Intrahepatic cholestasis of pregnancy (ICP), characterized by pruritus in the second half of pregnancy, entails an increased risk to the fetus. This study was designed to determine the incidence and fetal complication rates in ICP, and to define groups at increased risk. In an prospective cohort study conducted between February 1, 1999, and January 31, 2002, all 45,485 pregnancies in a defined region of Sweden (Västra Götaland) were screened for ICP, defined as otherwise unexplained pruritus of pregnancy in combination with fasting serum bile acid levels >10 mol/L. Pruritus was reported by 937 (2.1%) women, and ICP was diagnosed in 693 (1.5%). Simple logistic regression analyses showed that the probability of fetal complications (spontaneous preterm deliveries, asphyxial events, and meconium staining of amniotic fluid, placenta, and membranes) increased by 1%-2% per additional mol/L of serum bile acids. Complementary analyses showed that fetal complications did not arise until bile acid levels were >40 mol/L. Gallstone disease and a family history of ICP were significantly (P < .001) more prevalent in the group of ICP patients with higher bile acid levels. In conclusion, we found an incidence of ICP in our population of 1.5%. From complication rates recorded prospectively, we could define a mild (81%) and a severe (19%) form of ICP, the latter with bile acid levels >40 mol/L. No increase in fetal risk was detected in ICP patients with bile acid levels < 40 mol/L, and we propose that these women be managed expectantly, which would significantly reduce the costs of medical care. I ntrahepatic cholestasis of pregnancy (ICP) is a condition characterized by pruritus in the second half of pregnancy. It persists until delivery, after which it ceases promptly. A genetic background is suggested by family clustering and demographic variations, with the highest incidences reported from Chile-Bolivia (6%-27%) and Sweden (1-1.5%). 1 ICP is associated with an increased risk of preterm delivery in 19%-60%, 2-5 intrapartum fetal distress in 22%-41%, and intrauterine fetal death (IUFD) in 0.75%-1.6% of the affected pregnancies. [3][4][5][6] The diagnostic criteria for ICP have varied over time in different reports, making complication rates difficult to compare. When, in addition to pruritus, clinical jaundice was used to define ICP, higher fetal complication rates were reported than when diagnosis was based only on elevated bile acid and transaminase levels. 2,3,6 -8 The Swedish ICP incidence figure is taken from a study using only pruritus in pregnancy as the inclusion criterion, and that study did not report increased fetal risk associated with ICP. 9 Nowadays, elevation of serum bile acids is considered to be the most appropriate laboratory parameter for diagnosis of the condition. 8,10 -12 It is reasonable to believe that ICP constitutes a continuum, ranging from light to severe forms, but there has been an absence of algorithms to identify pregnancies entailing increased fetal risk. The aims of this prospective cohort stu...

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Intrahepatic cholestasis of pregnancy (ICP) is characterized by troublesome maternal pruritus, elevated serum bile acids (>10 mol/L) and increased fetal risk. Recently we determined a cutoff level of serum bile acids, >40 mol/L, to be associated with impaired fetal outcome. We have now studied the effects of ursodeoxycholic acid (UDCA) and dexamethasone on pruritus, biochemical markers of cholestasis, and fetal complication rates in a double-blind, placebo-controlled trial. For this purpose, 130 women with ICP were randomly allocated to UDCA (1 g/day for three weeks), or dexamethasone (12 mg/day for 1 week and placebo during weeks 2 and 3), or placebo for 3 weeks. Pruritus and biochemical markers of cholestasis were analyzed at inclusion and after 3 weeks of treatment. Fetal complications (spontaneous preterm delivery; asphyxial events; and meconium staining of amniotic fluid, placenta, and membranes) were registered at delivery. An intention-to-treat analysis showed significant reduction of alanine aminotransferase (ALT) (P ‫؍‬ .01) and bilirubin (P ‫؍‬ .002) in the UDCA group only. In a subgroup analysis of ICP women with serum bile acids >40 mol/L at inclusion (n ‫؍‬ 34), UDCA had significant effects on pruritus (؊75%), bile acids (؊79%), ALT (؊80%), and bilirubin (؊50%) as well, but not on fetal complication rates. Dexamethasone yielded no alleviation of pruritus or reduction of ALT and was less effective than UDCA at reducing bile acids and bilirubin. In conclusion, 3 weeks of UDCA treatment improved some biochemical markers of ICP irrespective of disease severity, whereas significant relief from pruritus and marked reduction of serum bile acids were only found in patients with severe ICP. (HEPATOLOGY 2005;42:1399-1405

