Reply
Authors: Hanns-Ulrich Marschall, Olof Stephansson
Journal: Hepatology (2014)

We thank Dr. Reyes for his insightful comments on our Hepatology article1 on the association between intrahepatic cholestasis of pregnancy (ICP) and prevalent or future hepatobiliary diseases. The diagnostic criteria for ICP includes both clinical signs of otherwise unexplained pruritus as well as elevated bile acids and/or transaminases in the second or third trimester of pregnancy. We agree with Dr. Reyes that the diagnosis of ICP should exclude other liver disease. However, at the time of discharge from the hospital we do not know whether liver values will improve to normal levels within 3 weeks after delivery. Hence, there is a risk of misclassification of women, which may have influenced the findings. However, as most women with unexplained pruritus and elevated bile acids and/or transaminases spontaneously recover, the extent of misclassification is likely to be small leading to only a marginal influence of the findings. Dr. Reyes raised the important question about the incidence of hepatobiliary diseases in recurrent ICP. In our study group of 10,067 women with ICP, 1,172 (11.6%) were given this diagnosis more than once in subsequent pregnancies (1,165 twice; 158 three or more times). Indeed, recurrent ICP was correlated with a higher incidence of subsequent hepatobiliary disorders, rising from 14.5% to 18.9%. The hazard ratio (HR) of any hepatobiliary disorder in women with recurrent ICP was increased by 1.29 (95% confidence interval [CI], 1.12-1.49). Significantly increased risks in women with at least two pregnancies with ICP compared to women with one ICP pregnancy were found for chronic hepatitis (0.6% versus 0.2%; HR 3.79; 95% CI 1.53-9.42), liver fibrosis/cirrhosis (0.7% versus 0.3%; HR 2.89; 95% CI 1.29-6.49), gallstone disease (14.4% versus 11.4%; HR 1.25; 95% CI 1.07-1.48), and cholangitis (1.2% versus 0.6%; HR 2.18; 95% CI 1.20-3.95). The risk of a later diagnosis of hepatitis C (combined hepatitis non-A/non-B and C) did not differ significantly between women with ICP in one pregnancy compared to women with at least two ICP pregnancies. Interestingly, the diagnosis of ICP did not affect the number of subsequent pregnancies when compared to the 10 times larger control population without this diagnosis. Thus, one might conclude that ICP does not affect fertility and that women once exposed to cholestatic pruritus are not discouraged from further pregnancies. In the present study we were not able to estimate the severity of ICP, as we did not have access to levels of serum bile acids. We had information on gestational age at delivery but we could not be certain that preterm delivery was a consequence of ICP or due to other causes. As Dr. Reyes points out, it would be interesting in future research to correlate severity of ICP with later risk of hepatobiliary disorders. Finally, we strongly agree with Dr. Reyes' recommendation to test for hepatitis C in any women featuring signs of underlying liver disease. Hanns-Ulrich Marschall, M.D., Ph.D.1 Olof Stephansson, M.D., Ph.D.2 1Sahlgrenska Academy Institute of Medicine Department of Molecular and Clinical Medicine University of Gothenburg Gothenburg, Sweden 2Clinical Epidemiology Unit Department of Medicine, Solna Karolinska University Hospital and Institutet Stockholm, Sweden