Postprandial total serum bile acid helps identify IHCP women at increased risk of stillbirth: Study
Intrahepatic cholestasis of pregnancy (ICP) is defined by gestational pruritus and elevated total serum bile acids (TSBA). The incidence of ICP varies between 0.2 and 5.6% of pregnancies, which may be accounted for by differences in ethnic populations as well as the diagnostic criteria used. Diagnostic thresholds for ICP range from ≥6 to >15 lmol/l, depending upon hospital and national guidelines and there is currently no consensus as to whether TSBA should be measured fasting or postprandially, although it is well documented that TSBA concentrations rise after food.
Intrahepatic cholestasis of pregnancy is associated with an increased risk of adverse pregnancy outcomes, including meconium-stained amniotic fluid, neonatal unit admission, spontaneous preterm birth and stillbirth.
No pharmacological treatment or monitoring strategy has been found to reduce stillbirth in ICP, such that many women undergo iatrogenic preterm birth with the aim of reducing this risk. However, preterm birth is associated with an increased risk for the neonate, including respiratory distress and cognitive impairment in childhood. As a result, correct diagnosis of the severity of ICP is necessary to enable clinicians to identify women with TSBA levels associated with increased risk of stillbirth to facilitate informed decision-making about timing of deliver.
To address concerns regarding accuracy and thresholds for ICP diagnosis, Mitchell AL and team performed three interlinked studies. In the first, they measured fasting and serial postprandial TSBA levels in response to standardised meals in women with ICP and uncomplicated pregnancies. In the second study, they determined reference intervals for postprandial TSBA from a separate cohort of women in their third trimester of uncomplicated pregnancy. In the third study, data from a published individual patient data meta-analysis were used to compare rates of adverse perinatal outcomes for women with ICP but peak TSBA below the upper reference limit for TSBA identified in Study 2 with matched normal populations, to determine the effect of altering the diagnostic threshold for ICP.
The study was Case–control, retrospective cohort study. It was carried out at Antenatal clinics in clinical research facilities. Women with ICP or uncomplicated pregnancies were included. 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. Sensitivity and specificity of common TSBA thresholds for ICP diagnosis, using fasting and postprandial TSBA. Calculation of normal reference ranges of non-fasting TSBA.
Concentrations of TSBA increased markedly postprandially in all groups, with overlap between healthy pregnancy and mild ICP (TSBA<40 lmol/l).
The specificity of ICP diagnosis was higher when fasting, but corresponded to <30% sensitivity for diagnosis of mild disease.
Using TSBA ≥40 lmol/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 lmol/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.
This study revealed the diurnal variation in TSBA in both cholestatic and uncomplicated pregnancies, demonstrating the difficulties in determining clinically appropriate diagnostic thresholds to identify affected women with acceptable sensitivity and specificity. Considering that the adverse perinatal outcomes of ICP are associated with peak TSBA concentration, measuring non-fasting rather than fasting TSBA has greater clinical relevance for decisions about patient management according to severity of hypercholanaemia.
As a woman's typical TSBA concentrations are probably more relevant to the fetal bile acid exposure and stillbirth risk than TSBA results after a fixed meal stimulant, authors suggest that this non-fasting reference range is of greater clinical relevance. Fasting TSBA concentrations of women with mild ICP from standardised diet study were generally below the current diagnostic thresholds, and most women who had severe ICP (TSBA ≥40 lmol/l13) would not have been diagnosed as such using fasting samples. The European Association for the Study of Liver threshold currently suggests that fasting TSBA ≥11 lmol/l is diagnostic. However, this may miss correct risk stratification, as TSBA levels in women whose fasting TSBA level is <40 lmol/l can rise postprandially to ≥40 lmol/l, when risk of perinatal complications is increased, or even higher to ≥100 lmol/l, when the risk of stillbirth is elevated.
Based upon the results of this study, authors suggest that a non-fasting TSBA value of ≥19 lmol/l is used as a clinical diagnostic threshold for ICP, as an alternative to fasting thresholds. It is important that pregnant woman with otherwise unexplained pruritus whose non-fasting TSBA levels are <19 lmol/l are monitored regularly for changes in TSBA, given that pruritus often predates hypercholanaemia.
Use of appropriate diagnostic levels is likely to reduce the number of women diagnosed with ICP, thereby reducing maternal anxiety, avoiding unnecessary antenatal consultations and potential complications associated with iatrogenic preterm birth. Furthermore, the use of postprandial TSBA measurements is more likely to identify women with TSBA ≥100 lmol/l and at increased risk of stillbirth, and will empower clinicians to individualise interventions aimed at reducing the risk of adverse outcomes in this small but important group of women.
Source: Mitchell AL, Ovadia C, Syngelaki A, Souretis K et al. BJOG 2021;128: 1635–1644.