Chapter 3: Cofactors in human papillomavirus carcinogenesis--role of parity, oral contraceptives, and tobacco smoking.

It is now well established that infection with oncogenic human papillomavirus (HPV) types is the necessary cause of cervical cancer (CC) and its immediate precursor cervical intraepithelial neoplasia 3. However, HPV infection alone may not be sufficient to cause CC, and other exogenous and endogenous factors may exist that, in conjunction with HPV, influence the risk of progression from cervical HPV infection to CC. In this chapter, we review the evidence for the role of parity, oral contraceptive (OC) use, and tobacco smoking in CC. We also discuss limitations and methodologic problems encountered in assessing available data and outline recommendations for future research. Based on key studies on high-grade squamous intraepithelial lesions (HSILs) and CC conducted among HPV-positive women, it can be concluded that high parity, smoking, and less consistently long-term OC use are cofactors that may modulate the risk of progression from HPV infection to HSIL/CC. From a public health point of view, parity seems to be the behavioral cofactor explaining the highest proportion of CC cases among HPV-infected women. Smoking and long-term OC use may have a similar impact in populations that are heavily exposed to HPV and to these cofactors. Large prospective and retrospective cohort studies of HSIL and CC among middle-aged women in which several markers of HPV exposure are used and HPV persistence is documented would be valuable to study the role of these and other cofactors in HPV carcinogenesis. If confirmed, our conclusions may imply that multiparous women, women who are smokers, and women on long-term OC use may need closer surveillance for cytologic abnormalities and HPV infections than women in the general population.