Long-term risk of endometrial cancer after assisted reproductive technology
Authors: Spaan Mandy , van den Belt-Dusebout Alexandra W , Lambalk Cornelis B , van Boven Hester , van Loendersloot Laura L , Broekmans Frank J M , Laven Joop S E , van Santbrink Evert J P , Nap Annemiek W , van der Westerlaken Lucette A J , Cohlen Ben J , Cantineau Astrid E P , Smeenk Jesper M J , van Rumste Minouche M , Goddijn Mariëtte , van Golde Ron J T , Meeuwissen Paul A M , de Bruin Jan P , Ouwens Gabriële M , Gerritsma Miranda A , Schaapveld Michael , Burger Curt W , van Leeuwen Flora E 
Published: January 2025

Abstract

STUDY QUESTION
What is the risk of endometrial cancer after long-term follow-up in women treated with ART between 1983 and 2001 compared with women in the general population and subfertile women who did not undergo ART?

SUMMARY ANSWER
The risk of endometrial cancer is not increased in women who underwent ART in the Netherlands between 1983 and 2001, neither compared with women from the general population nor compared with subfertile women not treated with ART.

WHAT IS KNOWN ALREADY
Concerns have been raised that subfertility treatment may be associated with increased risk of endometrial cancer. However, published studies show inconsistent results regarding the effects of ovarian stimulation and specific subfertility diagnoses on endometrial cancer risk.

STUDY DESIGN, SIZE, DURATION
A nationwide historic cohort study (the OMEGA-cohort) was conducted to examine the risk of cancer in women after ovarian stimulation for ART. The OMEGA-cohort comprises 30 625 women who received ovarian stimulation for ART (ART group) in 1983–2000 and 9988 subfertile women not treated with ART (non-ART group). After a median follow-up of 24 years, endometrial cancer incidence was ascertained through linkage with the Netherlands Cancer Registry. Endometrial cancer risk in the cohort was compared with that in the general population using person-years analyses, and between the ART group and non-ART group using multivariable Cox regression analyses.

PARTICIPANTS/MATERIALS, SETTING, METHODS
Detailed ART-treatment data were obtained from the medical records and complete information on parity and age at first birth was obtained through linkage with the Personal Records Database. Information on hysterectomy and endometriosis was collected through linkage with the Dutch Nationwide Pathology Databank (Palga). Data about lifestyle factors, including BMI, were obtained through a self-administered questionnaire.

MAIN RESULTS AND THE ROLE OF CHANCE
After a median follow-up duration of 24 years, 137 endometrial cancers were diagnosed. Endometrial cancer risk after ART was not significantly increased compared with that in the general population (standardized incidence ratio = 1.19; 95% CI = 0.97–1.44) nor compared with that in the non-ART group (multivariably adjusted hazard ratio = 1.11; 95% CI = 0.74–1.67). Risk of endometrial cancer did not increase with longer follow-up or with more ART cycles, and the risk within the cohort, did not vary by cause of subfertility (male, tubal, unexplained, and other). Irrespective of ART treatment, endometrial cancer risk was increased in obese women and women with endometriosis, but decreased among parous women and women who used oral contraceptives.

LIMITATIONS, REASONS FOR CAUTION
Although the findings of the study are reassuring, the median age of the women at the end of follow-up (median age 56 years) was still rather young. Therefore, there is a need for at least 10–15 additional follow-up years to draw definitive conclusions. In addition, other large studies are needed to investigate the risk of endometrial cancer in women who underwent ART.

WIDER IMPLICATIONS OF THE FINDINGS
The results of this study contribute to knowledge about long-term health after ART treatment, which is valuable to subfertile couples, considering or undergoing fertility treatments, and their healthcare providers.

STUDY FUNDING/COMPETING INTEREST(S)
This study was supported by a grant from the Dutch Cancer Society (NKI 2006-3631) and a departmental grant from the Department of Obstetrics and Gynecology of Erasmus Medical Center, Rotterdam, the Netherlands (2011-019). Ma.S. is Associate Editor of Human Reproduction Open; A.W.vd.B.-D received support for attending meetings and/or travel from the Dutch Cancer Society; C.B.L. is Editor-in-Chief of Human Reproduction; A.E.P.C. is Associate Editor of Human Reproduction Update, received royalties from Uptodate Hyperthecosis, and participated at the Data Safety Monitoring Board of the DSMB POEM Study; F.B. has received research support from Merck, honoraria or consultation fees from Merck Healthcare KGaA, Bensis Healthcare, CooperSurgical, and participated in an advisory board for Merck and Ferring; J.L. has received research support from Ferring, Merck, and Roche Diagnostics, consulting fees and honoraria from Ferring, participated on a Data Safety Monitoring Board or Advisory Board of the LOCI trial, is President of the AE-PCOS society, and Member of the ASRM Integrity Committee; J.M.J.S. has received honoraria from Ferring and Merck, support for attending meetings and/or travel from Ferring, Merck, and Good Life, and participated in the advisory board of Merck; L.L.v.L. received support for attending meetings and/or travel from Olympus Medical Expert training; M.M.v.R. received support for attending meetings and/or travel from Ferring; M.G. declares departmental research and educational grants from Ferring (location VUmc), unrelated to the presented work. The other authors declare no competing interests.

TRIAL REGISTRATION NUMBER
N/A.