Smoking Is a Risk Factor for Cervical Intraepithelial Neoplasia Grade 3 among Oncogenic Human Papillomavirus DNA–Positive Women with Equivocal or Mildly Abnormal Cytology

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Abstract
Background: Smoking is a potential risk factor for cervical cancer and its immediate precursor, cervical intraepithelial neoplasia grade 3 (CIN3), but few studies have adequately taken into account the possible confounding effect of oncogenic human papillomavirus (HPV) infection. Methods: Women (n = 5,060) with minimally abnormal Papanicolaou smears were enrolled in the ASCUS and LSIL Triage Study, a clinical trial to evaluate management strategies, and were seen every 6 months for the 2-year duration of the study. Cervical specimens were tested for HPV DNA using both Hybrid Capture 2 and PGMY09/11 L1 consensus primer PCR with reverse line blot hybridization for genotyping. Multivariate logistics regression models were used to assess associations [odds ratio (OR) with 95% confidence intervals (95% CI)] between smoking behaviors and rigorously reviewed cases of cervical intraepithelial neoplasia grade 3 or cancer (≥CIN3) identified throughout the study (n = 506) in women with oncogenic HPV (n = 3,133). Results: Current smoking was only weakly associated with increased HPV infection. Among infected women, current smokers (OR, 1.7; 95% CI, 1.4-2.1) and past smokers (OR, 1.7; 95% CI, 1.2-2.4) were more likely to be diagnosed with ≥CIN3 than nonsmokers. Greater smoking intensity (PTrend < 0.0005) and duration (PTrend < 0.0005) increased the strength of the association, with smoking ≥2 packs/d (OR, 3.3; 95% CI, 1.5-7.5) and smoking for ≥11 years (OR, 2.1; 95% CI, 1.5-2.9) most strongly associated with ≥CIN3 as compared to non-smokers. The effects of intensity and duration seemed additive. Conclusions: Women with oncogenic HPV and minimally abnormal Papanicolaou smears who smoke were up to three times more likely to be diagnosed with ≥CIN3 than nonsmokers. Smoking cessation trials targeting this population might be warranted.