Search tips
Search criteria 


Logo of jcoHomeThis ArticleSearchSubmitASCO JCO Homepage
J Clin Oncol. 2009 June 1; 27(16): 2677–2685.
Published online 2009 April 13. doi:  10.1200/JCO.2008.20.1541
PMCID: PMC2690392

Fertility of Female Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study



This study was undertaken to determine the effect, if any, of treatment for cancer diagnosed during childhood or adolescence on fertility.

Patients and Methods

We reviewed the fertility of female participants in the Childhood Cancer Survivor Study (CCSS), which consisted of 5-year survivors, and a cohort of randomly selected siblings who responded to a questionnaire. Medical records of all members of the cohort were abstracted to obtain chemotherapeutic agents administered; the cumulative dose of drug administered for several drugs of interest; and the doses, volumes, and dates of administration of all radiation therapy.


There were 5,149 female CCSS participants, and there were 1,441 female siblings of CCSS participants who were age 15 to 44 years. The relative risk (RR) for survivors of ever being pregnant was 0.81 (95% CI, 0.73 to 0.90; P < .001) compared with female siblings. In multivariate models among survivors only, those who received a hypothalamic/pituitary radiation dose ≥ 30 Gy (RR, 0.61; 95% CI, 0.44 to 0.83) or an ovarian/uterine radiation dose greater than 5 Gy were less likely to have ever been pregnant (RR, 0.56 for 5 to 10 Gy; 95% CI, 0.37 to 0.85; RR, 0.18 for > 10 Gy; 95% CI, 0.13 to 0.26). Those with a summed alkylating agent dose (AAD) score of three or four or who were treated with lomustine or cyclophosphamide were less likely to have ever been pregnant.


This large study demonstrated that fertility is decreased among female CCSS participants. The risk factors identified may be utilized for pretreatment counseling of patients and their parents.


The treatment of children and adolescents who have cancer has become increasingly successful. Approximately 78% of all patients diagnosed before 15 years of age will survive for 5 years.1 The majority are expected to survive for many years after diagnosis.

The treatment that these patients receive may affect germ cell survival. Ovarian damage results in both sterilization and loss of hormone production. High-dose radiation to the hypothalamic-pituitary axis can produce secondary hypogonadism as a result of gonadotropin deficiency.2

There are limited epidemiologic data that assess fertility in exposed populations. Byrne et al3 evaluated the fertility of 2,283 childhood cancer survivors diagnosed between 1945 and 1975, excluding women who had never married; who married before their diagnosis of cancer; who became pregnant before their first marriage; who had never menstruated; or who had undergone sterilizing surgery. The adjusted relative fertility of female survivors was 0.93 (95% CI, 0.83 to 1.04). The absence of a significant difference in the relative fertility for female survivors in that report may be partly explained by the exclusion criteria employed and/or the exposure of few of those studied to potentially gonadal toxic therapy.3

This study was undertaken to evaluate fertility in the female participants in the Childhood Cancer Survivor Study (CCSS) and to determine risk factors for decreased fertility.


A cohort of 20,720 previously untreated patients who were younger than 21 years of age at diagnosis, who survived for at least 5 years after the date of diagnosis, and who were diagnosed with an eligible cancer between January 1, 1970 and December 31, 1986, was identified at the 26 participating institutions of the CCSS (Fig 1). The study design, cohort characteristics, and baseline data collection are presented in detail elsewhere. Age at pregnancy, marital status, educational level, and smoking status were self reported.4

Fig 1.
Flowchart of cohort subgroups for female fertility analysis.

The CCSS collected data for all surgical procedures performed for cancer treatment. In addition, participants and siblings were asked about additional surgical procedures performed and the methods employed for contraception, including tubal ligation and vasectomy. Those participants or their partners who underwent an operation that resulted in sterilization (eg, tubal ligation, hysterectomy, vasectomy) were classified as surgically sterile as a result of contraceptive or noncontraceptive reasons and were excluded from this analysis.5 On the basis of these definitions, 516 female CCSS participants and/or their partners who were age 15 to 44 years at follow-up were categorized as surgically sterile (contraceptive reasons, n = 474; noncontraceptive reasons, n = 42). This analysis focused on the 5,149 female survivors who were not surgically sterile (Fig 1).

