Risk factors for human papillomavirus infection, cervical intraepithelial neoplasia and cervical cancer: an umbrella review and follow-up Mendelian randomisation studies

Abstract

Background: Persistent infection by oncogenic human papillomavirus (HPV) is necessary although not sufficient for development of cervical cancer. Behavioural, environmental, or comorbid exposures may promote or protect against malignant transformation. Randomised evidence is limited and the validity of observational studies describing these associations remains unclear.

Methods: In this umbrella review, we searched electronic databases to identify meta-analyses of observational studies that evaluated risk or protective factors and the incidence of HPV infection, cervical intra-epithelial neoplasia (CIN), cervical cancer incidence and mortality. Following re-analysis, evidence was classified and graded based on a pre-defined set of statistical criteria. Quality was assessed with AMSTAR-2. For all associations graded as weak evidence or above, with available genetic instruments, we also performed Mendelian randomisation to examine the potential causal effect of modifiable exposures with risk of cervical cancer. The protocol for this study was registered on PROSPERO (CRD42020189995).

Results: We included 171 meta-analyses of different exposure contrasts from 50 studies. Systemic immunosuppression including HIV infection (RR = 2.20 (95% CI = 1.89-2.54)) and immunosuppressive medications for inflammatory bowel disease (RR = 1.33 (95% CI = 1.27-1.39)), as well as an altered vaginal microbiome (RR = 1.59 (95% CI = 1.40-1.81)), were supported by strong and highly suggestive evidence for an association with HPV persistence, CIN or cervical cancer. Smoking, number of sexual partners and young age at first pregnancy were supported by highly suggestive evidence and confirmed by Mendelian randomisation.

Conclusions: Our main analysis supported the association of systemic (HIV infection, immunosuppressive medications) and local immunosuppression (altered vaginal microbiota) with increased risk for worse HPV and cervical disease outcomes. Mendelian randomisation confirmed the link for genetically predicted lifetime smoking index, and young age at first pregnancy with cervical cancer, highlighting also that observational evidence can hide different inherent biases. This evidence strengthens the need for more frequent HPV screening in people with immunosuppression, further investigation of the vaginal microbiome and access to sexual health services.

Keywords: CIN; Cervical cancer; Cervical intraepithelial neoplasia; HPV; Mendelian randomisation; Microbiome; Umbrella.

Fig. 1

PRISMA flow chart of study-selection

Fig. 2

Distribution of studies across evidence grade for all exposures of either increased or decreased risk (y-axis) by exposure category (X-axis) from the main analysis (summary random effects for cohort studies only) and outcome a HPV infection; b cervical intraepithelial neoplasia; and c cervical cancer

Fig. 3

Forest plot of effect estimates and 95% confidence intervals for all exposure-outcome pairs for all outcomes (HPV, CIN (cervical intraepithelial neoplasia) and cervical cancer) in the main analysis (summary random effects for cohort studies only), which graded as strong or highly suggestive evidence (n = 6)

Fig. 4

Forest plot demonstrating inverse variance weighted Mendelian randomisation results for all identified known environmental risk or protective factors for cervical cancer with available GWAS, to determine effect sizes by OR and 95% CI (x-axis; n = 11)

Fig. 5

Summary of results from umbrella review and Mendelian randomisation: associations with strong evidence in the main analysis (left): HIV for human papillomavirus incidence, vaginal dysbiosis for development of cervical intraepithelial neoplasia, and inflammatory bowel disease on immunosuppressive therapy for cervical cancer and Mendelian randomisation results supporting an association with cervical cancer incidence (right: rheumatoid arthritis, smoking, number of sexual partners and older age at first pregnancy (protective effect))