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Risks of Ovarian, Breast, and Corpus Uteri Cancer in Women Treated With Assisted Reproductive Technology in Great Britain, 1991–2010: Data Linkage Study Including 2.2 Million Person Years of Observation

Assisted reproductive therapy such as exposure of women to supraphysiological levels of estradiol, exogenous gonadotropins, and multiple ovarian punctures are suspected to incur an increased risk of cancer. Studies investigating the carcinogenic effects of these exposures are largely inconsistent. Specific concern surrounds the potentially increased risks of breast, endometrial, and ovarian cancers. This large population-based cohort study aimed to provide risk estimates for ovarian, breast, and corpus uteri cancer in women undergoing assisted reproduction. Data were obtained on all women undergoing assisted reproduction between 1991 and 2010 in Great Britain through the Human Fertilisation and Embryology Authority (HFEA). UK law mandates reporting of all assisted reproduction cycles to the HFEA, making this a very robust representation of the target population. Data on cancer prevalence in this population were obtained from the National Health Service Central Registers of England, Wales, and Scotland, and these were linked to HFEA records through a one-off linkage. The HFEA database was also used to obtain data on potential confounding variables including demographics, infertility diagnosis, parity, and treatment details. Follow-up was calculated from the date of first treatment to the date of any cancer diagnosis, death, emigration, or end of study. National incidence rates and person years of expected risk were used to calculate expected cancer rates. Standardized incidence ratios (SIRs) were calculated by comparison of observed outcomes versus expected outcomes. A total of 255,786 women contributed 2,257,789 person years of follow-up for analysis. Median follow-up duration was 8.8 years, and median age at first treatment was 34.5 years. Subjects had a median of 1.8 stimulated cycles with 50,485 (20%) having more than 2 stimulated cycles. No increase in risk of breast cancer overall (SIR, 0.98; 95% confidence interval Health, Inc. All rights reserved. 90 Obstetrical and Gynecological Survey [CI], 0.94–1.01) or invasive breast cancer (SIR, 0.96; 95% CI, 0.92–1.00) posttreatment was observed. No overall increase in corpus uteri cancer was observed (SIR, 1.12; 95% CI, 0.95–1.30). A small increased risk of in situ breast cancer was observed (SIR, 1.15; 95% CI, 1.02–1.29), which was associated with the number of treatment cycles (P = 0.03). An overall increased risk of ovarian cancer was observed (SIR, 1.39; 95% CI, 1.26–1.53) with a trend of increasing risk with decreasing age at first treatment (P < 0.001). Significantly increased risks for ovarian cancer were also observed in women with diagnosis of female factor infertility particularly endometriosis (SIR, 2.31; 95% CI, 1.74–3.01) and tubal disease (SIR, 1.68; 95% CI, 1.43–1.97). This large, national population-based study found that after assisted reproductive treatment, there was an increased risk of ovarian cancer and increased risk of situ breast cancer associated with increasing number of treatment cycles. No increased risks for corpus uteri or invasive breast cancer were observed.


ABSTRACT
Assisted reproductive therapy such as exposure of women to supraphysiological levels of estradiol, exogenous gonadotropins, and multiple ovarian punctures are suspected to incur an increased risk of cancer. Studies investigating the carcinogenic effects of these exposures are largely inconsistent. Specific concern surrounds the potentially increased risks of breast, endometrial, and ovarian cancers.
This large population-based cohort study aimed to provide risk estimates for ovarian, breast, and corpus uteri cancer in women undergoing assisted reproduction. Data were obtained on all women undergoing assisted reproduction between 1991 and 2010 in Great Britain through the Human Fertilisation and Embryology Authority (HFEA). UK law mandates reporting of all assisted reproduction cycles to the HFEA, making this a very robust representation of the target population. Data on cancer prevalence in this population were obtained from the National Health Service Central Registers of England, Wales, and Scotland, and these were linked to HFEA records through a one-off linkage. The HFEA database was also used to obtain data on potential confounding variables including demographics, infertility diagnosis, parity, and treatment details. Follow-up was calculated from the date of first treatment to the date of any cancer diagnosis, death, emigration, or end of study. National incidence rates and person years of expected risk were used to calculate expected cancer rates. Standardized incidence ratios (SIRs) were calculated by comparison of observed outcomes versus expected outcomes.
A total of 255,786 women contributed 2,257,789 person years of follow-up for analysis. Median follow-up duration was 8.8 years, and median age at first treatment was 34.5 years. Subjects had a median of 1.8 stimulated cycles with 50,485 (20%) having more than 2 stimulated cycles. No increase in risk of breast cancer overall (SIR, 0.98; 95% confidence interval [CI], 0.94-1.01) or invasive breast cancer (SIR, 0.96; 95% CI, 0.92-1.00) posttreatment was observed. No overall increase in corpus uteri cancer was observed (SIR, 1.12; 95% CI, 0.95-1.30). A small increased risk of in situ breast cancer was observed (SIR, 1.15; 95% CI, 1.02-1.29), which was associated with the number of treatment cycles (P = 0.03). An overall increased risk of ovarian cancer was observed (SIR, 1.39; 95% CI, 1.26-1.53) with a trend of increasing risk with decreasing age at first treatment (P < 0.001). Significantly increased risks for ovarian cancer were also observed in women with diagnosis of female factor infertility particularly endometriosis (SIR, 2.31; 95% CI, 1.74-3.01) and tubal disease (SIR, 1.68; 95% CI, 1.43-1.97).
This large, national population-based study found that after assisted reproductive treatment, there was an increased risk of ovarian cancer and increased risk of situ breast cancer associated with increasing number of treatment cycles. No increased risks for corpus uteri or invasive breast cancer were observed.

EDITORIAL COMMENT
(Assisted reproductive therapy (ART) is now widely practiced across the globe, and accounts for a growing proportion of pregnancies and births. So understanding its effect on maternal health is essential. ART exposes women to supraphysiological levels of sex steroids, exogenous gonadotropins, and multiple ovarian punctures, which could increase the risk of some cancers. This large population-based cohort study estimates risks for ovarian, breast, and corpus uteri cancer in women undergoing ART. All women undergoing ART between 1991 and 2010 in Great Britain were studied. Data on cancer prevalence were obtained from the National Health Service Central Registers of England, Wales, and Scotland. These data sources were linked. Potential confounding variables, including demographics, infertility diagnosis, parity, and treatment details, were obtained through the data bank. National incidence rates and person years of expected risk were used to calculate expected cancer rates. Standardized incidence ratios were calculated by comparison of observed versus expected outcomes.
Almost 250,000 women contributed 2,257,789 person years of follow-up. No increased risk of breast or uterine cancer was found. A small but significant increase in risk of in situ breast cancer was observed, which was associated with the number of treatment cycles. Ovarian cancer risk also was increased, with a trend toward increasing risk with decreasing age at first treatment. Risks for ovarian cancer were observed in women with diagnosis of female factor infertility particularly endometriosis and tubal disease. The increased risk of ovarian cancer did not persist in women undergoing ART for male factor, an important finding, because infertility itself is a risk factor for ovarian cancer. Given the increasing evidence that progesterone more than estrogen increases breast cancer risk, consideration should be given to minimizing supraphyisological levels of progesterone during ART, for example, by administering progesterone via the vaginal rather than the intramuscular routes.-DK)