Permission was requested from a random sample of the cohort to contact their nearest-age siblings.4 Three thousand forty eight (80.5%) participated among 4,782 eligible siblings, of whom 1,441 were women between the ages of 15 to 44 years who were not surgically sterile. These siblings were used as controls for comparisons to survivors in the CCSS cohort. Two hundred ninety-four female siblings of CCSS participants and/or their partners who were age 15 to 44 years at follow-up were categorized as surgically sterile (contraceptive reasons, n = 288; noncontraceptive reasons, n = 6).

This study was approved by the institutional review board at each participating institution, and informed consent for participation was obtained from all participants who were 18 years of age or older, or from their parents if the participants were younger than 18 years of age.

Exposure Assessment

Detailed data regarding the chemotherapeutic agents administered to the patient for treatment of the original cancer; any recurrences of the cancer; the cumulative dose of drug administered for several drugs of interest; and the doses, volumes, and dates of administration of all radiation therapy were recorded on the Medical Record Abstract Form for 12,492 of those who completed the baseline questionnaire.

The cumulative doses of a number of chemotherapeutic agents were obtained. The distribution of cumulative doses for each of the agents was divided into tertiles (Table 1). Among patients exposed to an alkylating agent, the alkylating agent dose (AAD) score was calculated by adding the tertile score (1, 2, or 3) for each of the alkylating agents given to a particular patient.6 An AAD score of 0 was assigned to nonexposed patients.

Table 1.
Tertile Distribution of Alkylating Agents in Cumulative Dose

Radiation doses to the ovaries, uterus, and hypothalamus/pituitary7 were estimated for each patient by reviewing and abstracting details of the radiation therapy from records submitted by the treating institutions. For organs in a beam, standard radiotherapy depth dose data were used to estimate dose. For organs outside a treatment beam, measurements in a water phantom were applied to a three-dimensional mathematical phantom that simulated the size and shape of patients of various ages. Any field blocking used during treatment was accounted for in estimating doses. Details of the dosimetry methods were described by Stovall et al.8,9

Statistical Methods

Cox proportional hazard models that used age as the time scale were used to compare hazards of a pregnancy, as previously described by Yasui et al.10 Participants entered the risk set for regression analyses at the age at which they entered the CCSS cohort (ie, 5 years after date of diagnosis of primary cancer) or at age 15 years, whichever was older, and were observed until the minimum age of first pregnancy, death, completion of baseline questionnaire, or age of 44 years, whichever came first. To create a similar age-based follow-up period, siblings were assigned a pseudo-diagnosis date that corresponded to the age of their survivor sibling at diagnosis of their primary cancer, and identical methods were used to define their time-to-event variables. Within-family correlation was accounted for with the use of sandwich standard-error estimates.11 Multiple-imputation methodology for event-time imputations12,13 was employed for those who reported one or more pregnancies but who did not report age at first pregnancy. Age at first pregnancy was available for 81.0% (1,111 of 1,372) of survivors and for 86.6% (479 of 553) of siblings, and the age was imputed for the remaining 19.0% (261 of 1,372) of female survivors and for the remaining 13.4% (74 of 553) of female siblings. Analyses of treatment (exposure) variables were restricted to those female survivors for whom medical record abstraction was completed (n = 4,317), whereas those analyses that required only demographic data (eg, age at questionnaire, diagnosis) included all women age 15 to 44 years who had completed the baseline questionnaire.

