Risk of infertility in female adolescents and young adults with cancer: a population-based cohort study

Study Question — Do female adolescents and young adults (AYAs) with cancer have a higher risk of subsequent infertility diagnosis than AYAs without cancer?

Summary Answer — Female AYAs with breast, hematological, thyroid and melanoma cancer have a higher risk of subsequent infertility diagnosis.

What is Known Already — Cancer therapies have improved substantially, leading to dramatic increases in survival. As survival improves, there is an increasing emphasis on optimizing the quality of life among cancer survivors. Many cancer therapies increase the risk of infertility, but we lack population-based studies that quantify the risk of subsequent infertility diagnosis in female AYAs with non-gynecological cancers. The literature is limited to population-based studies comparing pregnancy or birth rates after cancer against unexposed women, or smaller studies using markers of the ovarian reserve as a proxy of infertility among female survivors of cancer.

Study Design, Size, Duration — We conducted a population-based cohort study using universal healthcare databases in the province of Ontario, Canada. Using data from the Ontario Cancer Registry, we identified all women 15-39 years of age diagnosed with the most common cancers in AYAs (brain, breast, colorectal, leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, thyroid and melanoma) from 1992 to 2011 who lived at least 5 years recurrence-free (Exposed, n = 14,316). Women with a tubal ligation, bilateral oophorectomy or hysterectomy previous to their cancer diagnosis were excluded. We matched each exposed woman by age, census subdivision, and parity to five randomly selected unexposed women (n = 60,975) and followed subjects until 31 December 2016.

Participants/Materials, Setting, Methods — Infertility diagnosis after 1 year of cancer was identified using information on physician billing codes through the Ontario Health Insurance Plan database (ICD-9 628). Modified Poisson regression models were used to assess the risk of infertility diagnosis (relative risk, RR) adjusted for income quintile and further stratified by parity at the time of cancer diagnosis (nulliparous and parous).

Main Results and the Role of Chance — Mean age at cancer diagnosis was 31.4 years. Overall, the proportion of infertility diagnosis was higher in cancer survivors compared to unexposed women. Mean age of infertility diagnosis was similar among cancer survivors and unexposed women (34.8 years and 34.9 years, respectively). The overall risk of infertility diagnosis was higher in cancer survivors (RR 1.30; 95% CI 1.23-1.37). Differences in infertility risk varied by type of cancer. Survivors of breast cancer (RR 1.46; 95% CI 1.30-1.65), leukemia (RR 1.56; 95% CI 1.09-2.22), Hodgkin lymphoma (RR 1.49; 95% CI 1.28-1.74), non-Hodgkin lymphoma (RR 1.42; 95% CI 1.14, 1.76), thyroid cancer (RR 1.20; 95% CI 1.10-1.30) and melanoma (RR 1.17; 95% CI 1.01, 1.35) had a higher risk of infertility diagnosis compared to women without cancer. After stratification by parity, the association remained in nulliparous women survivors of breast cancer, leukemia, lymphoma and melanoma, whereas it was attenuated in parous women. In survivors of thyroid cancer, the association remained statistically significant in both nulliparous and parous women. In survivors of brain or colorectal cancer, the association was not significant, overall or after stratification by parity.

Limitations, Reasons for Caution — Non-biological factors that may influence the likelihood of seeking a fertility assessment may not be captured in administrative databases. The effects of additional risk factors, including cancer treatment, which may modify the associations, need to be assessed in future studies.

Wider Implications of the Findings — Reproductive health surveillance in female AYAs with cancer is a priority, especially those with breast cancer, leukemia and lymphoma. Our finding of a potential effects of thyroid cancer (subject to over-diagnosis) and, to a lesser extent, melanoma need to be further studied, and, if an effect is confirmed, possible mechanisms need to be elucidated.

Study Funding/Competing Interest(s) — Funding was provided by the Faculty of Health Sciences and Department of Obstetrics and Gynecology, Queen's University. There are no competing interests to declare.