ArticlesBreast and ovarian cancer incidence after infertility and in vitro fertilisation
Abstract
Concern has been expressed that exposure to fertility drugs might be associated with a risk of ovarian cancer. We have examined the incidence of breast and ovarian cancer in a cohort of 10 358 women referred for in-vitro fertilisation (IVF) treatment in Victoria, Australia, between 1978 and 1992. The "exposed" group (n=5564) had had ovarian stimulation to induce multiple folliculogenesis and the "unexposed" group (n=4794) had been referred for IVF but were untreated or had had "natural cycle" treatment without ovarian stimulation. Duration of follow-up ranged from 1 to 15 years. Cases of cancer were determined by record linkage with data from population-based cancer registries. 34 cases of invasive breast cancer and 6 of invasive ovarian cancer were observed. A comparison with the expected numbers, derived by applying age-standardised general population rates to the cohort gave standardised incidence ratios (SIR) for breast cancer of 0·89 (95% Cl 0·55-1·46) in the exposed group and 0·98 (0·62-1·56) in the unexposed group, and for ovarian cancer SIRs were 1·70 (0·55-5·27) and 1·62 (0·52-5·02), respectively. Rates of all cancers were not significantly different from general population rates. The relative risk (RR) of cancer, adjusted for age and infertility type, was, in the treated group compared with the untreated group, 1·11 (95% Cl 0·56-2·20) for breast cancer and 1·45 (0·28-7·55) for ovarian cancer. The risk of body of uterus cancer was increased in the exposed and unexposed groups combined (SIR 2·84 [1·18-6·81]). Women with unexplained infertility, independent of IVF exposure, had significantly increased risks of ovarian cancer (RR=19·19 [2·23-165·0]) and body of uterus cancer (RR=6·34 [1·06-38·0]) compared with women with known causes of infertility. This relatively short-term follow-up suggests that ovarian stimulation with IVF is not associated with an increased risk of breast cancer. Although there was no significantly increased risk of ovarian cancer after ovarian stimulation with IVF the small number of cases limits the conclusions that can be drawn. Longer-term follow-up of large cohorts of women who have been in IVF programmes will be necessary.
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Cited by (314)
The risk of breast cancer and gynecologic malignancies after ovarian stimulation: Meta-analysis of cohort study
2024, Critical Reviews in Oncology/HematologyThe effects of ovarian stimulation on breast and gynecological tumor incidence remain controversial. Therefore, the aim of this meta-analysis was to study the risk of cancer in ovarian stimulation. Of the 22713 studies initially identified, 28 were eligible for inclusion. The results revealed that the impact of ovarian cancer (RR = 1.33, [1.05; 1.69]) and cervical cancer (RR = 0.67, [0.46; 0.97]) is significant among the overall effects. In subgroup analysis, in the nulliparous population (RR = 0.81 [0.68; 0.96]) was the protective factor for the breast cancer. In the Caucasians subgroup (RR = 1.45, [1.12; 1.88]), the ovarian cancer incidence was statistically significant. In the Asian subgroup (RR = 1.51, [1.00; 2.28]), the endometrial cancer incidence was statistically significant. In the subgroup of Asians (RR = 0.55 [0.44; 0.68]) and the multiparous population (RR = 0.31, [0.21; 0.46]), them can be the statistically protective factor for the cervical cancer.
A prospective cohort study of infertility and cancer incidence
2023, Fertility and SterilityTo investigate the association between infertility and the incidence of invasive cancer.
Prospective cohort study (1989–2015).
Not applicable.
A total of 103,080 women aged 25–42 years in the Nurses’ Health Study II who were cancer-free at baseline (1989).
The infertility status (failure to conceive after 1 year of regular, unprotected sex) and causes of infertility were self-reported at baseline and biennial follow-up questionnaires.
Cancer diagnosis was confirmed through medical record review and classified as obesity-related (colorectal, gallbladder, kidney, multiple myeloma, thyroid, pancreatic, esophageal, gastric, liver, endometrial, ovarian, and postmenopausal breast) or non–obesity-related (all other cancers). We fit the Cox proportional-hazards models to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of the association between infertility and cancer incidence.
