Introduction

Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-associated liver disease. It classically presents in the third trimester, the cardinal clinical symptom is pruritus, and the specific laboratory examination is an elevated total serum bile acids (TSBA) level1,2.
The prevalence of the condition is 0.2%-2%, but varies greatly among ethnic groups and geographic regions. The pathogenesis is multifactorial: increased reproductive hormones synthesis, environmental factors, genetic predisposition and underlying liver disease are all considered contributions to disease development and severity1,3-5. ICP is a relatively nonthreatening condition to the mother, but it is associated with fetal complications such as spontaneous preterm delivery, meconium passage, and, in severe cases, intrauterine death7. The increased risk of stillbirth is possibly due to bile acids toxicity on fetal cardiomyocytes or to vasoconstriction of chorionic vessels22-24.
Internationally, there is lack of consensus regarding the diagnostic criteria for ICP. Most guidelines agree on the requirement of pruritus accompanied by otherwise unexplained abnormal liver function, both of which resolve rapidly after delivery. TSBA are the most often used biomarker for the diagnosis9-11.
The Royal College of Obstetricians and Gynaecologists (RCOG) guideline recommends that the upper limit of pregnancy-specific ranges of TSBA should be used for diagnosis25. Nevertheless, reference ranges used in clinical laboratories are most often fasting values measured in nonpregnant subjects, a result of extremely limited data for pregnancy-specific reference ranges4,11,17,29. Consequently, there is a wide range of diagnostic criteria for ICP. Most guidelines recommend the use of TSBA values of 10 to 15 µmol/L as a diagnostic threshold, but this may be reduced to 6-10 µmol/L in fasting women1,9,10. In clinical practice, the most widely used threshold is non-fasting 10 µmol/L, despite not being supported by strong evidence9,29.
Recently, only extremely high TSBA levels (100 µmol/L or higher) were shown to markedly increase the risk of stillbirth8. Nevertheless, since no pharmacological treatment has been shown to reduce adverse perinatal outcomes12,27,30, early delivery is still often recommended to prevent the subsequent risk of stillbirth2,7,8. Policies of active management result, however, in increased intervention, caesarean-section rate and iatrogenic prematurity that must be balanced against possible reductions in perinatal mortality. The diagnosis of ICP has serious implications for maternal, and especially fetal and neonatal health18, therefore a correct diagnosis is essential.
The aim of this study was to investigate values of fasting and postprandial TSBA in healthy pregnant women and to establish the reference standard in pregnancy.