Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Epidemiology

Risk of ovarian cancer in women who give birth after assisted reproductive technology (ART)—a registry-based Nordic cohort study with follow-up from first pregnancy

British Journal of Cancer volume 128, pages 825–832 (2023)Cite this article

Subjects

Abstract

Background

There is concern that assisted reproductive technology (ART) may increase ovarian cancer risk, but previous studies are inconclusive. We compared ovarian cancer risk for women who gave birth after ART vs natural conception.

Methods

Through linkage of nationwide registry data, we followed 3,303,880 initially nulliparous women in Denmark (1994–2014), Finland (1990–2014), Norway (1984–2015) and Sweden (1985–2015) from first pregnancy ≥22 weeks to ovarian cancer, emigration, death or end of follow-up (2014/2015). We estimated hazard ratios (HRs), adjusting for age, parity, maternal birth year and country, and for body mass index and smoking in subsamples.

Results

Mean age at first birth was 27.7 years. During a mean follow-up of 14.4 person-years, 2683 participants (0.08%) developed ovarian cancer; 135 after ART and 2548 after natural conception only (incidence rates 11.6 and 5.5 per 100,000 person-years, respectively). The risk was higher for women who ever gave birth after ART (HR 1.70, 95% confidence interval 1.42–2.03) compared to natural conception. Associations were stronger for conventional in vitro fertilisation than for intracytoplasmic sperm injection.

Conclusions

Among parous women, ART-conception was associated with a higher risk of ovarian cancer than natural conception. Further studies should decipher whether this is causal or confounded by infertility or other factors.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

The data that support the findings of this study were used under license for the current study and are not publicly available. Restrictions apply to data availability, but data may be accessed through Statistics Denmark upon reasonable request to the authors and with permission from the relevant authorities, ethics committees and Statistics Denmark.

References

  1. Webb PM, Jordan SJ. Epidemiology of epithelial ovarian cancer. Best Pract Res Clin Obstet Gynaecol. 2017;41:3–14.

    Article  PubMed  Google Scholar 

  2. Twombly R. Too early to determine cancer risk from infertility treatments. J Natl Cancer Inst. 2012;104:501–2.

    Article  PubMed  Google Scholar 

  3. Fathalla MF. Incessant ovulation-a factor in ovarian neoplasia? Lancet. 1971;2:163.

    Article  CAS  PubMed  Google Scholar 

  4. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J Med. 1994;331:771–6.

    Article  CAS  PubMed  Google Scholar 

  5. Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol. 1992;136:1184–203.

    Article  CAS  PubMed  Google Scholar 

  6. Kessous R, Davidson E, Meirovitz M, Sergienko R, Sheiner E. The risk of female malignancies after fertility treatments: a cohort study with 25-year follow-up. J Cancer Res Clin Oncol. 2016;142:287–93.

    Article  CAS  PubMed  Google Scholar 

  7. van Leeuwen FE, Klip H, Mooij TM, van de Swaluw AM, Lambalk CB, Kortman M, et al. Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort. Hum Reprod. 2011;26:3456–65.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Luke B, Brown MB, Spector LG, Missmer SA, Leach RE, Williams M, et al. Cancer in women after assisted reproductive technology. Fertil Steril. 2015;104:1218–26.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Trabert B, Lamb EJ, Scoccia B, Moghissi KS, Westhoff CL, Niwa S, et al. Ovulation-inducing drugs and ovarian cancer risk: results from an extended follow-up of a large United States infertility cohort. Fertil Steril. 2013;100:1660–6.

    Article  CAS  PubMed  Google Scholar 

  10. Brinton LA, Trabert B, Shalev V, Lunenfeld E, Sella T, Chodick G. In vitro fertilization and risk of breast and gynecologic cancers: a retrospective cohort study within the Israeli Maccabi Healthcare Services. Fertil Steril. 2013;99:1189–96.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kallen B, Finnstrom O, Lindam A, Nilsson E, Nygren KG, Olausson PO. Malignancies among women who gave birth after in vitro fertilization. Hum Reprod. 2011;26:253–8.

    Article  CAS  PubMed  Google Scholar 

  12. Williams CL, Jones ME, Swerdlow AJ, Botting BJ, Davies MC, Jacobs I, et al. Risks of ovarian, breast, and corpus uteri cancer in women treated with assisted reproductive technology in Great Britain, 1991–2010: data linkage study including 2.2 million person years of observation. BMJ. 2018;362:k2644.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Reigstad MM, Larsen IK, Myklebust TA, Robsahm TE, Oldereid NB, Omland AK, et al. Cancer risk among parous women following assisted reproductive technology. Hum Reprod. 2015;30:1952–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Reigstad MM, Storeng R, Myklebust TA, Oldereid NB, Omland AK, Robsahm TE, et al. Cancer risk in women treated with fertility drugs according to parity status—a registry-based cohort study. Cancer Epidemiol Biomark Prev. 2017;26:953–62.

