Abstract: Our search yielded 5073 references, but at the end of our selection process, only 16 studies fulfilled the review inclusion criteria. Nine of these provided individual participant data. We analysed only data concerning TSBA, cholic acid (CA), glycocholic acid (GCA), chenodeoxycholic acid (CDCA), and CA/CDCA because the remaining planned index tests were assessed in few studies. Only one study had low risk of bias in all four QUADAS-2 domains. The most biased domains were the patient sampling and the reference standard domains. When considering all studies with a cut-off of 10 μmol/L, TSBA overall sensitivity ranged from 0.72 to 0.98 and specificity ranged from 0.81 to 0.97. After a sensitivity analysis excluding case-control studies, TSBA sensitivity ranged from 0.48 to 0.66 and specificity from 0.52 to 0.99. After a sensitivity analysis excluding studies in which TSBA was part of the reference standard, TSBA sensitivity ranged from 0.49 to 0.65 and specificity from 0.53 to 0.99. We found the estimates of the overall accuracy for some serum bile acid components (CA, GCA, CDCA, and CA/CDCA) to be imprecise, with the CI for sensitivity and specificity very wide or impossible to calculate. Indirect comparisons between serum bile acid profile components and TSBA were not statistically significant. None of the heterogeneity analysis performed was statistically significant, except for the timing of assessment of TSBA (onset of symptoms, peak value among multiple assessments, delivery) but without clinically relevant results. We could not analyse the diagnostic accuracy of combinations of index tests because none of the included studies carried them out, and because of the small number of included studies. The overall high risk of bias, the existing concern regarding applicability of the results in clinical practice, and the great heterogeneity of the results in the included studies prevents us from making recommendations and reaching definitive conclusions at the present time. Thus, we do not find any compelling evidence to recommend or refute the routine use of any of these tests in clinical practice. So far, the diagnostic accuracy of TSBA for intrahepatic cholestasis of pregnancy might have been overestimated. There were too few studies to permit a precise estimate of the accuracy of serum bile acid profile components. Further primary clinical research is mandatory. We need both further phase II and phase III diagnostic studies.

Plain-language summary: This review considered all evidence provided by studies that assess the diagnostic accuracy of total serum bile acids (TSBA) and any component of serum bile acid profile for intrahepatic cholestasis of pregnancy in woman claiming onset of pruritus during pregnancy. We assessed all available reports from a wide, systematic search of databases of medical literature, irrespective of design, publication status, language, and study design. We finally included 16 studies, most of them assessing the accuracy (sensitivity and specificity) of TSBA with a cut-off of 10 μmol/L. Most studies had a case-control design, and these studies could have overestimated the diagnostic accuracy. When considering the studies with a cut-off of 10 μmol/L for TSBA serum concentration, TSBA overall sensitivity (the ability to correctly identify women with the disease) ranged from 72% to 98% and specificity (the ability to correctly identify women without the disease) ranged from 81% to 97%. However, after performing two different analyses excluding studies with probably less reliable results, the diagnostic accuracy seemed lower. We calculated the overall accuracy also of some components of serum bile acid profile, but the small number of studies and the high variability of the results led to very imprecise data. Only one of the 16 included studies was performed and reported well (low risk of bias). The remaining 15 studies had problems with study design or reporting (high risk of bias). Only five studies seemed to show low concern regarding applicability of the results in clinical practice. The overall high risk of bias, the existing concern regarding applicability of the results in clinical practice, and the poor uniformity of our results in the included studies prevents us from making recommendations and reaching definitive conclusions at present. Thus, we do not find any compelling evidence to recommend or refute the routine use of any of these tests in clinical practice. So far, the diagnostic accuracy of TSBA for intrahepatic cholestasis of pregnancy might have been overestimated. There were too few studies to permit a precise estimate of the accuracy of serum bile acid profile components. Further primary clinical research is mandatory. We need both further phase II and phase III diagnostic studies.