Abstract
Smoking, nutrition, parity and oral contraceptive use have been reported as major environmental risk factors for cervical cancer. After the discovery of the very strong link between human papillomavirus (HPV) infection and cervical cancer, it is unclear whether the association of these environmental factors with cervical cancer reflect secondary associations attributable to confounding by HPV, if they are independent risk factors or whether they may act as cofactors to HPV infection in cervical carcinogenesis. To investigate this issue, we performed a population-based case–control study in the Västerbotten county of Northern Sweden of 137 women with high-grade cervical intra-epithelial neoplasia (CIN 2–3) and 253 healthy age-matched women. The women answered a 94-item questionnaire on diet, smoking, oral contraceptive use and sexual history and donated specimens for diagnosis of present HPV infection (nested polymerase chain reaction on cervical brush samples) and for past or present HPV infections (HPV seropositivity). The previously described protective effects of dietary micronutrients were not detected. Pregnancy appeared to be a risk factor in the multivariate analysis (P< 0.0001). Prolonged oral contraceptive use and sexual history were associated with CIN 2–3 in univariate analysis, but these associations lost significance after taking HPV into account. Smoking was associated with CIN 2–3 (odds ratio (OR) 2.6, 95% confidence interval (CI) 1.7–4.0), the effect was dose-dependent (P = 0.002) and the smoking-associated risk was not affected by adjusting for HPV, neither when adjusting for HPV DNA (OR 2.5, CI 1.3–4.9) nor when adjusting for HPV seropositivity (OR 3.0, CI 1.9–4.7). In conclusion, after taking HPV into account, smoking appeared to be the most significant environmental risk factor for cervical neoplasia. © 2000 Cancer Research Campaign
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Geijersstam V, Kibur M, Wang Z, Koskela P, Pukkala E, Schiller JT, Lehtinen M and Dillner J (1998) Stability over time of serum antibody levels to human papillomavirus type 16. J Infect Dis 177: 1710–1714
Andersson-Ellström A, Dillner J, Hagmar B, Schiller J, Sapp M, Forssman L and Milsom I (1996) Comparison of development of serum antibodies to HPV16 and HPV33 and aquisition of cervical HPV DNA among sexually experienced and virginal young girls. A longitudinal cohort study. Sexually Transm Dis 23: 234–238
Bauer HM, Ting Y, Greer CE, Chambers JC, Tashiro CJ, Chimera J, Reingold A and Manos MM (1991) Genital human papillomavirus infection in female university students as determined by a PCR-based method. JAMA 265: 472–478
Burger MPM, Hollema H, Gouw ASH, Pieters WJLM and Quint WGV (1993) Cigarette smoking and human papillomavirus in patents with reported cervical cytological abnormality. Br Med J 306: 749–752
Butterworth CE, Hatch KD, Gore H, Mueller H and Krumdieck CL (1982) Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr 35: 73–82
Butterworth CE, Hatch KD, Macaluso M, Cole P, Sauberlich HE, Soong S-J, Borst M and Baker VV (1992) Folate deficiency and cervical dysplasia. JAMA 267: 528–533
Cuzick J, De-Stavola BL, Russel MJ and Thomas BS (1990a) Vitamin A, vitamin E and the risk of cervical intraepithelial neoplasia. Br J Cancer 62: 651–652
Cuzick J, Singer A, De-Stavola BL and Chomet J (1990b) Case-control study of risk factors for cervical intraepithelial neoplasia in young women. Eur J Cancer 26: 684–690
Cuzick J, Terry G, Ho L, Hollingworth T and Anderson M (1994) Type-specific human papillomavirus DNA in abnormal smears as a predictor of high-grade cervical intraepithelial neoplasia. Br J Cancer 69: 167–171
