There was little association, if any, between ever using oral contraceptives and the risk of liver cancer, a large population-based study showed, although risk slightly increased with longer duration of use, a meta analysis suggested.
Across two UK prospective cohorts, ever-use compared with never-use of oral contraceptives was not linked with a higher risk of liver cancer in either the Million Women Study (MWS) or the UK Biobank, reported Katherine McGlynn, PhD, of the NIH's National Cancer Institute in Rockville, Maryland, and colleagues in The Lancet Oncology.
Medpage reports that of 1.3m m participants in the MWS with a median follow-up of 21.4 years, 2 765 (o.21%) developed liver cancer, with no association emerging between ever-use of oral contraceptives and liver cancer risk (HR 1.05, 95% CI 0.97-1.13).
The same held true for the UK Biobank cohort: 191 (0.08%) of 253 408 participants developed liver cancer (median follow-up 12.6 years), with no significant relationship between ever-use of oral contraceptives and liver cancer (HR 1.08, 95% CI 0.76-1.55).
A meta-analysis of 23 observational studies came up with similar results, showing no links between ever- versus never-use of oral contraceptives and liver cancer (RR 1.04, 95% CI 0.98-1.11) regardless of histological type, hepatocellular carcinoma (HCC), or intrahepatic cholangiocarcinoma.
However, the meta-analysis did reveal a slightly increased risk of liver cancer per five years of use of oral contraceptives (RR 1.06, 95% CI 1.02-1.10), with RRs of 1.07 (95% CI 1.00-1.14) for HCC and 1.06 (95% CI 1.01-1.11) for intrahepatic cholangiocarcinoma.
“This could be due to other reasons, like inadequate adjustment for confounders,” McGlynn and colleagues wrote.
Furthermore, they pointed out that if there is a causal association between oral contraceptive use and and liver cancer risk, “based on the RR estimate presented here, and the low incidence of liver cancer observed in women, the absolute risk difference would be very small”.
McGlynn and co-authors noted that in 1999, the International Agency for Research on Cancer (IARC) stated that there was sufficient evidence that oral contraceptive pills cause HCC, the main subtype of liver cancer, in the absence of viral hepatitis infections.
This statement was reinforced in a 2012 IARC report indicating that long-term use of oral contraceptives was associated with HCC risk.
But liver cancer is relatively rare in female individuals compared with other cancers and with males, so “few prospective studies have had a sufficient number of participants to assess the association between oral contraceptive use and liver cancer risk”, the authors observed.
In an accompanying comment, Lisa Iversen, PhD, of the University of Aberdeen in Scotland, said that evaluating the use of oral contraceptives and cancer risk is complex because women use different kinds of contraceptives through their reproductive lives.
Iversen also pointed out that women of reproductive age in the 1960s and 1970s were likely to use older pill formulations compared with contemporary formulations that contain lower oestrogen doses and newer progestogens.
McGlynn and colleagues noted that while it is possible earlier oral contraceptive formulations could be associated with an increased cancer risk, a sensitivity analysis by age at recruitment found no evidence of heterogeneity in the MWS and UK Biobank cohorts.
Although the small increased risk of liver cancer associated with longer duration of contraceptive use in the meta-analysis might be explained by bias or confounding, “there is a need for evidence from sufficiently large and long-running prospective studies in which more nuanced patterns of oral contraceptive usage, such as current use, recency of use, and duration of use can be examined with sufficient statistical power”, Iversen said.
The findings may not be generalisable because most women evaluated in the study were from Britain. In both MWS and UK Biobank, oral contraceptive use and duration were self-reported and susceptible to errors in memory.
Study details
Oral contraceptive use and risk of liver cancer: a population-based study, systematic review, and meta-analysis
Cody Watling, Siân Sweetland, Aika Wojt et al.
Published in Lancet Oncology on 2 July 2025
Summary
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; I2 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; I2 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 (pheterogeneity=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.
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