During 2,149,385 person-years of follow-up, 26,208 women reported a history of infertility, and we documented 6,925 incident invasive cancer cases. After adjusting for body mass index and other risk factors, women who reported infertility had a higher risk of developing cancer than gravid women without a history of infertility (HR, 1.07; 95% CI, 1.02–1.13). This association was stronger among obesity-related cancers (HR, 1.13; 95% CI, 1.05–1.22; vs. non–obesity-related cancers, HR, 0.98; 95% CI, 0.91–1.06) and, in particular, obesity-related reproductive cancers (postmenopausal breast, endometrial, and ovarian cancers; HR, 1.17; 95% CI, 1.06–1.29) and was stronger among women who first reported infertility earlier in life (≤25 years, HR, 1.19; 95% CI, 1.07–1.33; 26–30 years, HR, 1.11; 95% CI, 0.99–1.25; >30 years, HR, 1.07; 95% CI, 0.94–1.22; P trend < .001).
A history of infertility may be associated with the risk of developing obesity-related reproductive cancers; further study is needed to elucidate the underlying mechanisms.
Un estudio prospectivo de cohortes sobre infertilidad e incidencia de cáncer
Investigar la asociación entre infertilidad e incidencia de cáncer invasivo.
Estudio de cohortes prospectivo (1989-2015).
No aplicable.
Un total de 103.080 mujeres de entre 25 y 42 años del Nurses' Health Study II que no tenían cáncer al inicio del estudio (1989).
El estado de infertilidad (imposibilidad de concebir tras 1 año de relaciones sexuales regulares sin protección) y las causas de infertilidad fueron informadas en los cuestionarios basales y de seguimiento bienal.
El diagnóstico de cáncer se confirmó mediante la revisión de la historia clínica y se clasificó como relacionado con la obesidad (colorrectal, vesícula biliar, riñón, mieloma múltiple, tiroides, páncreas, esófago, estómago, hígado, endometrio, ovarios y mama posmenopáusica) o no relacionados con la obesidad (todos los demás cánceres). Se ajustaron los modelos de riesgos proporcionales de Cox para estimar los cocientes de riesgos (CRI) e intervalos de confianza (IC) del 95% de la asociación entre infertilidad e incidencia de cáncer.
Durante 2.149.385 años-persona de seguimiento, 26.208 mujeres declararon antecedentes de infertilidad y se documentaron 6.925 casos de cáncer invasivo. Tras ajustar por el índice de masa corporal y otros factores de riesgo, las mujeres que declararon infertilidad tenían un mayor riesgo de desarrollar cáncer que las grávidas sin antecedentes de infertilidad (HR, 1,07; IC 95%, 1,02-1,13). Esta asociación fue mayor entre los cánceres relacionados con la obesidad (HR, 1,13; IC 95%, 1,05-1,22; frente a los cánceres no relacionados con la obesidad, HR, 0,98; IC 95%, 0,91-1,06) y, en particular, los cánceres reproductivos relacionados con la obesidad (cánceres posmenopáusicos de mama, endometrio y ovario; HR, 1,17; IC 95%, 1,06-1,29) y fue mayor entre las mujeres que declararon infertilidad por primera vez a una edad más temprana (%25 años, HR, 1,19; IC 95%,1,07-1,33; 26-30 años, HR, 1,11; IC 95%, 0,99-1,25; >30 años, HR, 1,07; IC 95%, 0,94-1,22; tendencia de P < 0,001).
Los antecedentes de infertilidad pueden estar asociados con el riesgo de desarrollar cánceres reproductivos relacionados con la obesidad. Se necesitan más estudios para dilucidar los mecanismos que intervienen en estos procesos.
Risk of colorectal cancer after use of fertility drugs—results from a large Danish population-based cohort of women with infertility
2022, Fertility and SterilityTo study the association between use of fertility drugs and colorectal cancer among women with infertility.
Population-based cohort study.
Not applicable.
The study cohort was obtained from the Danish Infertility Cohort and consisted of all women with infertility aged 20–45 years living in Denmark during 1995–2017.
Information on the use of specific types of fertility drugs, colorectal cancer diagnoses, covariates, and vital status were obtained from the Danish Infertility Cohort and Danish national registers.
Cox proportional hazard models adjusted for potential confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for colorectal cancer overall and rectal and colon cancer separately.
