Mandy Spaan1, Alexandra W van den Belt-Dusebout1, Cornelis B Lambalk2, Hester H van Boven3, Roel Schats2, Marian Kortman4, Frank J M Broekmans4, Joop S E Laven5, Evert J P van Santbrink6, Didi D M Braat7, Lucette A J van der Westerlaken8, Ben J Cohlen9, Astrid E P Cantineau10, Jesper M J Smeenk11, Minouche M van Rumste12, Mariëtte Goddijn13, Ron J T van Golde14, Paul A M Meeuwissen15, Carl J C M Hamilton16, Gabriële M Ouwens1, Miranda A Gerritsma1, Michael Schaapveld1, Curt W Burger5, Flora E van Leeuwen1. 1. Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands. 2. Department of Obstetrics & Gynecology, Amsterdam University Medical Center (UMC) Location, VU University Medical Center, Amsterdam, the Netherlands. 3. Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands. 4. Department of Reproductive Medicine and Gynecology, University Medical Center Utrecht, Utrecht, the Netherlands. 5. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus Medical Center, Rotterdam, the Netherlands. 6. Department of Reproductive Medicine, Reinier de Graaf Hospital, Voorburg, the Netherlands. 7. Department of Obstetrics and Gynecology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands. 8. Department of Obstetrics, Gynecology and Reproductive Medicine, Leiden University Medical Center, Leiden, the Netherlands. 9. Department of Obstetrics and Gynecology, Isala Clinics, Zwolle, the Netherlands. 10. Department of Obstetrics and Gynecology, University Medical Center Groningen, University Groningen, Groningen, the Netherlands. 11. Department of Obstetrics and Gynecology, St Elisabeth Hospital, Tilburg, the Netherlands. 12. Department of Obstetrics and Gynecology, Catharina Hospital, Eindhoven, the Netherlands. 13. Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Amsterdam UMC Location, Academic Medical Center, Amsterdam, the Netherlands. 14. Department of Obstetrics and Gynecology, Maastricht University Medical Center, Maastricht, the Netherlands. 15. Department of Obstetrics and Gynecology, Admiraal de Ruyter Hospital, Vlissingen, the Netherlands. 16. Department of Obstetrics and Gynecology, Jeroen Bosch Ziekenhuis, 's-Hertogenbosch, the Netherlands.
Abstract
BACKGROUND: Long-term effects of assisted reproductive technology (ART) on ovarian tumor risk are unknown. METHODS: This nationwide cohort study comprises 30 625 women who received ovarian stimulation for ART in 1983-2000 and 9988 subfertile women not treated with ART. Incident invasive and borderline ovarian tumors were ascertained through linkage with the Netherlands Cancer Registry and the Dutch Pathology Registry until July 2018. Ovarian tumor risk in ART-treated women was compared with risks in the general population and the subfertile non-ART group. Statistical tests were 2-sided. RESULTS: After a median follow-up of 24 years, 158 invasive and 100 borderline ovarian tumors were observed. Ovarian cancer risk in the ART group was increased compared with the general population (standardized incidence ratio [SIR] = 1.43, 95% confidence interval [CI] = 1.18 to 1.71) but not when compared with the non-ART group (age- and parity-adjusted hazard ratio [HR] = 1.02, 95% CI = 0.70 to 1.50). Risk decreased with higher parity and with a larger number of successful ART cycles (resulting in childbirth, Ptrend = .001) but was not associated with the number of unsuccessful ART cycles. Borderline ovarian tumor risk was increased in ART-treated women compared with the general population (SIR = 2.20, 95% CI = 1.66 to 2.86) and with non-ART women (HR = 1.84, 95% CI = 1.08 to 3.14). Risk did not increase with more ART cycles or longer follow-up time. CONCLUSIONS: Increased ovarian cancer risk in ART-treated women compared with the general population is likely explained by nulliparity rather than ART treatment. The increased risk of borderline ovarian tumors after ART must be interpreted with caution because no dose-response relationship was observed.
BACKGROUND: Long-term effects of assisted reproductive technology (ART) on ovarian tumor risk are unknown. METHODS: This nationwide cohort study comprises 30 625 women who received ovarian stimulation for ART in 1983-2000 and 9988 subfertile women not treated with ART. Incident invasive and borderline ovarian tumors were ascertained through linkage with the Netherlands Cancer Registry and the Dutch Pathology Registry until July 2018. Ovarian tumor risk in ART-treated women was compared with risks in the general population and the subfertile non-ART group. Statistical tests were 2-sided. RESULTS: After a median follow-up of 24 years, 158 invasive and 100 borderline ovarian tumors were observed. Ovarian cancer risk in the ART group was increased compared with the general population (standardized incidence ratio [SIR] = 1.43, 95% confidence interval [CI] = 1.18 to 1.71) but not when compared with the non-ART group (age- and parity-adjusted hazard ratio [HR] = 1.02, 95% CI = 0.70 to 1.50). Risk decreased with higher parity and with a larger number of successful ART cycles (resulting in childbirth, Ptrend = .001) but was not associated with the number of unsuccessful ART cycles. Borderline ovarian tumor risk was increased in ART-treated women compared with the general population (SIR = 2.20, 95% CI = 1.66 to 2.86) and with non-ART women (HR = 1.84, 95% CI = 1.08 to 3.14). Risk did not increase with more ART cycles or longer follow-up time. CONCLUSIONS: Increased ovarian cancer risk in ART-treated women compared with the general population is likely explained by nulliparity rather than ART treatment. The increased risk of borderline ovarian tumors after ART must be interpreted with caution because no dose-response relationship was observed.
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