Heterozygosity for the common ABCB11 mutations accounts for 1% of European ICP cases; these two mutants probably reduce the folding efficiency of BSEP. N591S is a recurrent mutation; however, the mechanism may be independent of protein stability or function. The V444A polymorphism is a significant risk factor for ICP in this population.

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Background: Intrahepatic cholestasis of pregnancy (ICP) is characterised by troublesome maternal pruritus, raised serum bile acid levels and increased fetal risk. Mutations of the ABCB4 gene encoding the hepatobiliary phospholipid transporter have been identified in a small proportion of patients with cholestasis of pregnancy. In a recent prospective study on 693 patients with cholestasis of pregnancy, a cut-off level for serum bile acid (>40 mmol/l) was determined for increased risk of fetal complications. Objectives: To investigate whether common combinations of polymorphic alleles (haplotypes) of the genes encoding the hepatobiliary ATP-binding cassette (ABC) transporters for phospholipids (ABCB4) and bile acids (ABCB11) were associated with this severe form of cholestasis of pregnancy. Methods: For genetic analysis, 52 women with bile acid levels >40 mmol/l (called cases) and 52 unaffected women (called controls) matched for age, parity and geographical residence were studied. Gene variants tagging common ABCB4 and ABCB11 haplotypes were genotyped and haplotype distributions were compared between cases and controls by permutation testing. Results: In contrast with ABCB11 haplotypes, ABCB4 haplotypes differed between the two groups (p = 0.019), showing that the severe form of cholestasis of pregnancy is associated with the ABCB4 gene variants. Specifically, haplotype ABCB4_5 occurred more often in cases, whereas haplotypes ABCB4_3 and ABCB4_7 were more common in controls. These associations were reflected by different frequencies of at-risk alleles of the two tagging polymorphisms (c.711A: odds ratio (OR) 2.27, p = 0.04; deletion intron 5: OR 14.68, p = 0.012). Conclusion: Variants of ABCB4 represent genetic risk factors for the severe form of ICP in Sweden.

OBJECTIVES:Intrahepatic cholestasis of pregnancy (ICP) has a complex etiology with a significant genetic component. Heterozygous mutations of canalicular transporters occur in a subset of ICP cases and a population susceptibility allele (p.444A) has been identified in ABCB11. We sought to expand our knowledge of the detailed genetic contribution to ICP by investigation of common variation around candidate loci with biological plausibility for a role in ICP (ABCB4, ABCB11, ABCC2, ATP8B1, NR1H4, and FGF19).METHODS:ICP patients (n=563) of white western European origin and controls (n=642) were analyzed in a case–control design. Single-nucleotide polymorphism (SNP) markers (n=83) were selected from the HapMap data set (Tagger, Haploview 4.1 (build 22)). Genotyping was performed by allelic discrimination assay on a robotic platform. Following quality control, SNP data were analyzed by Armitage's trend test.RESULTS:Cochran–Armitage trend testing identified six SNPs in ABCB11 together with six SNPs in ABCB4 that showed significant evidence of association. The minimum Bonferroni corrected P value for trend testing ABCB11 was 5.81×10−4 (rs3815676) and for ABCB4 it was 4.6×10−7(rs2109505). Conditional analysis of the two clusters of association signals suggested a single signal in ABCB4 but evidence for two independent signals in ABCB11. To confirm these findings, a second study was performed in a further 227 cases, which confirmed and strengthened the original findings.CONCLUSIONS:Our analysis of a large cohort of ICP cases has identified a key role for common variation around the ABCB4 and ABCB11 loci, identified the core associations, and expanded our knowledge of ICP susceptibility.