Journal Article

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

Tsilidis, Konstantinos K., Kyrgiou, Maria, Ellis, Laura Burney, Flanagan, James M., Athanasiou, Antonios, Kalliala, Ilkka, Bowden, Sarah J., Bouras, Emmanouil, Markozannes, Georgios, Kechagias, Konstantinos S., Grout-Smith, Harriet, Doulgeraki, Triada, Chadeau-Hyam, Marc, Zuber, Verena

2023

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Biomedicine / Cancer / Cervical cancer / Cervical intraepithelial neoplasia / Cervix dysplasia / CIN / Cohort analysis / Comorbidity / Data analysis / Development and progression / Diagnosis / Estimates / Exposure / Female / Follow-Up Studies / Gastrointestinal diseases / Genetic transformation / Genetics / Health aspects / Health risk assessment / Health risks / HIV / HIV infection / HIV Infections - complications / HPV / Human immunodeficiency virus / Human papillomavirus / Human Papillomavirus Viruses / Humans / Immunosuppression / Immunotherapy / Infection / Infections / Inflammatory bowel diseases / Medicine / Medicine & Public Health / Mendelian randomisation / Mendelian Randomization Analysis / Meta-analysis / Microbiomes / Microbiota (Symbiotic organisms) / Mortality / Observational studies / Oncology, Experimental / Papillomavirus infections / Papillomavirus Infections - complications / Papillomavirus Infections - epidemiology / Papillomavirus Infections - genetics / Papillomaviruses / Pregnancy / Quality assessment / Randomization / Research Article / Risk Factors / Sensitivity analysis / Sexual partners / Sexually transmitted diseases / Smoking / STD / Umbrella / Uterine Cervical Dysplasia - diagnosis / Uterine Cervical Dysplasia - epidemiology / Uterine Cervical Dysplasia - pathology / Uterine Cervical Neoplasms - diagnosis / Vagina