Two sets of models were evaluated. The first compared fertility for survivors versus siblings and controlled for education level, marital status, age at diagnosis (or age at pseudo-diagnosis), ethnicity, and smoking status. A second set of models, among survivors only, evaluated the impact of treatment variables and adjusted for the same variables as the first set. Candidate treatment variables that were evaluated included summed AAD score, ovarian/uterine radiation dose, hypothalamic/pituitary radiation dose, and the following individual chemotherapy agents: dactinomycin, carmustine (BCNU), lomustine (CCNU), cyclophosphamide, cisplatin, cytarabine, daunorubicin, doxorubicin, dacarbazine (DTIC), nitrogen mustard, procarbazine, vinblastine, vincristine, teniposide (VM26), etoposide (VP16), thiotepa, ifosfamide, and melphalan. Univariate and multivariate analyses were carried out, and final treatment variables that were included in the multivariate model were significant at the .05 level or were those that markedly influenced (> 10% change) the effect of another factor in the model (ie, a confounder). Two separate, multivariate models were fit to evaluate the impact of separate chemotherapy agents and combined alkylating agents by using the previously described AAD score. Interactive effects between the two radiation volumes (ie, ovary/uterus and hypothalamus/pituitary) were evaluated to the extent possible, and they were not significant. Cut points for radiation categories were selected on the basis of both biologic plausibility2,1419 and statistical separation of groups. The referent group for ovarian/uterine radiation was selected to include those with ≤ 2.5 Gy and no radiation exposure to this region. Similarly, for the hypothalamic/pituitary radiation, the referent group consisted of those without radiation exposure to this region and those with ≤ 10 Gy exposure.


Six thousand six hundred forty-three women returned a baseline questionnaire, 5,149 of whom were between the ages of 15 and 44 years at the time of completion of the questionnaire and were not surgically sterile. One thousand three hundred seventy-two women indicated that they had ever been pregnant 5 or more years after the date of the primary cancer diagnosis.

The CCSS participants were younger (P < .001), more likely to be of minority ethnicity (P < .001), less likely to have a bachelor's degree or higher (P < .001), more likely to have never been married (P < .001), and more likely to have never smoked (P < .001) than the sibling cohort (Table 2). The distributions listed in Table 3 are those of calculated, organ-specific radiation exposure to each ovary, uterus, ovaries/uterus combination, and hypothalamus/pituitary.

Table 2.
Demographic and Treatment Characteristics of Female Survivors of Childhood Cancer and of Siblings Who Were Not Surgically Sterile
Table 3.
Distribution of Radiation Dose Exposure of Female Survivors of Childhood Cancer Who Were Not Surgically Sterile

When analysis was adjusted for age at diagnosis, marital status, educational attainment, ethnicity, and smoking status, the relative risk (RR) of a survivor ever being pregnant was 0.81 (95% CI, 0.73 to 0.90; P < .001), compared with the sibling cohort. Multivariate models among survivors were developed (Table 4). A dose-response relationship was present for decreased risk of pregnancy with increasing dose of ovarian/uterine radiation. The RR of pregnancy was 0.56 (95% CI, 0.37 to 0.85) for exposure of 5 to 10 Gy and was 0.18 (95% CI, 0.13 to 0.26) for exposure of greater than 10 Gy to the ovaries/uterus (Table 4). The risk of pregnancy was decreased for hypothalamic/pituitary doses greater than 30 Gy (RR, 0.61; 95% CI, 0.44 to 0.83). In the multivariate model that assessed the summed AAD score, a score of three (RR, 0.72; 95% CI, 0.58 to 0.90; P = .003) or four (RR, 0.65; 95% CI, 0.45 to 0.96; P = .03) was associated with lower observed risk of pregnancy compared with those who had no alkylating agent exposure. Increasing AAD score was statistically significantly associated with the risk of not having been pregnant (P = .004). Multivariate models that evaluated individual chemotherapeutic agents demonstrated lower risk of pregnancy for those who were treated with CCNU (RR, 0.44; 95% CI, 0.24 to 0.80; P = .008) or cyclophosphamide (RR, 0.8; 95% CI, 0.68 to 0.93; P = .005). The impacts of these single drugs were dose related, and fertility decreased with increasing dose (CCNU first tertile RR, 0.76; 95% CI, 0.30 to 1.93; P = .57; CCNU second or third tertile RR, 0.31; 95% CI, 0.11 to 0.88; P = .028; cyclophosphamide first tertile RR, 0.83; 95% CI, 0.65 to 1.06; P = .13; cyclophosphamide second tertile RR, 1.06; 95% CI, 0.84 to 1.33; P = .63; cyclophosphamide third tertile RR, 0.72; 95% CI, 0.58 to 0.90; P = .003). Although both were statistically significant in univariate analyses, neither oophoropexy nor treatment with nitrogen mustard, cytarabine, cisplatin, procarbazine, vinblastine, VM26, or VP16 remained significant in the multivariate models. In both multivariate models, treatment that included doxorubicin was associated with a statistically significant increased risk of pregnancy (RR, 1.21; 95% CI, 1.01 to 1.45; and RR, 1.22; 95% CI, 1.04 to 1.45). The models yielded qualitatively identical results whether constructed with or without inclusion of those participants for whom age at first pregnancy was imputed.