Among 148,036 women in the final study cohort, 205 women were diagnosed with colorectal cancer. Ever use of clomiphene citrate (CC) was associated with a lower rate of colorectal cancer (unadjusted HR, 0.67; 95% CI, 0.51–0.89; adjusted HR, 0.68; 95% CI, 0.50–0.93). However, the lower rate was only seen among women who first used CC >8 years ago (unadjusted HR, 0.56; 95% CI, 0.41-0.76; adjusted HR, 0.52; 95% CI, 0.36–0.75). No marked associations were found between the use of any of other types of fertility drugs and colorectal cancer. The results for colon and rectal cancer analyzed separately were similar, except for a suggestion of a decreased risk of rectal cancer associated with the use of gonadotropins (adjusted HR, 0.46; 95% CI, 0.20–1.08).
Among women with infertility, the use of most types of fertility drugs was not associated with colorectal cancer. However, CC may decrease the risk of colorectal cancer and gonadotropins might decrease the risk of rectal cancer, but we cannot rule out that these findings may be more related to the underlying conditions in these women or are chance findings. Consequently, the results from this study should be investigated further in large epidemiological studies.
Riesgo de cáncer colorrectal después del uso de medicamentos para fertilidad – resultados de una gran cohorte basada en población danesa de mujeres con infertilidad.
Estudiar la asociación entre el uso de medicamentos para fertilidad y cáncer colorrectal entre mujeres con infertilidad.
Estudio de cohorte basado en la población.
No aplica.
La cohorte de estudio se obtuvo de la Cohorte Danesa de Infertilidad y consistió en todas las mujeres con infertilidad entre 20-45 años viviendo en Dinamarca durante 1995-2017.
Información sobre el uso de tipos específicos de medicamentos para fertilidad, diagnóstico de cáncer colorrectal, covariables, y estado vital se obtuvieron de la Cohorte Danesa de Infertilidad y de los registros nacionales Daneses.
Modelos de riesgos proporcionales de Cox ajustados para potenciales variables de confusión fueron utilizados para estimar relaciones de riesgo (HRs) e intervalos de confianza 95% (CIs) para cáncer colorrectal en general y cáncer rectal y de colon por separado.
Entre 148,036 mujeres en la cohorte final de estudio, 205 mujeres fueron diagnosticadas con cáncer colorrectal. El uso citrato de clomifeno (CC) alguna vez se asoció con una baja tasa de cáncer colorrectal (HR no ajustado, 0.67; 95% CI, 0.51-0.89; HR ajustado, 0.68; 95% CI, 0.50-0.93). Sin embargo, la tasa más baja se vio solamente en mujeres que usaron por primera vez CC >8 años atrás (HR no ajustado, 0.56; 95% CI, 0.41-0.76; HR ajustado, 052; 95% CI, 0.36-0.75). No se encontraron asociaciones marcadas entre el uso de cualquiera de los otros tipos de medicamentos para fertilidad y cáncer colorrectal. Los resultados para cáncer de colon y rectal analizados separadamente fueron similares, excepto por una sugerencia de disminución de riesgo de cáncer rectal asociado con el uso de gonadotropinas (HR ajustado, 0.46; 95% CI, 0.20-1.08).
Entre las mujeres con infertilidad, el uso de la mayoría de los tipos de medicamentos para fertilidad no se asoció con cáncer colorrectal. Sin embargo, CC podría disminuir el riesgo de cáncer colorrectal y las gonadotropinas podrían disminuir el riesgo de cáncer rectal, pero no podemos descartar que estos hallazgos pueden estar más relacionados con las condiciones subyacentes en estas mujeres o son hallazgos fortuitos. Como consecuencia, los resultados de este estudio deberían ser investigados más a fondo en grandes estudios epidemiológicos.
Use of Fertility Drugs and Risk of Malignant Melanoma: Results from a Large Danish Population-Based Cohort Study
2021, Journal of Investigative DermatologyFertility drugs have not definitively been linked to malignant melanoma. By the use of data from a large nationwide cohort of women aged 20.0–45.0 years and living in Denmark between January 1, 1995 and December 31, 2011, we assessed the association between the use of fertility drugs and the risk of malignant melanoma. Information on fertility status and the use of fertility drugs was obtained from the population-based Danish Infertility Cohort. Cox proportional hazard regression models were applied to estimate hazard ratios and 95% confidence intervals with adjustment for potential confounders. The study population comprised 1,330,954 women, of whom 86,231 (6.5%) were treated with fertility drugs. During a median follow-up of 21.0 years, 6,139 women were diagnosed with malignant melanoma. Compared with fertile women, women with fertility challenges who had used any fertility drugs had an increased risk of malignant melanoma (hazard ratio = 1.14; 95% confidence interval = 1.02–1.27). Furthermore, the use of specific types of fertility drugs (clomiphene, gonadotropins, human chorionic gonadotropin, gonadotropin-releasing hormone preparations, and progesterone) was also associated with an increased risk of malignant melanoma, with hazard ratios ranging between 1.09 and 1.13; however, the association did not reach statistical significance. Our findings indicate that the use of fertility drugs was associated with a modestly increased risk of malignant melanoma.
