagnostic threshold for ICP
• >40 μmol/L: Increased risk of adverse pregnancy outcomes
• >100 μmol/L: Significantly increased risk of stillbirth after 35 weeks gestation 1

Early-onset ICP (before 33 weeks) is associated with increased fetal complications 1.

Management

Pharmacological Treatment

1. First-line treatment: Ursodeoxycholic acid (UDCA)

   • Recommended dosage: 10-15 mg/kg/day 1
   • Benefits:
     • Reduces maternal pruritus
     • Improves liver function tests
     • Reduces bile acid content in the fetal compartment
     • Restores placental transfer of bile acids toward the mother 6
     • May improve fetal outcomes 6

2. Additional symptomatic treatment may include:

   • Antihistamines for pruritus
   • Rifampin in severe cases 3

Fetal Surveillance and Delivery Planning

1. Antenatal fetal surveillance:

   • Begin when delivery would be performed in response to abnormal testing
   • Weekly monitoring from 32 weeks gestation 1

2. Delivery timing based on bile acid levels:

   • Bile acids ≥100 μmol/L: Offer delivery at 36 0/7 weeks
   • Bile acids <100 μmol/L: Recommend delivery between 36 0/7 and 39 0/7 weeks 1

This timing is critical as ICP confers significant risks to the fetus, including:

• Preterm delivery
• Meconium-stained amniotic fluid
• Fetal distress
• Stillbirth 1

Follow-up

1. Postpartum monitoring:

   • Symptoms and laboratory abnormalities should resolve within 4-6 weeks after delivery 1
   • Persistence of abnormalities beyond this period warrants investigation for other chronic liver diseases 1

2. Future pregnancies:

   • High risk of recurrence in subsequent pregnancies 7
   • Early monitoring of bile acids in women with history of ICP

3. Long-term considerations:

   • Consider genetic testing in cases of early-onset, recurrent, or treatment-refractory ICP 3
   • Multidisciplinary management involving obstetricians, hepatologists, and genetic counselors may be beneficial in complex cases 3

Pitfalls and Caveats

• Pruritus can precede laboratory abnormalities, so repeat testing is warranted if symptoms persist 2
• UDCA treatment can affect total bile acid measurements 1
• ICP may be mistaken for other pruritic conditions of pregnancy; absence of primary rash is a key distinguishing feature 1
• Fetal monitoring does not prevent all cases of sudden fetal distress and death 4
• Normal laboratory values may vary; pregnancy-specific reference ranges should be used when available 1