Table 4.
Relative Risk of Pregnancy Among Female Childhood Cancer Survivors in Two Separate Multivariate Models


We undertook these analyses to determine the demographic and treatment factors that predicted the likelihood of pregnancy among female long-term survivors of childhood cancer. Overall, female survivors among the CCSS cohort were less likely to become pregnant compared with the participants in the sibling cohort. In contrast to previously published analyses,3 women with ovarian failure produced by either ovarian irradiation or specific chemotherapeutic exposures were included in our analyses, which thus provided a truer picture of overall fertility among long-term survivors. Those who had completed less than a high school education, were African American, were married, or were in the youngest age group at diagnosis were more likely to have become pregnant. The findings with regard to marital status, ethnicity, and educational attainment reflected general population trends.5 Those in the youngest age group at diagnosis (ie, 0 to 4 years) had an increased risk of pregnancy, which possibly reflected the greater number of ova present.20,21

In our treatment models, a hypothalamic/pituitary radiation dose greater than 30 Gy or an ovarian/uterine radiation dose greater than 5 Gy was a significant risk factor among female survivors for not having a pregnancy. Previous studies reported an increased risk of ovarian failure after whole-abdomen2224 or craniospinal irradiation25,26 during childhood. Direct irradiation of the hypothalamus and/or pituitary may produce impaired secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), especially when the dose is greater than 35 Gy.2,1619 Lower-dose exposures (18 to 24 Gy), such as those employed for prophylactic cranial irradiation of children with acute lymphoblastic leukemia (ALL), did not appear to produce major abnormalities in FSH or LH release to luteinizing hormone–releasing hormone27 or in 12-hour urinary excretion of FSH and LH,28 although Bath et al29 reported that LH excretion was decreased in patients with ALL compared with controls.

Abdominal radiation may damage the ovaries and/or uterus. Stillman et al30 reported ovarian failure in none of 34 women who received abdominal irradiation to a volume that did not include both ovaries, in 14% of 35 women whose ovaries were at the edge of the abdominal treatment volume, and in 68% of 25 women whose ovaries were entirely within the treatment volume. Chemaitilly et al14 demonstrated that ovarian doses greater than 10 Gy were associated with a high risk of acute ovarian failure among female CCSS participants.14 Lower doses rarely produced sterilization.15 Critchley et al31,32 reported that uterine length was significantly less, endometrial thickness did not increase in response to hormone replacement therapy, and blood flow was undetectable in women after abdominal irradiation. Similar changes were reported after total-body irradiation.33,34

Ovarian function may be impaired after treatment with chemotherapy that includes an alkylating agent (eg, nitrogen mustard, procarbazine, chlorambucil, and cyclophosphamide).14,3543 Six cycles of the combination of nitrogen mustard, vincristine, procarbazine, and prednisone, as originally reported by DeVita et al,44 exposes a patient to 8,400 mg/m2 (1,400 mg/m2/d × 14 days × six courses) of procarbazine and 72 mg/m2 (12 mg/m2/wk × 2 weeks × six courses) of nitrogen mustard and has an AAD score of six (Table 1). The risk of ovarian failure appeared to be directly correlated with cumulative dose but inversely correlated with age at exposure.40,43

