Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease in pregnancy. We aimed to estimate the risk of developing hepatobiliary disease in women with ICP and the odds of developing ICP in women with prevalent hepatobiliary disease. We analyzed data of women with births between 1973 and 2009 and registered in the Swedish Medical Birth Register. By linkage with the Swedish Patient Register, we identified 11,388 women with ICP who were matched to 113,893 women without this diagnosis. Diagnoses of preexisting or later hepatobiliary disease were obtained from the Patient Register. Main outcome measures were hazard ratios (HRs) for later hepatobiliary disease in women with ICP and odds ratios (ORs) for developing ICP in preexisting hepatobiliary disease. Risk estimates were calculated through Cox and logistic regression analyses. Women with ICP were more often diagnosed with later hepatobiliary disease (HR 2.62; 95% confidence interval [CI] 2.47-2.77; increment at 1% per year), hepatitis C or chronic hepatitis (HR 4.16; 3.14-5.51 and 5.96; 3.43-10.33, respectively), fibrosis/ cirrhosis (HR 5.11; 3.29-7.96), gallstone disease or cholangitis (HR 2.72; 2.55-2.91, and 4.22; 3.13-5.69, respectively) as compared to women without ICP (P < 0.001 for all HRs). Later ICP was more common in women with prepregnancy hepatitis C (OR 5.76; 1.30-25.44; P 5 0.021), chronic hepatitis (OR 8.66; 1.05-71.48; P 5 0.045), and gallstone disease (OR 3.29; 2.02-5.36; P < 0.0001). Conclusion: Women with ICP have substantially increased risk for later hepatobiliary disease. Beyond gallstone-related morbidity we found a strong positive association between ICP and hepatitis C both before and after ICP diagnosis. Thus, we advocate testing for hepatitis C in women with ICP, in particular, since this potentially life-threatening infection can be treated successfully in the majority of patients. (HEPATOLOGY 2013;58:1385-1391 I ntrahepatic cholestasis of pregnancy (ICP) is the most common liver disease during pregnancy, 1 with reported prevalence rates of between 0.4% and 1.5%.2,3 ICP is characterized by otherwise unexplained pruritus with elevated bile acids and/or transaminases in the late second and third trimester of pregnancy.2,3 Genetic predisposition (variants of hepatobiliary transport proteins), impaired turnover of reproductive hormones, and environmental factors play key roles in the etiology and pathogenesis of ICP. 2,3 By definition, ICP is a diagnosis of exclusion. Pruritus in ICP spontaneously resolves and deranged liver function tests typically normalize within 4 weeks after delivery. Thus, ICP is usually a self-limiting, benign condition for the mother, although the fetus is at increased risk of adverse outcome, in particular preterm delivery. 4,5 In a small number of women with ICP, liver function does not return to normal, suggesting an underlying hepatobiliary disease that needs further diagnostic testing.6 These women might have been misclassified as suffering from ICP only.Abbreviations: CI, confidence interva...

Objective To determine the risk for adverse pregnancy and fetal outcomes in intrahepatic cholestasis of pregnancy (ICP).Design Population-based cohort study. Setting Swedish Medical Birth Register (MBR) 1997-2009.Population A total of 1 213 668 singleton deliveries.Methods Linkage of Hospital Discharge Register for exposure (ICP; n = 5477) with MBR for covariates.Main outcome measures Gestational diabetes, pre-eclampsia, prematurity, and stillbirth.Results Intrahepatic cholestasis (ICP) was diagnosed in 0.32-0.58% of all pregnancies, with an increasing trend until 2005 (P < 0.0001). Compared with women who did not have ICP, women with ICP were more likely to have gestational diabetes (adjusted odds ratio, aOR, 2.81; 95% CI 2.32-3.41) and preeclampsia (aOR 2.62, 95% CI 2.32-2.78). Women with ICP were also more likely to have spontaneous (aOR 1.60, 95% CI 1.47-1.93) and iatrogenic (aOR 5.95, 95% CI 5.23-6.60) preterm delivery, with increased rates of induction of labour (aOR 11.76, 95% CI 11.04-11.62). However, this actively managed cohort of ICP cases was not at increased risk of stillbirth (aOR 0.92, 95% CI 0.52-1.62). Infants in ICP deliveries were more likely to have a low (<7) 5-minute Apgar score (aOR 1.45, 95% CI 1.14-1.85) and be large for gestational age at birth (aOR 2.27, 95% CI 2.02-2.55).Conclusions Over time, a greater proportion of Swedish pregnant women have received a diagnosis of ICP, probably because of an increased awareness of the disorder. Our data confirm an increased risk of preterm delivery, but not of stillbirth, in actively managed ICP. The high rates of gestational diabetes and pre-eclampsia are new findings, and need to be considered in the management of ICP pregnancies.Keywords Bile acids, gestational diabetes, intrahepatic cholestasis of pregnancy, intrauterine fetal death, obstetric cholestasis, pre-eclampsia, stillbirth, ursodeoxycholic acid.Please cite this paper as: Wikstr€ om Shemer E, Marschall HU, Ludvigsson JF, Stephansson O. Intrahepatic cholestasis of pregnancy and associated adverse pregnancy and fetal outcomes: a 12-year population-based cohort study. BJOG 2013;120:717-723.

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Lower 1,25-D3 levels in ICP are inversely correlated by meconium staining, a major indicator of fetal distress. Our finding may have pathogenetic and clinical implications since vitamin D regulates steroid metabolism and 1,25-D3 deficiency may impair fetal outcome.