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Grand Rounds

Risk of Stillbirth with Intrahepatic Cholestasis of Pregnancy: What do Bile Acid Concentrations Tell Us?

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BACKGROUND AND PURPOSE:

  • Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcome
  • The association with the concentration of specific biochemical markers is unclear
  • Ovadia et al. (The Lancet, 2019)
    • Quantified the adverse perinatal effects of intrahepatic cholestasis of pregnancy (ICP) in women with increased serum bile acid concentration
    • Determined whether elevated bile acid concentrations were associated with risk of stillbirth and preterm birth, including whether there is a threshold concentration that could be used clinically

METHODS:

  • Systematic review and meta-analysis
    • Initial search: Studies that reported perinatal outcomes for women with ICP and serum bile acid concentrations
  • Inclusion criteria
    • ICP definition based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations
    • Case-control, cohort population-based studies and RCTs
      • Minimum 30 participants | Perinatal outcomes and bile acid concentrations available
  • Exclusion criteria
    • Case reports, non-cohort studies
    • Selection bias such as exclusion of patient groups with poor outcomes
    • ‘Letters to the Editor’ without clear peer review
  • Statistical Analysis
    • ICP and adverse perinatal outcomes: Random effects meta-analysis to determine risks
    • Associations between biochemical markers and adverse outcomes
      • Logistic and stepwise logistic regression, using individual patient data (requested from study authors)

RESULTS:

  • Association of ICP with adverse outcomes
    • 23 studies available for meta-analysis (out of 109)
    • 5,557 ICP cases |165,136 controls
  • Relationship between biomarker levels and adverse outcomes
    • 27 study authors provided individual patient data | 5,269 ICP cases
  • ICP and association with stillbirth (p=0.0016)
    • ICP: 0.91%
    • Control: 0.32%
    • odds ratio (OR) 1.46 (95% CI, 0.73–2.89)
  • ICP was associated with higher risk for spontaneous preterm birth (OR 3.47) | Iatrogenic preterm birth (OR 3.65) | Meconium stained fluid (OR 2.60) | NICU admission (OR 2.12)
  • Association of stillbirth with biomarkers
    • For singleton pregnancies, stillbirth risk was associated with maximum total bile acid concentration (not alanine aminotransferase)
    • Total bile acid concentration area under the ROC curve: 0.83 (95% CI, 0.74–0.92)
    • Alanine aminotransferase area under the ROC curve: 0.46 (0.35–0.57)
    • Treatment with ursodeoxycholic acid did not significantly affect this association
  • Stillbirth prevalence in ICP higher when total bile acids ≥100 μmol/L
    • <40 μmol/L: 0.13% (95% CI, 0.02–0.38)
    • 40–99 μmol/L: 0.28% (95% CI, 0.08–0.72)
    • ≥100 μmol/L: 3.44% (95% CI, 2.05–5.37) | Hazard ratio 30.50 (8.83–105.30; p<0.0001)

CONCLUSION:

  • Authors recognize study limitations, including
    • Possibility of incomplete data related to confounders
    • Significant number of iatrogenic preterm deliveries could bias study
  • The risk of stillbirth with ICP increases compared to a general population when serum bile acid concentrations are ≥100 μmol/L
  • Authors of this study and the Lancet commentary suggest management based on serum bile acid concentrations
    • <100 μmol/L: Women with ICP can be reassured
      • Repeat weekly bile acid testing should be done until delivery
    • “In comparison, in women with total bile acid concentrations of 100 μmol/L or more, delivery should probably occur by 35–36 weeks of gestation” (‘Comment in the Lancet’, see below)

Learn More – Primary Sources:

Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses

Comment in the Lancet: Management of intrahepatic cholestasis in pregnancy

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Related ObG Topics:

ACOG Recommendations: When to Deliver Medically Complicated Pregnancies
Is Rifampin an Option for the Treatment of Intrahepatic Cholestasis in Pregnancy?
Acute Fatty Liver of Pregnancy: A True Obstetric Emergency
Results from the MiNESS Trial: Does Supine vs Left-Sided Sleeping Position Impact Risk of Stillbirth?

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