Cumulative cyclophosphamide doses used in contemporary regimens for Hodgkin's disease (3.2 g/m2 to 4.8 g/m2)45 and rhabdomyosarcoma (4.8 g/m2 to 16.8 g/m2; S. Spunt, personal communication, 2008) correspond to AAD scores of one to three. Current regimens for Ewing sarcoma include cyclophosphamide (8.4 g/m2) and ifosfamide (63 g/m2) in combination, which results in an AAD score of six.46

This study demonstrated a statistically significant reduction in the likelihood of pregnancy to be associated with ovarian/uterine radiation in a dose-dependent fashion. Moreover, we found that alkylating agent exposure was independently associated with reduced risk of pregnancy in a dose-dependent manner. Chiarelli et al47 did not demonstrate a significant reduction in fertility among childhood cancer survivors who were treated with abdominal-pelvic irradiation and/or alkylating agents. Byrne et al48 reported that the unadjusted fertility rate for female survivors of ALL was significantly lower than that of their siblings, but they were unable to demonstrate an effect of treatment with an alkylating agent or spinal irradiation on the fertility rates.

Unexpectedly, the risk of pregnancy was increased among those who had been treated with doxorubicin, independent of exposure to other potentially sterilizing modalities. There is no known mechanism whereby doxorubicin may enhance fertility; therefore, we consider this a spurious association.

This study has a number of strengths. The CCSS is the largest, most thoroughly characterized cohort of survivors of cancer diagnosed during childhood or adolescence, and it utilizes a sibling comparison group. Thus, important questions regarding the frequency of outcomes that may be modified by treatment exposures, as well as the relationship of these exposures to significant, though uncommon, late events, can be evaluated with substantial statistical power.

There are certain limitations that must be taken into account when interpreting this data. The participants were ascertained retrospectively; 15% of the eligible participants were lost to follow-up, and 16% declined participation. Participants, however, did not differ from nonparticipants with regard to demographics or cancer characteristics.4 Radiation dosimetry was estimated by using the paper records supplied by the participating institutions without review of port films.

The CCSS utilized self-administered questionnaires for ascertainment of outcomes. In the general population, the frequency of pregnancies is under-reported by women, as approximately 22% of pregnancies detected by a transient increase in the serum level of human chorionic gonadotropin are not recognized clinically.49 Information relating to adjustment variables (eg, smoking, education) should be considered surrogate measures, because they are derived from a single point in time (ie, at baseline questionnaire). Thus, these factors do not directly measure their influence over time.

We did not evaluate fertility in light of personal choices regarding pregnancy. Women may have chosen not to attempt pregnancy on the basis of concerns that they might transmit a trait that would predispose their children to cancer, concerns that they thought or were told that they are or might be infertile, or concerns that their appearance, sexual preference, socioeconomic status, or neurocognitive function interfered with their abilities to form or maintain an intimate heterosexual relationship.5052 Some of these factors may be related to the therapeutic exposures considered in this analysis. We cannot determine how these factors may have confounded the results of this study.

We have demonstrated that fertility is impaired in female childhood cancer survivors, and we have provided treatment-specific and dose-specific risk estimates. Women age 15 to 44 years who received a hypothalamic/pituitary radiation dose greater than 30 Gy; an ovarian/uterine radiation dose greater than 5 Gy; or CCNU, cyclophosphamide, or any AAD summed score of three or four were less likely to ever become pregnant. These data may be utilized to counsel patients and their parents before initiation of treatment and to identify those at exceptionally high risk for impaired fertility who may benefit from assisted reproduction techniques.


The Childhood Cancer Survivor Study (CCSS), which is funded as a resource by the National Cancer Institute (NCI), is a collaborative, multi-institutional project of individuals who survived 5 or more years after diagnosis of childhood cancer.

