Skip to main content

Advertisement

Log in

The risk of female malignancies after fertility treatments: a cohort study with 25-year follow-up

  • Original Article - Clinical Oncology
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Objective

To investigate whether an association exists between a history of fertility treatments and future risk of female malignancies.

Study design

A population-based study compared the incidence of long-term female malignancies in a cohort of women with and without a history of fertility treatments including in vitro fertilization (IVF) and ovulation induction (OI). Deliveries occurred between the years 1988–2013, with a mean follow-up duration of 12 years. Excluded from the study were women with known genetic predisposition for malignancies or known malignancies prior to the index pregnancy. Female malignancies were divided into specific types including ovarian, uterine, breast and cervix. Kaplan–Meier survival curve was used to estimate cumulative incidence of malignancies. Cox proportional hazard models were used to estimate the adjusted hazard ratios (HRs) for female malignancy.

Results

During the study period, 106,031 women met the inclusion criteria; 4.1 % (n = 4363) occurred in patients following fertility treatments. During the follow-up period, patients with a history of IVF treatments had a significantly increased risk of being diagnosed with ovarian and uterine cancer as compared to patients after OI and patients with no history of fertility treatments. Cox proportional hazard models were constructed for ovarian and uterine cancer separately, controlling for confounders such as maternal age and obesity. A history of IVF treatment remained independently associated with ovarian and uterine cancer (adjusted HR 3.9; 95 % CI 1.2–12.6; P = 0.022 and adjusted HR 4.6; 95 % CI 1.4–14.9; P = 0.011; respectively).

Conclusion

IVF treatments pose a significant risk of subsequent long-term ovarian and uterine cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Bernstein L (2002) Epidemiology of endocrine-related risk factors for breast cancer. J Mammary Gland Biol Neoplasia 7:3–15

    Article  PubMed  Google Scholar 

  • Boivin J, Bunting L, Collins JA, Nygren KG (2007) International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Hum Reprod 22:1506–1512

    Article  PubMed  Google Scholar 

  • Brinton LA, Lamb EJ, Moghissi KS, Scoccia B, Althuis MD, Mabie JE et al (2004a) Ovarian cancer risk associated with varying causes of infertility. Fertil Steril 82:405–414

    Article  PubMed  Google Scholar 

  • Brinton LA, Lamb EJ, Moghissi KS, Scoccia B, Althuis MD, Mabie JE et al (2004b) Ovarian cancer risk after the use of ovulation-stimulating drugs. Obstet Gynecol 103:1194–1203

    Article  PubMed  Google Scholar 

  • Brinton LA, Westhoff CL, Scoccia B, Lamb EJ, Trabert B, Niwa S et al (2013) Fertility drugs and endometrial cancer risk: results from an extended follow-up of a large infertility cohort. Hum Reprod 28:2813–2821

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Dor J, Lerner-Geva L, Rabinovici J, Chetrit A, Levran D, Lunenfeld B et al (2002) Cancer incidence in a cohort of infertile women who underwent in vitro fertilization. Fertil Steril 77:324–327

    Article  PubMed  Google Scholar 

  • Evers JL (2002) Female subfertility. Lancet 360:151–159

    Article  PubMed  Google Scholar 

  • IoS Silva, Wark PA, McCormack VA, Mayer D, Overton C, Little V et al (2009) Ovulation-stimulation drugs and cancer risks: a long-term follow-up of a British cohort. Br J Cancer 100:1824–1831

    Article  Google Scholar 

  • Jensen A, Sharif H, Frederiksen K, Kjaer SK (2009a) Use of fertility drugs and risk of ovarian cancer: Danish Population Based Cohort Study. BMJ 338:b249

    Article  PubMed  PubMed Central  Google Scholar 

  • Jensen A, Sharif H, Kjaer SK (2009b) Use of fertility drugs and risk of uterine cancer: results from a large Danish population-based cohort study. Am J Epidemiol 170:1408–1414

