#Grand Rounds

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

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

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)

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)

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)

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