CCSS is a retrospectively ascertained cohort of childhood cancer survivors diagnosed before age 21 years between 1970 and 1986 and a randomly selected subset of siblings of survivors who serve as a control group. The cohort was assembled through the efforts of 26 participating clinical research centers in the United States and Canada. The study is currently funded by a U24 resource grant (NCI Grant No. U24 CA55727) awarded to St Jude Children's Research Hospital. Currently, we are in the process of expanding the cohort to include an additional 14,000 childhood cancer survivors diagnosed before age 21 years between 1987 and 1999. For information on how to access and utilize the CCSS resource, visit

List of participating institutions and investigators.

St Jude Children's Research Hospital, Memphis, TN: Leslie L. Robison, PhD (Member, CCSS Steering Committee; Project Principal Investigator [grant No. U24 CA55727]), Melissa Hudson, MD (Institutional Principal Investigator; Member, CCSS Steering Committee), Greg Armstrong, MD (Member, CCSS Steering Committee), Daniel M. Green, MD (Member, CCSS Steering Committee), Kevin Kruce, PhD (Member, CCSS Steering Committee); Children's Healthcare of Atlanta/Emory University, Atlanta, GA: Lillian Meacham, MD (Institutional Principal Investigator), Ann Mertens, PhD (Member, CCSS Steering Committee); Children's Hospitals and Clinics of Minnesota Minneapolis/St Paul, MN: Joanna Perkins, MD (Institutional Principal Investigator); Children's Hospital and Medical Center, Seattle, WA: Douglas Hawkins, MD (Institutional Principal Investigator), Eric Chow, MD (Member, CCSS Steering Committee); Children's Hospital, Denver, CO: Brian Greffe, MD (Institutional Principal Investigator); Children's Hospital, Los Angeles, CA: Kathy Ruccione, RN, MPH (Institutional Principal Investigator); Children's Hospital, Oklahoma City, OK: John Mulvihill, MD (Member, CCSS Steering Committee); Children's Hospital of Philadelphia, PA: Jill Ginsberg, MD (Institutional Principal Investigator), Anna Meadows, MD (Member, CCSS Steering Committee); Children's Hospital of Pittsburgh, PA: Jean Tersak, MD (Institutional Principal Investigator); Children's National Medical Center, Washington, DC: Gregory Reaman, MD (Institutional Principal Investigator), Roger Packer, MD (Member, CCSS Steering Committee); Cincinnati Children's Hospital Medical Center, Cincinnati, OH: Stella Davies, MD, PhD (Member, CCSS Steering Committee); City of Hope, Los Angeles, CA: Smita Bhatia, MD (Institutional Principal Investigator; Member, CCSS Steering Committee); Dana-Farber Cancer Institute/Children's Hospital, Boston, MA: Lisa Diller, MD (Institutional Principal Investigator); Fred Hutchinson Cancer Research Center, Seattle, WA: Wendy Leisenring, ScD (Institutional Principal Investigator; Member, CCSS Steering Committee); Hospital for Sick Children, Toronto, Ontario, Canada: Mark Greenberg, MBChB (Institutional Principal Investigator), Paul C. Nathan, MD (Institutional Principal Investigator; Member, CCSS Steering Committee); International Epidemiology Institute, Rockville, MD: John Boice, ScD (Member, CCSS Steering Committee); Mayo Clinic, Rochester, MN: Vilmarie Rodriguez, MD (Institutional Principal Investigator); Memorial Sloan-Kettering Cancer Center, New York, NY: Charles Sklar, MD (Institutional Principal Investigator; Member, CCSS Steering Committee), Kevin Oeffinger, MD (Member, CCSS Steering Committee); Miller Children's Hospital, Long Beach, CA: Jerry Finklestein, MD (Former Institutional Principal Investigator); NCI, Bethesda, MD: Roy Wu, PhD (Member, CCSS Steering Committee), Nita Sibel, MD (Member, CCSS Steering Committee), Preetha Rajaraman, PhD (Member, CCSS Steering Committee), Peter Inskip, ScD (Member, CCSS Steering Committee), Julia Rowland, PhD (Member, CCSS Steering Committee); Nationwide Children's Hospital, Columbus, OH: Amanda Termuhlen, MD (Institutional Principal Investigator), Sue Hammond, MD (Member, CCSS Steering Committee); Riley Hospital for Children, Indianapolis, IN: Terry A. Vik, MD (Institutional Principal Investigator); Roswell Park Cancer Institute, Buffalo, NY: Martin Brecher, MD (Institutional Principal Investigator); St Louis Children's Hospital, MO: Robert Hayashi, MD (Institutional Principal Investigator); Stanford University School of Medicine, Stanford, CA: Neyssa Marina, MD (Institutional Principal Investigator), Sarah S. Donaldson, MD (Member, CCSS Steering Committee); Texas Children's Hospital, Houston, TX: Zoann Dreyer, MD (Institutional Principal Investigator); University of Alabama, Birmingham, AL: Kimberly Whelan, MD, MSPH (Institutional Principal Investigator); University of Alberta, Edmonton, Alberta, Canada: Yutaka Yasui, PhD (Member, CCSS Steering Committee); University of California-Los Angeles, CA: Jacqueline Casillas, MD MSHS (Institutional Principal Investigator), Lonnie Zeltzer, MD (Former Institutional Principal Investigator; Member, CCSS Steering Committee); University of California-San Francisco, CA: Robert Goldsby, MD (Institutional Principal Investigator); University of Michigan, Ann Arbor, MI: Raymond Hutchinson, MD (Institutional Principal Investigator); University of Minnesota, Minneapolis, MN: Joseph Neglia, MD, MPH (Institutional Principal Investigator; Member, CCSS Steering Committee); University of Southern California, Long Beach, CA: Dennis Deapen, DPH (Member, CCSS Steering Committee); University of Texas-Southwestern Medical Center at Dallas, TX: Dan Bowers, MD (Institutional Principal Investigator); The University of Texas M. D. Anderson Cancer Center, Houston, TX: Louise Strong, MD (Institutional Principal Investigator; Member, CCSS Steering Committee), Marilyn Stovall, MPH, PhD (Member, CCSS Steering Committee).


