Oral contraceptive use and risk of liver cancer: a population-based study, systematic review, and meta-analysis.

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.

尽管国际癌症研究机构在1999年得出结论认为有足够的证据表明存在相关性，但这一结论是基于病例对照研究，其中肝癌病例较少。

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 reviewand meta-analysisof previous observational studies.

我们旨在通过分析来自两个大型前瞻性英国队列的数据，并额外进行系统综述和以往观察性研究的荟萃分析，提供更稳健的流行病学证据来证明这种关联。

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.

在我们的基于人群的研究中，使用了百万妇女研究（MWS）和英国生物银行的数据，检验了口服避孕药使用与肝癌风险之间的关系。

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.

我们纳入了两个队列中在基线时没有现患癌症（除了非黑色素瘤皮肤癌）且提供了关于口服避孕药使用数据的女性；通过与国家卫生服务癌症登记处的链接确定了肝癌的初次诊断。

We compared risk in women who had ever used oral contraceptives with women who had never used oral contraceptives.

我们比较了曾经使用过口服避孕药的女性与从未使用过口服避孕药的女性的风险。

Multivariable Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% CIs.

使用多变量Cox比例风险回归模型计算风险比（HRs）和95%置信区间（CIs）。

For the systematic reviewand meta-analysis, we searched PubMed, Embase, CINAHL Plus, Web of Science, and Scopus from database inception to June 28, 2024, for existing observational studies.

在系统评价和荟萃分析中，我们从数据库建立之初至2024年6月28日，检索了PubMed、Embase、CINAHL Plus、Web of Science和Scopus，以寻找现有的观察性研究。

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).

将研究特定的对数比值比(ORs)或对数风险比(HRs)进行汇总，并使用固定效应模型确定了所有研究中口服避孕药使用与肝癌之间的相对风险(RR)（PROSPERO编号CRD42024552518）。

Results

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).

在MWS队列中，共有2765名（0.21%）参与者在中位随访21.4年（四分位数间距18.4-22.4）期间发展为肝癌，而在英国生物银行中，有191名（0.08%）参与者在中位随访12.6年（四分位数间距11.8-13.4）期间发展为肝癌。

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).

在MWS研究（HR 1·05, 95% CI 0·97-1·13; p=0·27）或UK Biobank（1·08, 0·76-1·55; p=0·66）中，未观察到口服避孕药的使用与肝癌风险之间存在关联。

The meta-analysisof 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).

对23项观察性研究的荟萃分析，包括5422名肝癌患者，未发现口服避孕药使用与肝癌之间存在关联（RR 1·04, 0·98-1·11; I2 45·9%, p=0·0080）。

In the meta-analysisof 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).

在口服避孕药使用时长的荟萃分析中，每增加5年口服避孕药的使用，肝癌风险略有增加（RR 1·06, 1·02-1·10; I2 63·9%, p<0·0001），相应的亚型特异性RR为1·07（1·00-1·14）对于肝细胞癌和1·06（1·01-1·11）对于肝内胆管癌（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.

观察性研究的总体表明，曾经使用与从未使用口服避孕药之间与肝癌风险无关联。

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.

当按口服避孕药使用时长分析时，与所有肝癌或其两个主要亚型之间几乎没有或没有关联。

There might be a small increased risk of liver cancer with longer duration of use, but residual confounding cannot be ruled out.

使用时间更长可能会有轻微增加的肝癌风险，但不能排除残余混杂因素。

funding

Canadian Institutes of Health Research, National Institutes of Health Intramural Program, and Cancer Research UK.

加拿大卫生研究院、美国国家卫生研究院内设项目以及英国癌症研究慈善机构。