The risk of liver neoplasia in relation to combined oral contraceptive use

Abstract

Benign liver tumors occurring in young women were rarely reported in the medical literature before the introduction of oral contraceptives in the early 1960s. Subsequently, there were numerous case reports from the U.S. and other countries of liver tumors in women who used combined oral contraceptives. These reports, coupled with data from two U.S. case-control studies, indicate that the risk of hepatocellular adenoma increases sharply with increasing duration of oral contraceptive use. Case reports suggest that there may be a similar effect on the risk of focal nodular hyperplasia, but this is not established because there have been no case-control studies of the lesion. The incidence of benign liver disease attributable to oral contraceptive use in the U.S. is small because of the very low incidence of the disease. There have also been numerous case reports of malignant liver tumors in young women who used oral contraceptives. Seven case-control studies have been conducted — two in Great Britain, two in the U.S., one in Italy, one in several developing countries (conducted by the World Health Organization (WHO)), and one in South Africa. Data from the first five studies, all conducted in low risk populations, indicated an association of hepatocellular carcinoma (largely in the absence of liver cirrhosis) with oral contraceptive use. Because of small numbers estimates were unstable, but the risk did not appear to be increased appreciably for durations of use less than about five years. For longer durations, the risk appeared increased by five- to tenfold or more. There was little evidence of hepatitis B infection in the cases, but systematic determinations were not carried out. An increased risk of cholangiocarcinoma was not established, but few of these lesions were studied. Because the incidence of primary liver cancer in Northern Europe and the U.S. is low, the incidence attributable to oral contraceptive use is also likely to be low. The WHO study was carried out in eight countries, most of which have a high incidence of liver cancer and a high prevalence of a predisposing factor, hepatitis B infection. Similarly, the South African study was carried out among black women, and virtually all of the cases had serological evidence of hepatitis B infection. Both studies indicated no association of short-term oral contraceptive use with risk of hepatocellular carcinoma, and the WHO study indicated a lack of association with cholangiocarcinoma. The prevalence of longterm use was too low for informative analysis. Future studies will be needed to assess whether long durations of oral contraceptive use increase the risk of liver cancer in countries in which both hepatitis B infection and liver cancer are common.