Supported by the National Institutes of Health, National Cancer Institute Grant No. U24 CA55727 (L.L.R.); by the Children's Cancer Research Fund to the University of Minnesota Cancer Center; and by the American Lebanese Syrian Associated Charities.

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


The author(s) indicated no potential conflicts of interest.


Conception and design: Daniel M. Green, Toana Kawashima, Marilyn Stovall, Wendy Leisenring, Charles A. Sklar, Ann C. Mertens, Sarah S. Donaldson, Julianne Byrne, Leslie L. Robison

Financial support: Leslie L. Robison

Administrative support: Ann C. Mertens, Leslie L. Robison

Collection and assembly of data: Toana Kawashima, Marilyn Stovall, Wendy Leisenring, Ann C. Mertens

Data analysis and interpretation: Daniel M. Green, Toana Kawashima, Marilyn Stovall, Wendy Leisenring, Charles A. Sklar, Sarah S. Donaldson, Leslie L. Robison

Manuscript writing: Daniel M. Green, Toana Kawashima, Marilyn Stovall, Wendy Leisenring, Charles A. Sklar, Ann C. Mertens, Sarah S. Donaldson, Julianne Byrne, Leslie L. Robison

Final approval of manuscript: Daniel M. Green, Toana Kawashima, Marilyn Stovall, Wendy Leisenring, Charles A. Sklar, Ann C. Mertens, Sarah S. Donaldson, Julianne Byrne, Leslie L. Robison