Risk of breast cancer in women treated with ovarian stimulation drugs for infertility: a systematic review and meta-analysis
2021, Fertility and SterilityTo evaluate the evidence addressing the association between the use of ovarian stimulation drugs and the risk of breast cancer.
Systematic review and meta-analysis.
Not applicable.
Women without any previous history of breast cancer undergoing ovarian stimulation.
Electronic databases were searched from 1990 until January 2020. All cohort studies reporting new incidences of breast cancer in infertile women using ovarian stimulating drugs were included. Treated (exposed) infertile women were compared with the unexposed general population with unexposed infertile women as controls.
New diagnosis of breast cancer within an infertile and general population after exposure to ovarian stimulation drugs.
Overall, the quality of evidence was very low because of the serious risk of bias and indirectness (nonrandomized studies). There was no significant increase in the risk of breast cancer among women treated with any ovarian stimulation drug for infertility compared with that in unexposed controls from the general population and the infertile population (pooled odds ratio 1.03, 95% Confidence interval 0.86 to 1.23, 20 studies, I2 = 88.41%, very low quality of evidence). Furthermore, no significant increase in the risk of breast cancer was found with the use of clomiphene citrate or gonadotropins, alone or in combination.
The current study found that the use of clomiphene citrate and gonadotropins in infertile women was not associated with an increased risk of breast cancer.
Riesgo de cáncer de mama en mujeres tratadas con fármacos de estimulación ovárica para la infertilidad: una revisión sistemática y metaanálisis.
Evaluar la evidencia que aborda la asociación entre el uso de fármacos de estimulación ovárica y el riesgo de cáncer de mama.
Revisión sistemática y metaanálisis.
No aplica.
Mujeres sin antecedentes de cáncer de mama sometidas a estimulación ovárica.
Se realizaron búsquedas en bases de datos electrónicas desde 1990 hasta enero de 2020. Se incluyeron todos los estudios de cohortes que informaron de nuevas incidencias de cáncer de mama en mujeres infértiles tratadas con fármacos para la estimulación ovárica. Se compararon las mujeres infértiles tratadas (expuestas) con la población general no expuesta con mujeres infértiles no expuestas como controles.
Diagnóstico de novo de cáncer de mama en una población infértil y general después de la exposición a fármacos de estimulación ovárica.
En general, la calidad de la evidencia fue muy baja debido al importante riesgo de sesgos y de resultados indirectos (estudios no aleatorizados). No hubo un aumento significativo en el riesgo de cáncer de mama entre las mujeres tratadas con algún fármaco de estimulación ovárica en infertilidad en comparación con el de los controles no expuestos de la población general y la población infértil (razón de probabilidad acumulada 1.03; intervalo de confianza del 95% 0.86 a 1.23, 20 estudios, I2 = 88.41%, evidencia de muy baja calidad). Además, no se encontró un aumento significativo en el riesgo de cáncer de mama con el uso de citrato de clomifeno o gonadotropinas, solos o en combinación.
El presente estudio encontró que el uso de citrato de clomifeno y gonadotropinas en mujeres infértiles no se asoció con un mayor riesgo de cáncer de mama.
Repetitive oocyte donation: a committee opinion
2020, Fertility and SterilityDonors should be advised of the number of cycles/donations that a given oocyte donor may undergo. Although existing data cannot permit conclusive recommendations, concern for the issues of safety and well-being of oocyte donors warrants consideration. This document replaces the document of the same name, previously published in 2014.
Donación repetitiva de ovocitos: una opinión del comité
Las donantes deben de ser informadas sobre el número de ciclos / donaciones a las que una donante de ovocitos puede someterse. Aunque los datos existentes no permiten realizar recomendaciones concluyentes, la preocupación por los temas de seguridad y bienestar de las donantes de ovocitos merecen tenerlo en consideración. Este documento reemplaza al documento del mismo nombre, publicado anteriormente en 2014