Abstract
BACKGROUND: Oral contraceptive use has been suggested to increase the risk of liver cancer. Although the International Agency for Research on Cancer concluded in 1999 that there was sufficient evidence of an association, this was based on case-control studies with few liver cancer cases. We aimed to provide more robust epidemiological evidence on this association by analysing data from two large prospective UK cohorts and additionally conducting a systematic review and meta-analysis of previous observational studies. METHODS: In our population-based study, the relationship between oral contraceptive use and liver cancer risk was examined using data from the Million Women Study (MWS) and the UK Biobank. We included women from both cohorts who did not have a prevalent cancer at baseline (except non-melanoma skin cancer) and had provided data on oral contraceptive use; incident liver cancer diagnoses were determined using linkage to National Health Service cancer registries. We compared risk in women who had ever used oral contraceptives with women who had never used oral contraceptives. Multivariable Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% CIs. For the systematic review and meta-analysis, we searched PubMed, Embase, CINAHL Plus, Web of Science, and Scopus from database inception to June 28, 2024, for existing observational studies. Study-specific log odds ratios (ORs) or log HRs were pooled and we determined the relative risk (RR) between oral contraceptive use and liver cancer across all studies using a fixed-effects model (PROSPERO number CRD42024552518). FINDINGS: A total of 2765 (0·21%) of 1 305 024 participants developed liver cancer in the MWS cohort (median follow-up 21·4 years; IQR 18·4-22·4) and 191 (0·08%) of 253 408 participants developed liver cancer in the UK Biobank (median follow-up 12·6 years; IQR 11·8-13·4). No association was observed between ever versus never use of oral contraceptives and liver cancer risk in either the MWS (HR 1·05, 95% CI 0·97-1·13; p=0·27) or the UK Biobank (1·08, 0·76-1·55; p=0·66). The meta-analysis of 23 observational studies, which included 5422 individuals with liver cancer, found no evidence of an association between ever versus never oral contraceptive use and liver cancer (RR 1·04, 0·98-1·11; I(2) 45·9%, p=0·0080). In the meta-analysis of duration of oral contraceptive use, there was a slightly increased risk of liver cancer per 5 years of use of oral contraceptives (RR 1·06, 1·02-1·10; I(2) 63·9%, p<0·0001), with corresponding subtype-specific RRs of 1·07 (1·00-1·14) for hepatocellular carcinoma and 1·06 (1·01-1·11) for intrahepatic cholangiocarcinoma (p(heterogeneity)=0·82). INTERPRETATION: The totality of observational studies suggests there is no association between ever versus never use of oral contraceptive and liver cancer risk. When looking at associations by duration of oral contraceptive use, there was little or no association with all liver cancer or its two main subtypes. There might be a small increased risk of liver cancer with longer duration of use, but residual confounding cannot be ruled out. FUNDING: Canadian Institutes of Health Research, National Institutes of Health Intramural Program, and Cancer Research UK.