What is cholestasis of pregnancy and how is it managed in a pregnant woman, particularly those with a history of liver disease, multiple gestations, or a family history of cholestasis?

Intrahepatic Cholestasis of Pregnancy: Explanation and Management

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by pruritus (typically affecting palms and soles, worsening at night) and elevated serum bile acids >10 μmol/L, usually presenting in the second or third trimester, that poses significant fetal risk including stillbirth, particularly when bile acids exceed 100 μmol/L. 1

Definition and Pathophysiology

ICP is the most common pregnancy-specific liver disease, occurring in 0.1-1.0% of pregnancies in most populations, though rates are higher in South American (9.2-15.6%) and Scandinavian countries (1.5%). 1, 2 The condition results from impaired bile acid transport, leading to accumulation of bile acids in maternal serum and the fetal-placental compartment. 3, 2 Genetic susceptibility (mutations in ABCB11, ABCB4, ATP8B1), hormonal factors (elevated progesterone metabolites), and environmental influences all contribute to disease development. 2

Clinical Presentation

The hallmark symptom is pruritus without a primary rash—only excoriations from scratching are visible. 1, 4 The itching characteristically:

• Affects palms and soles predominantly 4
• Worsens at night 4
• Begins in late second or third trimester (most commonly third trimester) 1, 5
• Occurs without abdominal pain 6

Jaundice develops in only 10-15% of cases, and when present, bilirubin remains <5 mg/dL (<85 μmol/L). 1, 4 Dark urine and significant jaundice should prompt immediate evaluation for more serious conditions like HELLP syndrome or acute fatty liver of pregnancy. 4

Diagnostic Approach

Laboratory Testing

Measure serum total bile acids (non-fasting) and liver transaminases (ALT/AST) immediately in any pregnant woman with pruritus in the second or third trimester. 1, 4

• Bile acids >10 μmol/L are diagnostic 1, 4
• Transaminases are typically elevated (up to 10-20 times upper limit of normal) but not required for diagnosis, usually <500 U/L 1, 4
• Bilirubin typically <6 mg/dL 1
• Alkaline phosphatase is commonly elevated in normal pregnancy and less specific 1

If initial bile acids are normal but symptoms persist, repeat testing after excluding other causes, as pruritus can precede bile acid elevation by several weeks. 4

Differential Diagnosis

Exclude life-threatening conditions first:

• HELLP syndrome (hemolysis, elevated liver enzymes, platelets <50,000/μL, maternal mortality 1-25%) 1, 4
• Acute fatty liver of pregnancy (liver failure with coagulopathy, encephalopathy, hypoglycemia, maternal mortality 7-18%) 1, 4
• Pre-eclampsia 4

Exclude chronic liver diseases:

• Primary biliary cholangitis, primary sclerosing cholangitis (may be unmasked by pregnancy) 1, 4
• Viral hepatitis, biliary obstruction 1
• ABCB4 deficiency (genetic transporter defect, elevated gamma-GT) 4

Perform hepatobiliary ultrasound to exclude gallstones/biliary obstruction. 4

Risk Stratification by Bile Acid Level

Serum bile acid levels directly correlate with fetal risk and dictate management. 1

• Bile acids >100 μmol/L: Highest risk for intrauterine fetal demise 1
• Bile acids 40-100 μmol/L: Intermediate risk 1, 4
• Bile acids <40 μmol/L: Lower risk but still elevated compared to normal pregnancy 4

Monitor bile acids at least weekly from 32 weeks' gestation to identify rising levels. 1

Treatment

Pharmacologic Management

Initiate ursodeoxycholic acid (UDCA) 10-15 mg/kg/day in divided doses immediately upon diagnosis. 1, 4 UDCA:

• Improves maternal pruritus 1
• Reduces serum bile acid and transaminase levels 1
• Decreases adverse outcomes including preterm birth and stillbirth 1
• Is safe throughout pregnancy (FDA Category B) 1, 7

If pruritus persists despite standard UDCA dosing, consider:

• Increasing UDCA to 25 mg/kg/day 1
• Adding cholestyramine, rifampicin, or S-adenosyl-L-methionine (though evidence is limited) 1

Fetal Surveillance

Begin antenatal fetal testing at the gestational age when delivery would be performed in response to abnormal results, or immediately if diagnosed later. 4 Increase testing frequency with higher bile acid levels, especially ≥100 μmol/L. 4

Place all ICP patients on continuous fetal monitoring during labor, as ICP-related stillbirth can occur suddenly even with recent reassuring testing. 4 Traditional fetal surveillance is less predictive because ICP-related fetal demise occurs through a non-placental mechanism. 4

Delivery Timing

Delivery timing is determined strictly by peak total bile acid levels:

• Bile acids ≥100 μmol/L: Deliver at 36 0/7 weeks or at diagnosis if after 36 weeks 1, 4
• Bile acids 40-99 μmol/L: Deliver between 36 0/7 and 37 0/7 weeks 4
• Bile acids <40 μmol/L: Deliver between 37 0/7 and 39 0/7 weeks, with management toward 39 weeks reasonable 1, 4

Never deliver before 37 weeks based on clinical suspicion alone without laboratory confirmation of elevated bile acids. 4 This avoids unnecessary prematurity risks when bile acids may be normal or minimally elevated. 4

Special Populations

Multiple Gestations

Multiple gestations increase ICP risk due to higher estrogen levels. 2 Apply the same bile acid-based delivery timing, though coordinate with maternal-fetal medicine regarding optimal timing given twin-specific considerations.

History of Liver Disease

Pre-existing cholestatic diseases (PBC, PSC) are associated with:

• 50% risk of worsening or de novo pruritus during pregnancy 1
• Increased preterm birth rates 1
• Up to 70% postnatal deterioration of liver tests 1

Monitor bile acids repeatedly in these patients, as higher bile acids correlate with reduced gestation length. 1

Family History

ICP has strong familial clustering with 45-70% recurrence risk in subsequent pregnancies. 1, 4 Consider genetic testing for ABCB11, ABCB4, or ATP8B1 mutations, particularly with early onset or marked hyperbilirubinemia. 4

Postpartum Management

ICP should resolve completely within 4-6 weeks after delivery. 4, 6 If pruritus or abnormal liver tests persist beyond 6 weeks postpartum, refer to hepatology for evaluation of underlying chronic hepatobiliary disease (PBC, PSC, chronic hepatitis C). 1, 4

Counsel patients about significantly elevated long-term risks:

• Chronic hepatitis (HR 5.96) 4
• Liver fibrosis/cirrhosis (HR 5.11) 4
• Hepatitis C (HR 4.16) 4
• Cholangitis (HR 4.2) 4

Advise about high recurrence risk (up to 90%) in future pregnancies. 4

Critical Pitfalls to Avoid

• Never assume ICP without excluding HELLP syndrome and acute fatty liver of pregnancy—these carry maternal mortality risk and require immediate delivery 4
• Never induce labor before laboratory confirmation of elevated bile acids, as this exposes the neonate to unnecessary prematurity complications 4
• Do not rely solely on normal fetal testing to reassure—ICP-related stillbirth occurs suddenly through mechanisms not detected by standard surveillance 4
• Do not delay repeat testing if symptoms persist with initially normal bile acids—levels can rise rapidly, particularly near term 4