    Article  PubMed  Google Scholar 

  • Lerner-Geva L, Liat LG, Rabinovici J, Jaron R, Olmer L, Liraz O et al (2012) Are infertility treatments a potential risk factor for cancer development? Perspective of 30 years of follow-up. Gynecol Endocrinol 28:809–814

    Article  PubMed  Google Scholar 

  • Li LL, Zhou J, Qian XJ, Chen YD (2013) Meta-analysis on the possible association between in vitro fertilization and cancer risk. Int J Gynecol Cancer 23:16–24

    Article  PubMed  Google Scholar 

  • Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel S, Stevens GA (2012) National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS Med 9:e1001356

    Article  PubMed  PubMed Central  Google Scholar 

  • Modan B, Ron E, Lerner-Geva L, Blumstein T, Menczer J, Rabinovici J et al (1998) Cancer incidence in a cohort of infertile women. Am J Epidemiol 147:1038–1042

    Article  PubMed  CAS  Google Scholar 

  • Ness RB, Cramer DW, Goodman MT, Kjaer SK, Mallin K, Mosgaard BJ et al (2002) Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies. Am J Epidemiol 155:217–224

    Article  PubMed  Google Scholar 

  • Potashnik G, Lerner-Geva L, Genkin L, Chetrit A, Lunenfeld E, Porath A (1999) Fertility drugs and the risk of breast and ovarian cancers: results of a long-term follow-up study. Fertil Steril 71:853–859

    Article  PubMed  CAS  Google Scholar 

  • Rizzuto I, Behrens RF, Smith LA (2013) Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility. Cochrane Database Syst Rev 8:CD008215

    PubMed  Google Scholar 

  • Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG (1994) Ovarian tumors in a cohort of infertile women. N Engl J Med 331:771–776

    Article  PubMed  CAS  Google Scholar 

  • Rossing MA, Tang MT, Flagg EW, Weiss LK, Wicklund KG (2004) A case-control study of ovarian cancer in relation to infertility and the use of ovulation-inducing drugs. Am J Epidemiol 160:1070–1078

    Article  PubMed  Google Scholar 

  • Sanner K, Conner P, Bergfeldt K, Dickman P, Sundfeldt K, Bergh T et al (2009) Ovarian epithelial neoplasia after hormonal infertility treatment: long-term follow-up of a historical cohort in Sweden. Fertil Steril 91:1152–1158

    Article  PubMed  Google Scholar 

  • Sergentanis TN, Diamantaras AA, Perlepe C, Kanavidis P, Skalkidou A, Petridou ET (2014) IVF and breast cancer: a systematic review and meta-analysis. Hum Reprod Update 20:106–123

    Article  PubMed  Google Scholar 

  • Siristatidis C, Sergentanis TN, Kanavidis P, Trivella M, Sotiraki M, Mavromatis I et al (2013) Controlled ovarian hyperstimulation for IVF: impact on ovarian, endometrial and cervical cancer—a systematic review and meta-analysis. Hum Reprod Update 19:105–123

    Article  PubMed  CAS  Google Scholar 

  • Trabert B, Lamb EJ, Scoccia B, Moghissi KS, Westhoff CL, Niwa S et al (2013) Ovulation-inducing drugs and ovarian cancer risk: results from an extended follow-up of a large United States infertility cohort. Fertil Steril 100:1660–1666

    Article  PubMed  CAS  Google Scholar 

  • van Leeuwen FE, Klip H, Mooij TM, van de Swaluw AM, Lambalk CB, Kortman M et al (2011) Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort. Hum Reprod 26:3456–3465

    Article  PubMed  PubMed Central  Google Scholar 

  • Whittemore AS, Harris R, Itnyre J (1992) 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 136:1184–1203

    PubMed  CAS  Google Scholar 

  • Wysowski DK (1993) Use of fertility drugs in the United States, 1973 through 1991. Fertil Steril 60:1096–1098

    PubMed  CAS  Google Scholar 

  • Yli-Kuha AN, Gissler M, Klemetti R, Luoto R, Hemminki E (2012) Cancer morbidity in a cohort of 9175 Finnish women treated for infertility. Hum Reprod 27:1149–1155

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to R. Kessous.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Human and animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.

