What is the risk of stillbirth in intrahepatic cholestasis of pregnancy (ICP)?

Risk of Stillbirth in Intrahepatic Cholestasis of Pregnancy (ICP)

The risk of stillbirth in ICP is significantly increased with total bile acid levels ≥100 μmol/L, with a 6.8% incidence of perinatal death compared to approximately 0.3-0.4% with lower bile acid levels. 1

Risk Stratification Based on Bile Acid Levels

ICP-associated stillbirth risk can be stratified based on maternal total bile acid (TBA) levels:

Risk Category	Bile Acid Level	Stillbirth Risk
High Risk	≥100 μmol/L	6.8% perinatal death [1]
Moderate Risk	40-99 μmol/L	0.3% perinatal death [1]
Lower Risk	<40 μmol/L	0.4% perinatal death [1]

Pathophysiology of Stillbirth in ICP

The mechanism of stillbirth in ICP is not fully understood but is believed to involve:

• Fetal cardiac dysfunction - elevated bile acids can cause:
  • Fetal arrhythmias 2
  • Prolonged PR intervals correlating with maternal TBA levels 3
  • Elevated NT-proBNP (marker of ventricular dysfunction) 3
  • Abnormal heart rate variability 3
• Vasospasm of placental chorionic surface vessels 2

Risk Factors for Adverse Outcomes

Several factors increase the risk of adverse perinatal outcomes in ICP:

• Total bile acid levels ≥40 μmol/L are associated with:

  • Increased risk of preterm birth (pooled RR 2.23) 2
  • Asphyxia/respiratory distress syndrome (pooled RR 1.67) 2
  • Meconium-stained amniotic fluid (pooled RR 2.27) 2

• Total bile acid levels ≥100 μmol/L are associated with:

  • Highest risk for stillbirth (HR 30.50) 2
  • Increased spontaneous preterm birth (18.2% vs 5.4% with TBA 10-39 μmol/L) 1
  • Increased iatrogenic preterm birth (35.8% vs 10.8% with TBA 10-39 μmol/L) 1
  • Increased meconium-stained amniotic fluid (31.6% vs 9.0% with TBA 10-39 μmol/L) 1

Management Implications

The risk of stillbirth directly impacts delivery timing recommendations:

• For TBA ≥100 μmol/L: Delivery at 36 0/7 weeks or at diagnosis if after 36 weeks 2, 4
• For TBA 40-99 μmol/L: Delivery between 36 0/7 and 39 0/7 weeks 2, 4
• For TBA <40 μmol/L: Delivery between 37 0/7 and 39 0/7 weeks 4

Treatment Effects on Stillbirth Risk

Ursodeoxycholic acid (UDCA) is the first-line treatment for ICP and may help reduce stillbirth risk:

• UDCA partially attenuates the abnormal fetal cardiac phenotype seen in untreated ICP 3
• UDCA-treated cases show normalized heart rate variability compared to untreated cases 3
• However, evidence on whether UDCA definitively reduces stillbirth risk remains inconclusive 2, 5

Important Clinical Considerations

• Continuous fetal monitoring during labor is recommended due to the higher risk of stillbirth 4
• Antenatal fetal surveillance should begin at a gestational age when delivery would be performed in response to abnormal testing 4
• The risk of stillbirth increases with gestational age, with most ICP-related stillbirths occurring after 37 weeks 2
• Of the perinatal deaths observed with TBA ≥100 μmol/L, 3 out of 8 occurred at or after 34 weeks 1

Long-term Implications

Women with a history of ICP should be counseled about:

• High recurrence risk (up to 90%) in future pregnancies 2, 4
• Increased risk for future hepatobiliary, immune-mediated, and cardiovascular diseases 4, 5
• Increased risk for preeclampsia (2.6-fold higher) in future pregnancies 4

Understanding the relationship between bile acid levels and stillbirth risk is crucial for appropriate management and timing of delivery in ICP to optimize maternal and fetal outcomes.