Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study

Abstract

These studies were undertaken to determine the effect, if any, of treatment for cancer diagnosed during childhood or adolescence on ovarian function and reproductive outcomes. We reviewed the frequency of acute ovarian failure, premature menopause, live birth, stillbirth, spontaneous and therapeutic abortion and birth defects in the participants in the Childhood Cancer Survivor Study (CCSS). Acute ovarian failure (AOF) occurred in 6.3% of eligible survivors. Exposure of the ovaries to high-dose radiation (especially over 10 Gy), alkylating agents and procarbazine, at older ages, were significant risk factors for AOF. Premature nonsurgical menopause (PM) occurred in 8% of participants versus 0.8% of siblings (rate ratio = 13.21; 95% CI, 3.26 to 53.51; P < .001). Risk factors for PM included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent score, and a diagnosis of Hodgkin's lymphoma. One thousand two hundred twenty-seven male survivors reported they sired 2,323 pregnancies, and 1,915 female survivors reported 4,029 pregnancies. Offspring of women who received uterine radiation doses of more than 5 Gy were more likely to be small for gestational age (birthweight < 10 percentile for gestational age; 18.2% v 7.8%; odds ratio = 4.0; 95% CI, 1.6 to 9.8; P = .003). There were no differences in the proportion of offspring with simple malformations, cytogenetic syndromes, or single-gene defects. These studies demonstrated that women treated with pelvic irradiation and/or increasing alkylating agent doses were at risk for acute ovarian failure, premature menopause, and small-for-gestational-age offspring. There was no evidence for an increased risk of congenital malformations. Survivors should be generally reassured although some women have to consider their potentially shortened fertile life span in making educational and career choices.

Fig 1.

Percentage of subjects with acute ovarian failure (AOF) by age at diagnosis of cancer of 0 to 12 years, 13 to 20 years, and radiation dose to the ovary.

Fig 2.

Cumulative incidence curves of nonsurgical premature menopause in survivors compared with siblings.

Fig 3.

Cumulative incidence curves of nonsurgical premature menopause in survivors according to treatment exposures. (A) Survivors treated with alkylating agents (AA) but not with abdominal-pelvic radiation therapy (A-P RT). (B) Survivors treated with A-P RT but not AA. (C) Survivors treated with AA and A-P RT.

Fig 4.

Distribution of birthweight of the offspring of female cancer survivors by abdominal-pelvic radiation (A-P RT).