What is the treatment for cholestasis of pregnancy?

Treatment of Intrahepatic Cholestasis of Pregnancy

Ursodeoxycholic acid (UDCA) at 10-15 mg/kg/day is the first-line treatment for intrahepatic cholestasis of pregnancy and should be initiated immediately upon diagnosis. 1, 2

First-Line Pharmacologic Treatment

UDCA Dosing and Administration

• Start UDCA at 10-15 mg/kg/day, divided into 2-3 daily doses (typical regimens: 300 mg twice or three times daily, or 500 mg twice daily). 1
• If pruritus persists after 1-2 weeks, titrate up to a maximum of 21 mg/kg/day. 1, 2
• UDCA is a GRADE 1A recommendation for treating maternal symptoms, with proven efficacy in relieving pruritus and improving laboratory abnormalities. 1
• Expect symptomatic improvement within 1-2 weeks and biochemical improvement (ALT, bile acids) within 3-4 weeks. 1, 2
• UDCA has no known adverse effects on the fetus and is safe during pregnancy. 1

Evidence Nuance on Perinatal Outcomes

The evidence on whether UDCA improves perinatal outcomes is mixed:

• Earlier meta-analyses showed UDCA reduced preterm birth (RR 0.56), fetal distress (RR 0.68), respiratory distress syndrome (RR 0.33), and NICU admissions (RR 0.55). 1
• However, a large 2019 randomized trial (n=605) found no difference in the composite outcome of perinatal death, preterm delivery, or NICU admissions (adjusted RR 0.85,95% CI 0.62-1.15), though maternal pruritus still improved. 1
• This discrepancy likely reflects that modern management with fetal surveillance and planned early delivery may mitigate risks, making UDCA's fetal benefit less apparent. 1

Despite the equivocal perinatal data, UDCA remains first-line because it definitively improves maternal symptoms and has no fetal harm. 1

Second-Line and Adjunctive Treatments

For Refractory Pruritus

When UDCA at maximum dose fails to control symptoms:

• Rifampicin 300-600 mg daily can be combined with UDCA for refractory cases, with documented improvement in pruritus. 1, 2
• Anion exchange resins (cholestyramine 4-8 g/day or colestipol 5-10 g/day) can be added, but must be given at least 4 hours after UDCA to prevent binding and loss of UDCA efficacy. 1
• S-adenosyl-methionine may improve pruritus but is less effective than UDCA; can be used in combination for additive effect. 1, 2
• Antihistamines (diphenhydramine, hydroxyzine) have limited benefit but can be tried. 1
• Topical treatments (menthol creams, calamine lotion) provide minimal relief since itching is typically widespread. 1, 3

Important Caveat on Cholestyramine

Cholestyramine has a significant side effect profile including constipation, diarrhea, abdominal pain, nausea, vomiting, and bloating, which limits its tolerability. 1

Vitamin K Supplementation

• Monitor for vitamin K deficiency, especially in patients using cholestyramine or rifampicin, as cholestasis itself can impair fat-soluble vitamin absorption. 1, 3
• Supplement vitamin K when prothrombin time is prolonged or in confirmed deficiency. 1, 3
• Monitoring coagulation tests is reasonable in women treated with these drugs. 3
• Neonates of women treated with rifampicin should receive vitamin K at birth. 3

Delivery Timing Based on Bile Acid Levels

The Society for Maternal-Fetal Medicine provides clear guidance on delivery timing:

• Bile acids ≥100 μmol/L: Deliver at 36 0/7 weeks or at diagnosis if after 36 weeks (highest risk for stillbirth). 2
• Bile acids <100 μmol/L but elevated: Deliver between 36 0/7 and 39 0/7 weeks. 2
• Bile acids <40 μmol/L: Consider delivery at term. 2
• Administer antenatal corticosteroids for fetal lung maturity if delivery occurs before 37 weeks. 2

Rationale for Early Delivery

Women with bile acids ≥40 μmol/L have increased risks for preterm birth (pooled RR 2.23), respiratory distress syndrome (pooled RR 1.67), and meconium-stained amniotic fluid (pooled RR 2.27). 1 The risk of stillbirth increases substantially with bile acid levels ≥100 μmol/L. 2

Fetal Surveillance

• Begin antepartum fetal surveillance at a gestational age when delivery would be performed in response to abnormal testing. 2
• Repeat bile acid levels to guide delivery timing, especially in severe cases. 2
• Important caveat: No specific fetal monitoring has been proven to prevent stillbirth in ICP, which can occur suddenly. 1

Post-Delivery Management

• Discontinue UDCA at delivery. 3, 2
• If symptoms persist postpartum, consider gradual reduction of UDCA over 2-4 weeks. 2
• If symptoms or abnormal liver tests persist for 4-6 weeks after delivery, repeat biochemical testing and investigate for underlying chronic liver diseases (primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis). 3, 2
• ICP should completely resolve after delivery; persistent abnormalities suggest alternative diagnosis. 1

Special Considerations

• Women with ICP have a 2.62-fold increased risk of preeclampsia, typically occurring 2-4 weeks after ICP diagnosis. 1
• The diagnosis of preeclampsia in ICP patients often presents with proteinuria preceding elevated blood pressure. 1
• ICP increases both spontaneous and iatrogenic preterm birth rates. 1