Association of Reproductive History with Human Papillomavirus and Cervical Intraepithelial Neoplasia Severity

Our objective was to uncover potential links between Human Papillomavirus infection, common reproductive outcomes and high-grade cervical pre-cancer. We evaluated common reproductive risk factors, by varied stratifications of histologic grade, among 2,055 women positive and 6,657 women negative for Human Papillomavirus (HPV), who were enrolled in the Shanxi Province Cervical Cancer Screening Study II. Logistic regression was used to generate odds ratios and their corresponding 95% confidence intervals. Risk-factor profiles diverged for Cervical Intraepithelial Neoplasia (CIN) II compared to CIN III, but were broadly similar for CIN II compared to CIN I. An increased risk of CIN III versus CIN II was seen for higher gravidity (≥ 3 pregnancies) [odds ratio (OR)=1.6 (95% confidence interval [CI]: 1.0, 2.6)] and sexual intercourse within four months of childbirth [OR=2.0 (1.3, 3.2)]. Risks associated with reproductive factors appeared comparable for CIN II and CIN I, except an inverse association observed for sexual intercourse within four months of childbirth for CIN II versus CIN I [OR= 0.64 (0.42, 0.97)]. If CIN III and CIN II are biologically similar, risk-factor profiles would be expected to be more similar between CIN III and CIN II. Instead, risk factor profiles between CIN II and CIN I were more similar. Utilizing these results, we investigated a broader spectrum of reproductive risk factors for CIN III versus ≤ CIN II. Higher gravidity (≥ 3 pregnancies) was associated with higher risk of CIN III versus ≤ CIN II [OR=1.5 (1.0, 2.1)], as was intercourse within four months of childbirth [OR=1.7 (1.2, 2.3)], and age. It is biologically plausible that elevated levels of hormones during pregnancy or immediately postpartum may act as promoters in cervical carcinogenesis, aiding the progression of cervical disease. These results add to the accumulating evidence that CIN II may be biologically more similar to CIN I than to CIN III, and that reproductive co-factors play an important role in the progression of HPV to high-grade pre-cancer. These results can provide impetus for investigators with prospective data to follow-up women with CIN II, and to analyze risk factors by histological grade