Originally published as JCO Early Release 10.1200/JCO.2008.21.1839 on April 13 2009

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Ovarian Failure and Reproductive Outcomes After Childhood Cancer Treatment: Results From the Childhood Cancer Survivor Study

From the the Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis; Department of Medicine, Vanderbilt University, Nashville, TN; Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY; International Epidemiology Institute, Rockville, MD; Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK; Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Radiation Physics, The University of Texas M. D. Anderson Cancer Center, Houston, TX; and the Department of Public Health Sciences, School of Public Health, University of Alberta, Edmonton, Alberta, Canada.

Corresponding author: Daniel M. Green, MD, Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 735, Memphis, Tennessee 38105-2794; e-mail: daniel.green{at}stjude.org.

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.

Support provided by the National Cancer Institute Grants No. U24 CA55727 (Principal investigator, L.L.R.) and R01CA104666 (Principal investigator, C.A.S.) for the National Institutes of Health and the American Lebanese Syrian Associated Charities.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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