Dillner J, Lehtinen M, Börge T, Luostarinen T, Youngman L, Jellum E, Koskela P, Gislefoss RE, Hallmans G, Paavonen J, Sapp M, Schiller JT, Hakulinen T, Thoresen S and Hakama M (1997) Prospective seroepidemiological study of human papillomavirus infection as risk factor for invasive cervical cancer. J Natl Cancer Inst 89: 1293–1299
Eluf-Neto J, Booth M, Munoz N, Bosch FX, Meijer CJLM and Walboomers JMM (1994) Human papillomavirus and invasive cervical cancer in Brazil. Br J Cancer 69: 114–119
Evander M, Edlund K, Boden E, Gustavsson Å, Jonsson M, Karlsson R, Rylander E and Wadell G (1992) Comparison of a one-step and a two-step polymerase chain reaction with degenerate general primers in a population-based study of human papillomavirus infection in young Swedish women. J Clin Microbiol 30: 987–992
Harper JM, Levine AJ, Rosenthal DL, Wiesmeier E, Hunt IF, Swendseid ME and Haile RW (1994) Erythrocyte folate levels, oral contraceptive use and abnormal cervical cytology. Acta Cytol 38: 324–330
Herrero R, Potischman N, Brinton LA, Reeves WC, Brenes MM, Tenorio F, de Britton RC and Gaitan E (1991) A case–control study of nutrient status and invasive cervical cancer. I. Dietary indicators. Am J Epidemiol 134: 1335–1346
Hildesheim A, Reeves WC, Brinton LA, Lavery C, Brenes M, De-La Guardia ME, Godoy J and Rawls WE (1990) Association of oral contraceptive use and human papillomaviruses in invasive cervical cancers. Int J Cancer 45: 860–864
Ho GYF, Kadish RDB, Basu J, Palan PR, Mikhail M and Romney SL (1998a) HPV 16 and cigarette smoking as risk factors for high-grade cervical intra-epithelial neoplasia. Int J Cancer 78: 281–285
Ho GYF, Palan PR, Basu J, Romney SL, Kadish AS, Mikhail M, Wasserteiler-Smoller S, Runowicz C and Burk RD (1998b) Viral characteristics of human papillomavirus infection and antioxidant levels as risk factors for cervical dysplasia. Int J Cancer 78: 594–599
Ho GYF, Bierman R, Beardsley L, Chang CJ and Burk RD (1998c) Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 338: 423–428
Johansson I, Hallmans G, Eriksson S, Hagman U, Bruce Å, Wikman Å, Kaaks R and Riboli E (1994) Evaluation of the accuracy of a dietary questionnaire aimed for the Västerbotten study. Scand J Nutr 38: 50–55
Kjellberg L, Wiklund F, Sjöberg I, Wadell G, Ångström T, Dillner J and Mählck CG (1998) A population-based study of HPV DNA testing for predicting cervical intraepithelial neoplasia. Am J Obstet Gynecol 179: 1497–1502
Kjellberg L, Wang Z, Wiklund F, Edlund K, Ångström T, Lenner P, Sjöberg I, Hallmans G, Wallin K-L, Sapp M, Schiller J, Wadell G, Mählck C-G and Dillner J (1999) Sexual Behavior and papillomavirus exposure in cervical intraepithelial neoplasia: a population based case–control study. Journal of General Virology 80: 391–398
Kruger-Kjaer S, van den Brule AJC, Svare EI, Engholm G, Sherman ME, Poll PA, Walboombers JMM, Bock JE and Meijer CJLM (1998) Different risk factor patterns for high-grade and low-grade intraepithelial lesions on the cervix among HPV-positive and HPV-negative young women. Int J Cancer 76: 613–619
Kwasniewska A, Charzewska J, Tukendorf A and Semczuk M (1998) Dietary factors in women with dysplasia colli uteri associated with human papillomavirus infection. Nutr Cancer 30: 39–45
Liu T, Soong SJ, Wikson NP, Craig CB, Cole P, Macaluso M and Butterworth CE Jr (1993) A case–control study of nutritional factors and cervical dysplasia. Cancer Epidemiol Biomakers Prevent 2: 525–530
Lorincz AT, Reid R, Jenson AB, Greenberg MD, Lancaster W and Kurman RJ (1992) Human papillomavirus infection of the cervix: relative risk associations of 15 common anogenital types. Obstet Gynecol 79: 328–337
