In the International Collaboration of
In 2007, the International Collaboration of Epidemiological Studies of Cervical Cancer combined individual participants’ data from 25 studies involving 16,573 women with invasive cervical cancer, in situ cervical cancer or CIN 3 (cases) and 35,509 women without cervical disease (controls) . The use of individual participant data provided the Collaboration far greater statistical control of sexual, gynaecological and obstetric confounders than previous meta-analyses of published effect estimates . The Collaboration found that the risk of invasive cervical cancer and CIN3/cervical cancer in situ was increased for current users of oral contraceptives [e.g. relative risk of invasive cancer for 5 or more years’ use versus never use, 1.90 (95%CI 1.69–2.13)] and declined after use ceased. Our findings are in agreement with results from the Collaboration, and other prospective studies reported subsequently as well as a previously conducted, Australian study of 117 women [, , ]. The Collaboration also found that injectable progestagen-only formulations increased the risk of cervical cancer. Although this Ethylmalonyl Coenzyme A was based on a small amount of data on progestagen-only contraceptives this finding was later confirmed by a large South African case-control study . Our data were insufficient for disentangling the potentially different effects of oestrogen-progestagen and progestagen-only formulations, however, we found an increased risk of high grade cervical disease with current use of hormonal contraceptives which is consistent with the findings of the Collaboration. We also found a pattern of increased risk of CIN2/3 with more recent use of hormonal contraceptives for ex-users which is in agreement with findings from the collaboration for CIN3/carcinoma in situ. The confidence intervals for our results, however, were wider by comparison, which could be due to smaller sample sizes. The mechanisms by which hormonal contraceptive use increases the risk of cervical neoplasms are not entirely clear. Epidemiological evidence suggests that use of hormonal contraceptives promotes persistence of oncogenic HPV infections [30,31] which could lead to progression to cervical cancer but does not increase the risk of new HPV infections [10,11,30]. In addition, a number of laboratory-based studies have reported hormone-related exposures inducing biological changes consistent with cervical disease progression. For example, studies of the female reproductive tract of HPV16-expressing transgenic mice have shown a possible synergistic mechanism between the oncogenes of HPV16 and chronic oestrogen exposure which in turn modulates squamous cell carcinogenesis [32,33]. More recently, genetic polymorphisms have also been identified that may act synergistically with hormonal contraceptives and HPV infections to promote cervical carcinogenesis [34,35]. We also found that the risk of high grade cervical disease was higher for current-smokers than never-smokers, increasing with the number of cigarettes smoked per day and with increased duration of smoking. These results are consistent with the largest pooled analysis of epidemiological studies of cervical cancer ever conducted on the association between tobacco smoking, invasive cervical cancer and CIN3/cervical cancer in situ . A nested case-control study of European women reported similar findings after adjusting for serological markers of exposure to HPV, Chlamydia trachomatis and Human Herpes Virus 2 . Although we found a small increased risk of CIN 2/3 for long-term ex-smokers (>10 years) compared with never-smokers this was not statistically significant, possibly due to small sample size or an attenuation of the risk from combining CIN2 and CIN3 cases together. Nevertheless, our data did show a significant trend of increased risk for ex-smokers with decreasing time since quitting.