Infertility, infertility treatment, and achievement of pregnancy in female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort

Abstract

Background: Previous studies have shown decreased pregnancy rates and early menopause in female cancer survivors; however, infertility rates and reproductive interventions have not been studied. We investigated infertility and time to pregnancy in female childhood cancer survivors, and analysed treatment characteristics associated with infertility and subsequent pregnancy.

Methods: The Childhood Cancer Survivor Study (CCSS) is a cohort study including 5 year cancer survivors from 26 Canadian and US institutions who were younger than 21 years at the time of diagnosis between Jan 1, 1970, and Dec 31, 1986, and a sibling control group. We included women aged 18-39 years who had ever been sexually active. We gathered demographic, medical, and reproductive data via a baseline questionnaire, and quantified exposure to alkylating agents and radiation therapy. Self-reported infertility, medical treatment for infertility, time to first pregnancy in survivors and siblings, and the risk of infertility in survivors by demographic, disease, and treatment variables were analysed.

Findings: 3531 survivors and 1366 female sibling controls who enrolled between Nov 3, 1992, and April 4, 2004, were included. Compared with their siblings, survivors had an increased risk (relative risk [RR] 1·48 [95% CI 1·23-1·78]; p<0·0001) of clinical infertility (ie, >1 year of attempts at conception without success), which was most pronounced at early reproductive ages (RR 2·92 [95% CI 1·18-7·20], p=0·020, in participants ≤24 years; 1·61 [1·05-2·48], p=0·029, in those aged 25-29 years; and 1·37 [1·11-1·69], p=0·0035, in those aged 30-40 years). Despite being equally likely to seek treatment for infertility, survivors were less likely than were their siblings to be prescribed drugs for treatment of infertility (0·57 [95% CI 0·46-0·70], p<0·0001). Increasing doses of uterine radiation and alkylating agent chemotherapy were strongly associated with infertility. Although survivors had an increased time to pregnancy compared with their siblings (p=0·032), 292 (64%) of 455 participants with self-reported clinical infertility achieved a pregnancy.

Interpretation: A more comprehensive understanding of infertility after cancer is crucial for counselling and decision making about future conception attempts and fertility preservation.

Funding: National Cancer Institute, American Lebanese Syrian Associated Charities, Swim Across America.

Figure 1. Flowchart of the cancer survivor cohort included in the infertility analyses

Figure 2. Distribution of time to first pregnancy among survivors and siblings

The distribution of time to first pregnancy in months was summarized using the empirically estimated cumulative distribution function in CCSS participants who reported having a first planned pregnancy and who completed the pregnancy questionnaire. In each panel, the horizontal axis indicates number of months to first pregnancy and the vertical axis indicates estimated probabilities. The height of the distribution curve at x months indicates the estimated probability of pregnancy in subjects achieving pregnancy in x months or less. For presentation purposes, plots were truncated at 40 months, however all available data were used in estimating distributions and group comparisons. Upper left panel, p=0.032; upper right panel p=0.045; lower left panel p=0.0091; lower right panel p=0.088.