Michaelsson K, Holmberg L, Ljunghall S, Mallmin H, Persson P-G and Wolk A (1996) Effect of prefracture versus postfracture dietary assessment on hip fracture risk estimates. Int J Epidemiol 25: 403–410
Olsen AO, Dillner J, Gjoen K and Magnus P (1997) Seropositivity against HPV 16 capsids: a better marker of past sexual behavior than presence of HPV DNA. Genitourin Med 73: 131–135
Olsen AO, Dillner J, Skrondal A and Magnus P (1998) Combined effect of smoking and human papillomavirus type 16 infection in cervical cancerogenesis. Epidemiology 9: 346–349
Östör AG (1993) Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol 12: 186–192
Palan PR, Chang CJ, Mikhail MS, Ho GY, Basu J and Romney SL (1998) Plasma concentrations of micronutrients during a nine-month clinical trial of beta-carotene in women with precursor cervical cancer lesions. Nutr Cancer 30: 46–52
Phillips AN and Smith GD (1993) Smoking and human papillomavirus infection. BMJ 306: 1268–1269
Schiffman MH and Brinton LA (1995) The epidemiology of cervical carcinogenesis. Cancer 76: 1888–1901
Schiffman MH, Bauer HM, Hoover RN, Glass AG, Cadell DM, Rush BB, Scott DR, Sherman ME, Kurman RJ, Wacholder S, Stanton CK and Manos MM (1993) Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst 85: 958–964
Slattery ML, Abbott TM, Overall JC, Robinson LM, French TK, Jolles C, Gardner JW and West DW (1990) Dietary vitamins A, C, and E and selenium as risk factors for cervical cancer. Epidemiology 1: 8–15
Szarewski A, Jarvis MJ, Sasienin P, Anderson M, Edwards R, Steele SJ, Guillebaud J and Cuzick J (1996) Effect of smoking cessation on cervical lesion size. Lancet 347: 941–943
Wideroff L, Potischman N, Glass AG, Greer CE, Manos MM, Scott DR, Burk RD, Sherman ME, Wacholder S and Schiffman M (1998) A nested case-control study of dietary factors and the risk of incident cytological abnormalities of the cervix. Nutr Cancer 30: 130–136
Winkelstein W (1990) Smoking and cervical cancer – current status: a review. Am J Epidemiol 131: 945–958
Ziegler RG, Jones CJ, Brinton LA, Norman SA, Mallin K, Levine RS, Lehman HF, Hamman RF, Trumble AC and Rosental JF (1991) Diet and the risk of in situ cervical cancer among white women in the United States. Cancer Causes Control 2: 17–29
Author information
Authors and Affiliations
Additional information
Department of Clinical Virology, University Hospital of Northern Sweden, S-901 85 Umeå, Sweden
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Kjellberg, L., Hallmans, G., Åhren, AM. et al. Smoking, diet, pregnancy and oral contraceptive use as risk factors for cervical intra-epithelial neoplasia in relation to human papillomavirus infection. Br J Cancer 82, 1332–1338 (2000). https://doi.org/10.1054/bjoc.1999.1100
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.1999.1100
Keywords
This article is cited by
-
Persistent HPV infection after conization of cervical intraepithelial neoplasia—— a systematic review and meta-analysis
BMC Women's Health (2023)
-
HPV Prevalence in Pregnancy with Demographic and Socioeconomic Considerations
Indian Journal of Gynecologic Oncology (2023)
-
Cervical intraepithelial neoplasia grade 3: development during pregnancy and postpartum
Archives of Gynecology and Obstetrics (2022)
-
Molecular and biological functions of gingerol as a natural effective therapeutic drug for cervical cancer
Journal of Ovarian Research (2021)
-
Dietary nutrient intake related to higher grade cervical intraepithelial neoplasia risk: a Chinese population-based study
Nutrition & Metabolism (2020)