Long-Term Risk of Ovarian Cancer and Borderline Tumors After Assisted Reproductive Technology

Despite inconclusive evidence, concerns that assisted reproductive technology may be associated with increased risk of ovarian cancer remain. Significant increases in gonadotropin levels and disruption of ovarian epithelium have been proposed as mechanisms to explain this potential association. Several studies investigating this have suggested the observed increased risk in those undergoing assisted reproductive technology (ART) may be more related to nulliparity and subfertility than the treatment itself.This nationwide retrospective cohort study with prospective follow-up aimed to determine long-term ovarian cancer risk among women treated with ART compared with women in the general population and compared with subfertile women not treated with ART. Also investigated was whether unsuccessful ART and successful ART leading to childbirth had different effects on ovarian cancer risk. Women treated with ART between 1983 and 2000 identified in the OMEGA-1 (OvariuMstimulatie En Gynecologische Aandoenginen-1) cohort were included in this analysis. The OMEGA-1 cohort included women starting ovarian stimulation for ART in in vitro fertilization (IVF) clinics in the Netherlands, as well as a comparison cohort of subfertile ART-native women. Eligible women entered into the study cohort on the date of first ART or first clinic visit for subfertility evaluation. Cancer diagnosis data were obtained through the population-based Netherlands Cancer Registry between 1989 and July 2018. Ovarian cancer incidence in the ART and non-ART cohorts were compared, and standardized incidence ratios (SIRs) were calculated based on the observed and expected numbers of tumors in each cohort.The final study cohort consisted of 30,625 ART-treated women and 9988 non-ART-treated women with a median follow-up of 24 years. A total of 158 ovarian cancers were observed in the follow-up period, 158 of which were invasive and 100 borderline. Ovarian cancer risk was increased in the ART group (SIR = 1.43; 95% confidence interval [CI], 1.18-1.71) but not in the non-ART group (SIR = 1.15; 95% CI, 0.81-1.59; P = 0.25) compared with the general population. Nulliparous women had a 2-fold increased risk of ovarian cancer compared with the general population, and each subfertility diagnosis was associated with an increase in ovarian cancer risk in ART-treated women but not in non-ART-treated women. When comparing the ART group and non-ART group and adjusting for age at start and parity, the hazards ratio (HR) for ovarian cancer was 1.02 (95% CI, 0.70-1.50), and this did not increase after more ART cycles. A decreased risk of ovarian cancer was associated with a larger number of successful ART cycles (1 successful ART cycle HR = 0.54; 95% CI, 0.35-0.87; >= 2 cycles HR = 0.37; 95% CI, 0.18-0.73; P = 0.001); however, a larger number of unsuccessful cycles was not associated with a greater risk. Borderline ovarian cancers were more common among both ART and non-ART women compared with the general population (SIR = 2.20; 95% CI, 1.66-2.86; SIR = 1.84; 95% CI, 1.05-2.99, respectively), and more common in ART-treated women compared with non-ART women (HR, 1.84; 95% CI, 1.08-3.14); however, risk did not increase with more ART cycles or follow-up time.The results of this study show an increased risk of ovarian cancer among ART-treated women compared with the general population, but not compared with subfertile women not treated with ART and is attributed to nulliparity.