    Article  CAS  Google Scholar 

  15. Rizzuto I, Behrens RF, Smith LA. Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility. Cochrane database Syst Rev (Online). 2019;6:CD008215.

    Google Scholar 

  16. Barcroft JF, Galazis N, Jones BP, Getreu N, Bracewell-Milnes T, Grewal KJ, et al. Fertility treatment and cancers-the eternal conundrum: a systematic review and meta-analysis. Hum Reprod. 2021;36:1093–107.

    Article  PubMed  Google Scholar 

  17. Lundberg FE, Iliadou AN, Rodriguez-Wallberg K, Gemzell-Danielsson K, Johansson ALV. The risk of breast and gynecological cancer in women with a diagnosis of infertility: a nationwide population-based study. Eur J Epidemiol. 2019;34:499–507.

  18. Tworoger SS, Fairfield KM, Colditz GA, Rosner BA, Hankinson SE. Association of oral contraceptive use, other contraceptive methods, and infertility with ovarian cancer risk. Am J Epidemiol. 2007;166:894–901.

    Article  PubMed  Google Scholar 

  19. Reid BM, Permuth JB, Sellers TA. Epidemiology of ovarian cancer: a review. Cancer Biol Med. 2017;14:9–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vassard D, Schmidt L, Glazer CH, Lyng Forman J, Kamper-Jørgensen M, Pinborg A. Assisted reproductive technology treatment and risk of ovarian cancer-a nationwide population-based cohort study. Hum Reprod. 2019;34:2290–6.

    Article  CAS  PubMed  Google Scholar 

  21. European Ivf Monitoring Consortium f.t.E.S.o.H.R., Embryology, Wyns C, De Geyter C, Calhaz-Jorge C, Kupka MS, et al. ART in Europe, 2018: results generated from European registries by ESHRE. Hum Reprod Open. 2022;2022:hoac022.

    Article  Google Scholar 

  22. Henningsen AK, Romundstad LB, Gissler M, Nygren KG, Lidegaard O, Skjaerven R, et al. Infant and maternal health monitoring using a combined Nordic database on ART and safety. Acta Obstet Gynecol Scand. 2011;90:683–91.

    Article  PubMed  Google Scholar 

  23. Opdahl S, Henningsen AA, Bergh C, Gissler M, Romundstad LB, Petzold M, et al. Data Resource Profile: Committee of Nordic Assisted Reproductive Technology and Safety (CoNARTaS) cohort. Int J Epidemiol. 2020;49:365–366f.

    Article  PubMed  Google Scholar 

  24. De Geyter C, Calhaz-Jorge C, Kupka MS, Wyns C, Mocanu E, Motrenko T, et al. ART in Europe, 2014: results generated from European registries by ESHRE: The European IVF-monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE). Hum Reprod. 2018;33:1586–601.

    Article  PubMed  Google Scholar 

  25. Engholm G, Ferlay J, Christensen N, Bray F, Gjerstorff ML, Klint A, et al. NORDCAN-a Nordic tool for cancer information, planning, quality control and research. Acta Oncol. 2010;49:725–36.

    Article  PubMed  Google Scholar 

  26. Nguyen TH, Larsen T, Engholm G, Møller H. Evaluation of ultrasound-estimated date of delivery in 17,450 spontaneous singleton births: do we need to modify Naegele’s rule? Ultrasound Obstet Gynecol. 1999;14:23–28.

    Article  CAS  PubMed  Google Scholar 

  27. Mansournia MA, Nazemipour M, Etminan M. Causal diagrams for immortal time bias. Int J Epidemiol. 2021;50:1405–9.

    Article  PubMed  Google Scholar 

  28. Spaan M, van den Belt-Dusebout AW, Lambalk CB, van Boven HH, Schats R, Kortman M, et al. Long-term risk of ovarian cancer and borderline tumors after assisted reproductive technology. J Natl Cancer Inst. 2020;113:699–709.

  29. Murugappan G, Li S, Lathi RB, Baker VL, Eisenberg ML. Risk of cancer in infertile women: analysis of US claims data. Hum Reprod. 2019;34:894–902.

    Article  PubMed  Google Scholar 

  30. Siristatidis C, Sergentanis TN, Kanavidis P, Trivella M, Sotiraki M, Mavromatis I, et al. Controlled ovarian hyperstimulation for IVF: impact on ovarian, endometrial and cervical cancer-a systematic review and meta-analysis. Hum Reprod Update. 2013;19:105–23.

    Article  CAS  PubMed  Google Scholar 

  31. Stewart LM, Holman CD, Aboagye-Sarfo P, Finn JC, Preen DB, Hart R. In vitro fertilization, endometriosis, nulliparity and ovarian cancer risk. Gynecol Oncol. 2013;128:260–4.