Appendix

Appendix

Dig

ICD code

Diagnosis

Ovary

7300

V1043

Personal history of malignant neoplasm of ovary

21899

183

Malignant neoplasm of ovary and other uterine adnexa

21900

1830

Malignant neoplasm of ovary

21901

1832

Malignant neoplasm of ovary

21905

1838

Malignant neoplasm of other specified sites of uterine adnexa

21906

1839

Malignant neoplasm of uterine adnexa, unspecified

21758

1588

Malignant neoplasm of specified parts of peritoneum

21759

1589

Malignant neoplasm of peritoneum, unspecified

Uterus

22575

2332

Carcinoma in situ of other and unspecified parts of uterus

21895

182

Malignant neoplasm of body of uterus

21896

1820

Malignant neoplasm of corpus uteri, except isthmus

21897

1821

Malignant neoplasm of isthmus

21898

1828

Malignant neoplasm of other specified sites of body of uterus

21888

179

Malignant neoplasm of uterus, part unspecified

7299

V1042

Personal history of malignant neoplasm of other parts of uterus

Cervical Ca

22575

2331

Carcinoma in situ of cervix uteri

7928

V1041

Personal history of malignant neoplasm of cervix uteri

21889

180

Malignant neoplasm of cervix uteri

21890

1800

Malignant neoplasm of endocervix

21891

1801

Malignant neoplasm of exocervix

21892

1808

Malignant neoplasm of other specified sites of cervix

Breast Ca

7295

V103

Personal history of malignant neoplasm of breast

22574

2330

Carcinoma in situ of breast

22630

2383

Neoplasm of uncertain behavior of breast

22642

2393

Neoplasm of unspecified nature of breast

21857

174

Malignant neoplasm of female breast

21858

1740

Malignant neoplasm of nipple and areola of female breast

21859

1741

Malignant neoplasm of central portion of female breast

21860

1742

Malignant neoplasm of upper-inner quadrant of female breast

21861

1743

Malignant neoplasm of lower-inner quadrant of female breast

21862

1744

Malignant neoplasm of upper-outer quadrant of female breast

21863

1745

Malignant neoplasm of lower-outer quadrant of female breast

21864

1746

Malignant neoplasm of axillary tail of female breast

21865

1747

Malignant neoplasm of other specified sites of female breast

21866

1748

Malignant neoplasm of breast (female), unspecified

Surgery Procedure for Breast Ca

1182–1183

Z8521

Local excision of lesion of breast

1184

Z85210

Local exc. breast lesion + reg. lymph node exc.

1185

Z85211

Local exc. breast lesion + rad. cervical node exc.

1186

Z8522

Resection of quadrant of breast

1187

Z85220

Quadrant resect. breast + rad. cervical node exc.

1188

Z85221

Quadrant resect. breast `regional. lymph node exc.

1189

Z8523

Subtotal mastectomy

1199

Z854

Mastectomy

1200

Z8541

Unilateral simple mastectomy

1201

Z8542

Bilateral simple mastectomy

1202

Z8543

Unilateral extended simple mastectomy

1203

Z85430

Radical modified mastectomy

1204

Z8544

Bilateral extended simple mastectomy

1205

Z8545

Unilateral radical mastectomy

1206

Z8546

Bilateral radical mastectomy

1207

Z8547

Unilateral extended radical mastectomy

1208

Z8548

Bilateral extended radical mastectomy

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kessous, R., Davidson, E., Meirovitz, M. et al. The risk of female malignancies after fertility treatments: a cohort study with 25-year follow-up. J Cancer Res Clin Oncol 142, 287–293 (2016). https://doi.org/10.1007/s00432-015-2035-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-015-2035-x

Keywords

Navigation