In a pregnant woman in the third trimester presenting with intense pruritus on the palms and soles and elevated serum bile acids, how should intrahepatic cholestasis of pregnancy be diagnosed and managed?

Intrahepatic Cholestasis of Pregnancy: Diagnosis and Management

Diagnostic Approach

Immediately measure serum total bile acids and liver transaminases (ALT/AST) using random (non-fasting) samples in any pregnant woman presenting with pruritus in the second or third trimester. 1, 2

Key Clinical Features

• Pruritus is generalized but predominantly affects palms and soles, worsens at night, and occurs without a primary rash (only excoriations from scratching may be present) 1, 2
• Onset typically occurs after 30 weeks gestation in approximately 80% of cases, though earlier presentation (second trimester) may indicate more severe disease 2
• Dark urine and jaundice are uncommon in ICP—only 10-15% develop mild jaundice with bilirubin <5 mg/dL; their presence should prompt evaluation for HELLP syndrome or acute fatty liver of pregnancy 1, 2

Diagnostic Criteria

• Total serum bile acids >10 μmol/L combined with pruritus confirms the diagnosis 1, 2, 3
• Liver transaminases (ALT/AST) are typically elevated but not required for diagnosis; levels are usually <500 U/L in ICP 1, 2
• Enzymatic bile acid assay provides results in 4 hours to 4 days and is preferred over mass spectrometry (4-14 days) when rapid results are needed 1

Critical Exclusions Before Confirming ICP

Always exclude HELLP syndrome and acute fatty liver of pregnancy first, as these carry significant maternal mortality risk (1-25% and 7-18%, respectively) and require immediate delivery. 2

• Order complete blood count with platelets to exclude HELLP (platelets <50,000/μL) 3
• Check coagulation studies (PT/INR) and glucose to exclude acute fatty liver of pregnancy (presents with coagulopathy and hypoglycemia) 3
• Measure total and direct bilirubin—levels >5 mg/dL suggest HELLP or AFLP rather than ICP 2, 3
• Obtain hepatobiliary ultrasound to exclude gallstones and biliary obstruction 2

Repeat Testing Strategy

• If initial bile acids are normal but pruritus persists, repeat testing every 1-2 weeks until symptoms resolve or diagnosis is confirmed, as pruritus can precede bile acid elevation by several weeks 2, 3
• Never diagnose ICP or make delivery decisions based on pruritus alone without laboratory confirmation of elevated bile acids 2, 3

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Pharmacologic Management

Initiate ursodeoxycholic acid (UDCA) at 10-15 mg/kg/day in 2-3 divided doses immediately upon confirming bile acids >10 μmol/L (GRADE 1A). 2, 4

• UDCA reduces maternal pruritus, lowers bile acid levels, decreases spontaneous preterm birth, and may reduce stillbirth risk 2, 4
• If pruritus remains uncontrolled, titrate UDCA up to 21-25 mg/kg/day 2, 4
• Discontinue UDCA at delivery or taper over 2-4 weeks postpartum if pruritus persists 2, 4

Second-Line Adjuncts for Refractory Pruritus

• Add cholestyramine 4-16 g daily in divided doses, ensuring 2-4 hour separation from UDCA to avoid binding interactions 4
• Monitor prothrombin time regularly with cholestyramine use and supplement vitamin K if prolonged, as the resin can exacerbate vitamin K deficiency leading to coagulopathy 4
• Consider rifampin 300-600 mg daily, but monitor hepatic function as it carries up to 12% risk of drug-induced hepatitis in cholestatic patients 4

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Fetal Surveillance

• Begin antenatal fetal testing at the gestational age when delivery would be performed for abnormal results, or immediately if ICP is diagnosed later in pregnancy 2, 4
• Increase testing frequency as bile acid levels rise—for bile acids ≥100 μmol/L, perform at least twice-weekly monitoring due to approximately 30-fold higher stillbirth hazard 2
• Apply continuous fetal monitoring during labor for all women with ICP, as fetal demise can occur suddenly through a non-placental mechanism even after recent reassuring testing 2, 4

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Delivery Timing Algorithm (Risk-Stratified by Peak Bile Acid Level)

Delivery timing is determined strictly by total bile acid levels, not by symptoms alone. 2

Severe ICP: Bile Acids ≥100 μmol/L

• Deliver at 36 0/7 weeks gestation (GRADE 1B) 2, 4
• Stillbirth risk rises approximately 30-fold at this threshold 2

Moderate ICP: Bile Acids 40-99 μmol/L

• Deliver between 36 0/7 and 39 0/7 weeks, favoring the earlier end of this window (GRADE 1C) 2, 4
• This range is associated with increased risks: preterm birth (RR 2.23), respiratory distress syndrome (RR 1.67), and meconium-stained amniotic fluid (RR 2.27) 2

Mild ICP: Bile Acids <40 μmol/L

• Deliver between 37 0/7 and 39 0/7 weeks; targeting 39 weeks is reasonable given minimal stillbirth risk (approximately 0.1%) 2, 4

Critical Pitfall

Do NOT deliver before 37 weeks based solely on clinical suspicion without documented elevated bile acids (GRADE 1B), as this exposes the neonate to unnecessary prematurity-related morbidity. 2, 4

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Maternal Monitoring

• Measure serum bile acids at least weekly from 32 weeks gestation until delivery, as concentrations can rise rapidly and directly guide delivery timing 2, 3
• Screen for preeclampsia, as ICP is associated with a 2.6-fold increased risk (adjusted OR 2.62) 2
• Monitor for spontaneous preterm labor, as elevated bile acids activate myometrial oxytocin receptors (pooled RR 2.23) 2

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Postpartum Follow-Up

• Repeat serum bile acids and liver transaminases at 4-6 weeks postpartum to confirm resolution 2, 4, 3
• ICP typically resolves completely within days to weeks after delivery 2
• Refer to hepatology if symptoms or laboratory abnormalities persist beyond 6 weeks postpartum, as this indicates possible underlying chronic hepatobiliary disease (primary biliary cholangitis, primary sclerosing cholangitis, ABCB4 deficiency, chronic hepatitis C) 2, 3

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Genetic Considerations and Long-Term Risks

• Consider genetic testing for ABCB11, ABCB4, or ATP8B1 mutations in cases with early onset (second trimester), severe disease (bile acids ≥100 μmol/L), marked hyperbilirubinemia, or family history of hepatobiliary disease 2
• Recurrence risk in subsequent pregnancies is 40-90%, reflecting strong genetic susceptibility 2, 4
• Women with ICP history have markedly elevated long-term risks: chronic hepatitis (HR 5.96), liver fibrosis/cirrhosis (HR 5.11), hepatitis C (HR 4.16), and cholangitis (HR 4.2) 2, 4