SMFM Recommendations: Intrahepatic Cholestasis of Pregnancy

SUMMARY:  

SMFM has released a Consult Series entry on Intrahepatic Cholestasis of Pregnancy (ICP), that typically presents in the second and third trimester of pregnancy. It is characterized by pruritus without rash, as well as elevated bile acids. The incidence is 0.3 to 0.5% and varies between populations. The risks are mostly fetal, including prematurity and IUFD.

Risk Factors

• Preexisting hepatobiliary disease, including
  • HCV | Cirrhosis | Gallstones
• Prior personal or family history with ICP
• Advanced maternal age

Evaluation 

History and Physical

• Detailed history and physical examination
• Chief complaint is that of pruritis
  • ICP generally not associated with a rash
  • Onset, severity, aggravating and alleviating factors

Order Serum Bile Acids & LFTs

• Serum bile acids
  • Total bile acid level is preferred as fractionated has demonstrated limited utility
  • Major differences have not been noted between fasting and postprandial levels
• Liver transaminases (alanine aminotransferase and aspartate aminotransferase)
  • May be elevated but not needed for diagnosis of ICP

Diagnosis 

• Pruritus, predominantly in in palms and feet and usually worse at night
  • Elevated bile acids >10 micromol/L (although document notes that this threshold is based on limited data)
  • +/- Elevated transaminases
• Absence of associated disease with similar symptoms
• Jaundice and dark urine are not typically seen in ICP | Consider other liver disorders (see Differential Diagnosis below)

Differential Diagnosis 

• Without rash
  • Chronic renal disease
  • Thyroid disease
  • Liver disease
  • Infectious: HIV | Parasitosis
  • Malignancy: Lymphoma
  • Drugs
• With rash
  • Atopic eruption of pregnancy
  • Polymorphic eruption of pregnancy
  • Pemphigoid gestationis

Complications 

Neonatal Adverse Outcomes

• Stillbirth
  • >37 weeks: 1.2% vs 0.1% to 0.3% in general population
  • Highest risk if bile acids above 100 micromol/L
  • Underlying mechanism: Possibly due to arrhythmia or placental vessel vasospasm
• Meconium-stained amniotic fluid
• Preterm birth

Maternal Adverse Outcome

• Preeclampsia
  • 2-to-5-fold increase, usually if bile acids are above 40 micromol/L
  • Typically 2 to 4 weeks after diagnosis of ICP

Management 

Laboratory Testing

• Follow-up laboratory testing maybe help guide delivery timing if clinically severe
  • However, serial testing is not recommended
  • If bile acids and liver function tests are still elevated postpartum, specialist referral is recommended

Antenatal Testing

• Efficacy to prevent stillbirth unknown
• Begin antenatal fetal surveillance when delivery would be performed due to abnormal testing
  • Continuous fetal monitoring in labor recommended at that point
• More frequent testing could be used for the following
  • Total bile acid levels of ≥100 micromol/L due to stillbirth risk
  • Additional comorbidities

Treatment

• First line: Ursodeoxycholic acid (UDCA)
  • Dosing: 10 to 15 mg/kg per day, divided in 2 to 3 doses | If pruritis persists beyond 2 weeks, may titrate dose to maximum 21 mg/kg per day
  • Maternal symptoms
    • Effective first line treatment | Pruritus should decrease within 2 weeks
  • Maternal laboratory results
    • Biochemical improvement within 3 to 4 weeks
  • Fetal outcomes
    • Cochrane review (2013) reported benefit for preterm births
    • More recent RCT did not find any fetal benefit (see ‘Related ObG Topics’ below)
• Second line
  • Cholestyramine | S-adenosyl-methionine | Rifampin | Antihistamine | Topical anti-pruritics
  • Have not been evaluated in RCTs

Delivery Timing

• Bile acids ≥100 micromol/L: 36w0d
• Bile acids <100 micromol/L
  • Uncomplicated: 36w0d to 39w0d
  • Complicated pregnancy (severe symptoms; prior stillbirth <36 weeks due to ICP or preexisting or acute hepatic disease): 34w0d to 36w0d

Risk of Recurrence

• May be as high as 90% | Data limited and therefore ranges for counseling are not available  
• Higher risk if underlying hepatic or biliary disease

KEY POINTS:

• ICP is characterized by new onset pruritus without rash, and elevated bile acids
• Risk factors include prior history of ICP and hepatic/biliary disease
• UDCA is first line for the treatment of maternal symptoms but data has not demonstrated impact on adverse neonatal outcomes
• Increase antenatal surveillance is recommended although data limited on optimal frequency
• Delivery timing depends on bile acids levels and maternal symptoms

Learn More – Primary Sources:

Society for Maternal-Fetal Medicine (SMFM) Consult Series 53: Intrahepatic Cholestasis of Pregnancy

PITCHES RCT: Ursodeoxycholic Acid and Intrahepatic Cholestasis of Pregnancy

BACKGROUND AND PURPOSE:

• Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse perinatal outcomes
  • Stillbirth, preterm birth, and NICU admission
• Ursodeoxycholic acid is a widely used treatment for ICP, although data in limited
• Chappell et al. (The Lancet, 2019) investigated whether ursodeoxycholic acid reduces adverse perinatal outcomes in women with ICP

METHODS:

• Pragmatic double-blind, multicenter, randomized placebo-controlled trial (RCT)
• Participants: Women with ICP (based on pruritis and bile acid above normal limit of local lab)
  • ≥18 years
  • GA between 20w0d and 40w6d
  • Singleton or twin pregnancy and no known lethal fetal anomalies
• Interventions (from enrollment till birth)
  • Ursodeoxycholic acid group: 500 mg (1 tablet) twice a day with adjustment based on clinician’s discretion (maximum four tablets | minimum one tablet)
  • Control group: placebo
• Primary outcome: Composite of
  • Perinatal death: IUFD or neonatal death up to 7 days after birth
  • Preterm delivery: <37 weeks
  • NICU admission for at least 4 hours

RESULTS:

• Primary outcome analysis
  • Ursodeoxycholic acid group: included 304 women and 322 infants
  • Control group: 300 women and 318 infants
• The primary outcome occurred in
  • Ursodeoxycholic acid group: 23%
  • Control group: 27%
  • Adjusted risk ratio (RR) 0.85 (95% CI, 0.62 to 1.15)
  • Serious events were recorded but none were attributable to the treatment
• Maternal itch score was significantly reduced in the ursodeoxycholic acid group but “had no clinically meaningful effect” (itch score measured as the worst episode of itch over a day on a 100-mm visual analogue scale)
  • Mean difference −5.7 mm (95% CI, −9.7 to −1.7; p=0·0054)
• Bile acid concentration reduction was less in the ursodeoxycholic acid group vs placebo (p=0.030)

CONCLUSION:

• Compared to placebo, ursodeoxycholic acid did not impact risk for adverse events related to ICP
• The authors of this study suggest that the use of ursodeoxycholic acid for ICP should be reconsidered because

Ursodeoxycholic acid does not seem to have any significant clinical benefit when used routinely for treatment of women with intrahepatic cholestasis of pregnancy

Learn More – Primary Sources:

Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial

Ursodeoxycholic acid for intrahepatic cholestasis in pregnancy