Re-evaluating diagnostic thresholds for intrahepatic cholestasis of pregnancy: case-control and cohort study

BJOG. 2021 Sep;128(10):1635-1644. doi: 10.1111/1471-0528.16669. Epub 2021 Apr 6.


Objective: To determine the optimal total serum bile acid (TSBA) threshold and sampling time for accurate intrahepatic cholestasis of pregnancy (ICP) diagnosis.

Design: Case-control, retrospective cohort studies.

Setting: Antenatal clinics, clinical research facilities.

Population: Women with ICP or uncomplicated pregnancies.

Methods: Serial TSBA measurements were performed pre-/postprandially in 42 women with ICP or uncomplicated pregnancy. Third-trimester non-fasting TSBA reference ranges were calculated from 561 women of black, south Asian and white ethnicity. Rates of adverse perinatal outcomes for women with ICP but peak non-fasting TSBA below the upper reference range limit were compared with those in healthy populations.

Main outcome measures: Sensitivity and specificity of common TSBA thresholds for ICP diagnosis, using fasting and postprandial TSBA. Calculation of normal reference ranges of non-fasting TSBA.

Results: Concentrations of TSBA increased markedly postprandially in all groups, with overlap between healthy pregnancy and mild ICP (TSBA <40 μmol/l). The specificity of ICP diagnosis was higher when fasting, but corresponded to <30% sensitivity for diagnosis of mild disease. Using TSBA ≥40 μmol/l to define severe ICP, fasting measurements identified 9% (1/11), whereas non-fasting measurements detected over 91% with severe ICP. The highest upper limit of the non-fasting TSBA reference range was 18.3 µmol/l (95% confidence interval: 15.0-35.6 μmol/l). A re-evaluation of published ICP meta-analysis data demonstrated no increase in spontaneous preterm birth or stillbirth in women with TSBA <19 µmol/l.

Conclusions: Postprandial TSBA levels are required to identify high-risk ICP pregnancies (TSBA ≥40 μmol/l). The postprandial rise in TSBA in normal pregnancy indicates that a non-fasting threshold of ≥19 µmol/l would improve diagnostic accuracy.

Tweetable abstract: Non-fasting bile acids improve the diagnostic accuracy of intrahepatic cholestasis of pregnancy diagnosis.

Keywords: Cholestasis; clinical decision-making; liver diseases in pregnancy.

Publication types

  • Evaluation Study

MeSH terms

  • Adult
  • Bile Acids and Salts / blood*
  • Biomarkers / blood
  • Case-Control Studies
  • Cholestasis, Intrahepatic / blood
  • Cholestasis, Intrahepatic / diagnosis*
  • Cohort Studies
  • Female
  • Humans
  • Pregnancy
  • Pregnancy Complications / blood
  • Pregnancy Complications / diagnosis*
  • Prenatal Diagnosis*
  • Retrospective Studies
  • Sensitivity and Specificity


  • Bile Acids and Salts
  • Biomarkers

Supplementary concepts

  • Intrahepatic Cholestasis of Pregnancy