    Article  PubMed  Google Scholar 

  32. Pukkala E, Engholm G, Hojsgaard Schmidt LK, Storm H, Khan S, Lambe M, et al. Nordic Cancer Registries—an overview of their procedures and data comparability. Acta Oncol. 2018;57:440–55.

    Article  PubMed  Google Scholar 

  33. Venn A, Watson L, Bruinsma F, Giles G, Healy D. Risk of cancer after use of fertility drugs with in-vitro fertilisation. Lancet. 1999;354:1586–90.

    Article  CAS  PubMed  Google Scholar 

  34. Malchau SS, Henningsen AA, Loft A, Rasmussen S, Forman J, Nyboe Andersen A, et al. The long-term prognosis for live birth in couples initiating fertility treatments. Hum Reprod. 2017;32:1439–49.

    Article  CAS  PubMed  Google Scholar 

  35. Gottschau M, Mellemkjaer L, Hannibal CG, Kjaer SK. Ovarian and tubal cancer in Denmark: an update on incidence and survival. Acta Obstet Gynecol Scand. 2016;95:1181–9.

    Article  PubMed  Google Scholar 

  36. Havrilesky LJ, Moorman PG, Lowery WJ, Gierisch JM, Coeytaux RR, Urrutia RP, et al. Oral contraceptive pills as primary prevention for ovarian cancer: a systematic review and meta-analysis. Obstet Gynecol. 2013;122:139–47.

    Article  CAS  PubMed  Google Scholar 

  37. Mortlock S, Corona RI, Kho PF, Pharoah P, Seo JH, Freedman ML, et al. A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes. Cell Rep Med. 2022;3:100542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the staff in Nordic fertility clinics and hospitals for taking time to complete the registry notifications in their busy working day. The details and completeness of their work provide a solid foundation for our study.

Funding

The project was supported by a grant from the Norwegian Cancer Society [grant number 182356–2016]. The establishment of the CoNARTaS cohort has additionally been supported by the Nordic Trial Alliance: a pilot project jointly funded by the Nordic Council of Ministers and NordForsk [grant number 71450], the Central Norway Regional Health Authorities [grant number 46045000], the Nordic Federation of Obstetrics and Gynaecology [grant numbers NF13041, NF15058, NF16026 and NF17043], the Interreg Öresund-Kattegat-Skagerrak European Regional Development Fund (ReproUnion project).

Author information

Authors and Affiliations

  1. Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway

    Marie Søfteland Sandvei & Signe Opdahl

  2. The Cancer Clinic, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

    Marie Søfteland Sandvei

  3. The Fertility Clinic, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Anja Pinborg & Anna-Karina Henningsen

  4. Department of Knowledge Brokers, THL Finnish Institute for Health and Welfare, Helsinki, Finland

    Mika Gissler

  5. Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

    Mika Gissler

  6. Academic Primary Health Care Centre, Region Stockholm, Sweden

    Mika Gissler

  7. Department of Obstetrics and Gynaecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden

    Christina Bergh & Ulla-Britt Wennerholm

  8. Spiren Fertility Clinic, Trondheim, Norway

    Liv Bente Romundstad

  9. Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway

    Liv Bente Romundstad

  10. Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Flora E. van Leeuwen & Mandy Spaan

  11. Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    Aila Tiitinen

Authors
  1. Marie Søfteland Sandvei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anja Pinborg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mika Gissler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christina Bergh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Liv Bente Romundstad
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Flora E. van Leeuwen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mandy Spaan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Aila Tiitinen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ulla-Britt Wennerholm
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Anna-Karina Henningsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Signe Opdahl
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AP, MG, CB, LBR, AT, UBW, AKH and SO conceived and designed the work that led to the submission and acquired the data. MSS and SO performed the statistical analyses. MSS drafted the manuscript. All authors played an important role in interpreting the results and revision of the manuscript, approved the final version and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Marie Søfteland Sandvei.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the registry-keeping authorities in each country. Permission was granted from the regional ethics committees in Norway (REC North 2010/1909) and Sweden (Dnr 214-12, T422-12, T516-15, T233-16, T300-17, T1144-17, T121-18, T1071-18, T2019 02347). In Denmark and Finland, study-specific ethical approval is not required when using national registry data for research purposes.

Consent for publication

Non applicable.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sandvei, M.S., Pinborg, A., Gissler, M. et al. Risk of ovarian cancer in women who give birth after assisted reproductive technology (ART)—a registry-based Nordic cohort study with follow-up from first pregnancy. Br J Cancer 128, 825–832 (2023). https://doi.org/10.1038/s41416-022-02097-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-022-02097-7

Search

Advanced search

Quick links