What is the management of cholestasis of pregnancy?

Management of Intrahepatic Cholestasis of Pregnancy

Ursodeoxycholic acid (UDCA) 10-15 mg/kg/day is the first-line treatment for intrahepatic cholestasis of pregnancy (ICP), and delivery timing should be risk-stratified based on total serum bile acid levels: deliver at 36 weeks for bile acids ≥100 μmol/L, between 36-39 weeks for bile acids <100 μmol/L, and toward 39 weeks for bile acids <40 μmol/L. 1

Diagnosis

• Confirm ICP with total serum bile acids >10 μmol/L in the presence of pruritus, typically presenting in the third trimester (though can occur earlier). 1, 2
• Obtain a complete liver panel including ALT, AST, bilirubin, and alkaline phosphatase at initial presentation. 1, 3
• If initial bile acids are normal but pruritus persists, repeat testing every 1-2 weeks as bile acid elevation may lag behind symptom onset by several weeks. 1, 4
• Rule out alternative diagnoses: check viral hepatitis serologies (HBsAg, anti-HCV, HAV IgM, HEV), autoimmune markers (AMA, ANA, SMA), and perform liver ultrasound to exclude biliary obstruction. 1, 3
• Consider pre-eclampsia, HELLP syndrome, and acute fatty liver of pregnancy in the differential, particularly if presentation is atypical or includes hypertension, thrombocytopenia, or coagulopathy. 1

Critical pitfall: Do not start UDCA before obtaining baseline bile acid levels, as this prevents subsequent diagnosis and may mask the biochemical signature. 4

Pharmacological Treatment

First-Line Therapy

• Start UDCA at 10-15 mg/kg/day divided into 2-3 doses for all confirmed ICP cases. 1, 2
• UDCA improves maternal pruritus (though effect is modest), reduces spontaneous preterm birth risk in singleton pregnancies, and may protect against stillbirth. 1, 2
• Clinical improvement in pruritus typically occurs within 1-2 weeks; biochemical improvement takes 3-4 weeks. 2
• If pruritus remains uncontrolled, titrate UDCA up to 21-25 mg/kg/day maximum. 1, 2

Second-Line Options for Refractory Pruritus

• Rifampicin can be added to UDCA for severe, refractory cases, though evidence is limited. 1
• S-adenosyl-L-methionine is less effective than UDCA alone but may have additive benefit when combined. 1, 2
• Cholestyramine, guar gum, and activated charcoal have limited evidence but can be considered. 1
• Topical emollients are safe but efficacy is unknown. 1

Avoid dexamethasone (12 mg/day for 7 days) as it is ineffective for reducing pruritus or ALT levels in ICP, though it promotes fetal lung maturity when preterm delivery is planned. 1

Monitoring Strategy

Maternal Monitoring

• Repeat bile acid and liver function tests weekly once diagnosis is confirmed, as bile acids may continue to rise with advancing gestation. 1, 2
• For early diagnosis (<32 weeks), check bile acids and LFTs every 2 weeks until 32 weeks, then weekly until delivery. 1

Fetal Surveillance

• Begin antenatal fetal surveillance only after ICP is confirmed with elevated bile acids, at a gestational age when delivery would be performed in response to abnormal testing. 1, 4
• Do not initiate fetal surveillance in patients with pruritus but persistently normal bile acids, as evidence does not support increased fetal risk in this population. 4
• No specific fetal monitoring method has proven superior; cardiotocography cannot predict sudden intrauterine death, which can occur acutely in ICP. 5

Delivery Timing: Risk-Stratified Approach

Bile Acids ≥100 μmol/L (Severe ICP)

• Deliver at 36 0/7 weeks of gestation or at diagnosis if after 36 weeks, as stillbirth risk increases substantially at this gestational age. 1, 2
• The risk of stillbirth rises markedly from 35 weeks' gestation in this group. 1

Bile Acids 40-99 μmol/L (Moderate ICP)

• Deliver between 36 0/7 and 39 0/7 weeks, with timing individualized based on patient-specific factors. 1
• Consider earlier delivery (closer to 36 weeks) in this range given intermediate risk. 1

Bile Acids <40 μmol/L (Mild ICP)

• Manage toward the later end of 36-39 weeks range, with induction by 39 weeks reasonable, given the low stillbirth risk. 1

Special Circumstances for Delivery 34-36 Weeks

Consider delivery between 34-36 weeks only for bile acids ≥100 μmol/L AND one of the following: 1

• Excruciating, unremitting pruritus not relieved with pharmacotherapy
• History of stillbirth before 36 weeks due to ICP with recurrence in current pregnancy
• Preexisting or acute hepatic disease with worsening hepatic function

Extensively counsel about prematurity morbidity before any delivery <36 weeks. 1

Antenatal Corticosteroids

• Administer betamethasone or dexamethasone for fetal lung maturity if delivering before 37 0/7 weeks and not previously given. 1, 2

Critical Delivery Pitfall

Never deliver preterm (<37 weeks) based on clinical suspicion alone without laboratory confirmation of elevated bile acids (GRADE 1B). 1, 4 This avoids iatrogenic prematurity-related morbidity when diagnosis is uncertain. 4

Management When Diagnosis is Uncertain

For early-term pregnancies (37-38 weeks) with pruritus suggestive of ICP but no bile acid results available: 1

• Use shared decision-making discussing uncertainty of diagnosis, risks of ICP versus early-term delivery, and patient values
• Diagnostic certainty improves if elevated transaminases present or history of ICP in prior pregnancies
• Enzymatic bile acid assays can shorten time to results and may be useful in this scenario. 1

Postpartum Management

Immediate Postpartum

• Stop UDCA at time of delivery. 1, 2
• If symptoms persist, consider gradual UDCA reduction over 2-4 weeks postpartum. 1, 2

Follow-Up Testing

• Ensure bile acids, ALT, AST, and bilirubin return to normal within 3 months of delivery. 1, 2, 3
• If abnormalities persist beyond 4-6 weeks postpartum, investigate for underlying chronic liver disease including primary biliary cholangitis, primary sclerosing cholangitis, ABCB4 deficiency, or chronic hepatitis C. 1, 3
• Refer to hepatology/liver specialist if serologic abnormalities persist. 1, 4, 3

Long-Term Counseling

• ICP recurs in up to 90% of subsequent pregnancies. 1, 3
• Women with history of ICP have increased risk of later developing chronic hepatitis (HR 5.96), liver fibrosis/cirrhosis (HR 5.11), hepatitis C (HR 4.16), and cholangitis (HR 4.2), with greatest risk in the first year after diagnosis. 1, 3
• Some experts advocate routine hepatitis C testing given the increased risk and availability of effective treatment. 1
• Consider genetic screening if family history of hepatobiliary disease, early onset (<33 weeks), or severe disease. 1

Key Clinical Pitfalls to Avoid

• Do not diagnose ICP based on pruritus alone without elevated bile acids—this leads to unnecessary preterm deliveries with neonatal morbidity. 4, 3
• Do not assume normal initial labs permanently rule out ICP—biochemical abnormalities may develop weeks after symptom onset. 4
• Do not start UDCA empirically before obtaining baseline bile acids—this prevents definitive diagnosis. 4
• Do not perform liver biopsy—it is not warranted for ICP diagnosis. 1
• Do not use obeticholic acid in pregnancy—it lacks safety data. 3