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.
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References
Bernstein L (2002) Epidemiology of endocrine-related risk factors for breast cancer. J Mammary Gland Biol Neoplasia 7:3–15
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
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
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
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
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
Evers JL (2002) Female subfertility. Lancet 360:151–159
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Wysowski DK (1993) Use of fertility drugs in the United States, 1973 through 1991. Fertil Steril 60:1096–1098
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
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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 |
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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
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DOI: https://doi.org/10.1007/s00432-015-2035-x