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Risk of cervical cancer after completed post-treatment follow-up of cervical intraepithelial neoplasia: population based cohort study

BMJ 2012; 345 doi: (Published 01 November 2012) Cite this as: BMJ 2012;345:e6855
  1. Matejka Rebolj, postdoctoral researcher12,
  2. Theo Helmerhorst, professor of gynaecology3,
  3. Dik Habbema, professor of medical decision sciences1,
  4. Caspar Looman, statistician1,
  5. Rob Boer, informatician/statistician1,
  6. Joost van Rosmalen, postdoctoral researcher1,
  7. Marjolein van Ballegooijen, associate professor of medical technology assessment1
  1. 1Department of Public Health, Erasmus MC, Rotterdam, Netherlands
  2. 2Department of Public Health, University of Copenhagen, Copenhagen, Denmark
  3. 3Department of Obstetrics and Gynaecology, Erasmus MC, Rotterdam, Netherlands
  1. Correspondence to: M Rebolj mare{at}
  • Accepted 27 September 2012


Objective To compare the risk of cervical cancer in women with histologically confirmed cervical intraepithelial neoplasia who returned to routine screening after having completed post-treatment follow-up with consecutive normal smear test results with women with a normal primary smear test result.

Design Population based cohort study using data from a nationwide pathology register.

Setting The Netherlands, 1994 to 2006.

Population 38 956 women with histologically confirmed intraepithelial neoplasia grades 1 to 3 with completed follow-up after treatment.

Intervention Routine post-treatment follow-up of cervical intraepithelial neoplasia, recommending smear tests at six, 12, and 24 months.

Main outcome measure Incidence of cervical cancer in the period from completed follow-up with negative test results after cervical intraepithelial neoplasia to the next primary test. 10-year hazard ratios were compared with periods after normal results for the primary smear test, adjusted for year in follow-up.

Results 20 cervical cancers were diagnosed during 56 956 woman years after completed follow-up of cervical intraepithelial neoplasia, whereas 1613 cervical cancers were diagnosed during 25 020 697 woman years after a normal primary smear test result. The incidence of 35.1 (95% confidence interval 21.4 to 54.2) per 100 000 woman years and 6.4 (6.1 to 6.8) per 100 000 woman years, respectively, led to an adjusted hazard ratio of 4.2 (95% confidence interval 2.7 to 6.5) for periods after completed follow-up compared with periods after normal primary smear test results. This hazard ratio was increased for all ages. No significant difference in risk of cervical cancer was observed by grade of cervical intraepithelial neoplasia.

Conclusions An excess risk of cervical cancer previously observed for women treated for cervical intraepithelial neoplasia was also observed in the subgroup of women who completed their post-treatment follow-up with three consecutive normal smear test results. The overall corrected risk of cervical cancer in these women was increased fourfold 35 cases per 100 000 woman years) compared with women with normal primary smear test results (6 per 100 000 woman years).


  • We thank Menno Dekker and Roel Faber for help with data management.

  • Contributors: MR, MvB, and DH designed the study. MR, CL, and JvR analysed the data. All authors interpreted the results, drafted the manuscript, and decided to submit the manuscript. MR and MvB are the guarantors. All authors had full access to all of the data in the study and wrote the manuscript independent of the funder.

  • Funding: This study was funded by the Dutch National Institute for Public Health and the Environment (RIVM, grant No 3022/07 DG MS/CvB/NvN). The RIVM had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the report; and the decision to submit the manuscript for publication. The researchers worked independently of the funders.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare that: MR is currently involved in a comparative study of new generation human papillomavirus tests, for which Roche Diagnostics, Genomica, Qiagen, and Gen-Probe provided assays and instrumentations. MR did not receive any salary, compensation, or bonuses for work on any of the projects from any of the companies, and does not hold companies’ stock. Concerning the present paper, there has been no involvement or support from any of the companies. Since 1989 RB has been participating in the screening research group at the Department of Public Health of Erasmus MC. Between 2009 and 2012 he was also director of health economics at Cerner LifeSciences, which is a consultancy that mainly works for the pharmaceutical industry and is part of Cerner that mainly develops and markets healthcare information technology. This research and article were not funded or supported by Cerner or their clients. RB’s institution has received a grant from Health Insurance Executive Board. MvB was the principal investigator until 2008 on a project on the cost effectiveness of human papillomavirus vaccination, financed by GSK (a pharmaceutical company that produces human papillomavirus vaccines against cervical cancer). There has been no collaboration with or support from GSK for the present paper. The authors have no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Data retrieval was approved by the board of PALGA, the Dutch nationwide network and register of histopathology and cytopathology.

  • Data sharing: No additional data available.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: and

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