1. Ries LA, Melbert D, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2005. Bethesda, MD: National Cancer Institute; 2008.
2. Sklar CA, Constine LS. Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys. 1995;31:1113–1121. [PubMed]
3. Byrne J, Mulvihill JJ, Myers MH, et al. Effects of treatment on fertility in long-term survivors of childhood or adolescent cancer. N Engl J Med. 1987;317:1315–1321. [PubMed]
4. Robison LL, Mertens AC, Boice JD, et al. Study design and cohort characteristics of the childhood cancer survivor study: A multi-institutional collaborative project. Med Pediatr Oncol. 2002;38:229–239. [PubMed]
5. Abma J, Chandra A, Mosher W, et al. Fertility, family planning, and women's health: New data from the 1995 National Survey of Family Growth. National Center for Health Statistics. Vital Health Stat. 1997;23:1–114. [PubMed]
6. Tucker MA, Medows AT, Boice JD, Jr, et al. Leukemia after therapy with alkylating agents for childhood cancer. J Natl Cancer Inst. 1987;78:459–464. [PubMed]
7. Packer RJ, Gurney JG, Punyko JA, et al. Long-term neurologic and neurosensory sequelae in adult survivors of a childhood brain tumor: Childhood cancer survivor study. J Clin Oncol. 2003;21:3255–3261. [PubMed]
8. Stovall M, Donaldson SS, Weathers RE, et al. Genetic effects of radiotherapy for childhood cancer: Gonadal dose reconstruction. Int J Radiat Oncol Biol Phys. 2004;60:542–552. [PubMed]
9. Stovall M, Weathers R, Kasper C, et al. Dose reconstruction for therapeutic and diagnostic radiation exposures: Use in epidemiological studies. Radiat Res. 2006;166:141–157. [PubMed]
10. Yasui Y, Liu Y, Neglia JP, et al. A methodological issue in the analysis of second-primary cancer incidence in long-term survivors of childhood cancers. Am J Epidemiol. 2003;158:1108–1113. [PubMed]
11. Therneau TM, Grambsch PM. Modeling survival data: Extending the Cox model. New York, NY: Springer-Verlag; 2000.
12. Rubin DB. Multiple imputation for nonresponse in surveys. New York, NY: John Wiley and Sons Inc; 1987.
13. Taylor JMG, Munoz A, Bass SM, Saah AJ, Chmiel JS, Kinglsey LA. Estimating the distribution of times for HIV seroconversion to AIDS using multiple imputation. Stat Med. 1990;9:505–514. [PubMed]
14. Chemaitilly W, Mertens AC, Mitby P, et al. Acute ovarian failure in the Childhood Cancer Survivor Study. J Clin Endocrinol Metab. 2006;91:1723–1728. [PubMed]
15. Le Floch O, Donaldson SS, Kaplan HS. Pregnancy following oophoropexy and total nodal irradiation in women with Hodgkin's disease. Cancer. 1976;38:2263–2268. [PubMed]
16. Bajorunas DR, Ghavimi F, Jereb F, et al. Endocrine sequelae of antineoplastic therapy in childhood head and neck malignancies. J Clin Endocrinol Metab. 1980;50:329–335. [PubMed]
17. Shalet S, Beardwell C, MacFarlane I, et al. Endocrine morbidity in adults treated with cerebral irradiation for brain tumours during childhood. Acta Endocrinol. 1977;84:673–680. [PubMed]
18. Rappaport R, Brauner R, Czernichow P, et al. Effect of hypothalamic and pituitary irradiation on pubertal development in children with cranial tumors. J Clin Endocrinol Metab. 1982;54:1164–1168. [PubMed]
19. Brauner R, Rappaport R. Precocious puberty secondary to cranial irradiation for tumors distant from the hypothalamo-pituitary area. Horm Res. 1985;22:78–82. [PubMed]
20. Hansen KR, Knowlton NS, Thyer AC, et al. A new model of reproductive aging: The decline in ovarian non-growing follicle number from birth to menopause. Hum Reprod. 2008;23:699–708. [PubMed]
21. Faddy MJ, Gosden RG, Gougeon A, et al. Accelerated disappearance of ovarian follicles in mid-life: Implications for forecasting menopause. Hum Reprod. 1992;7:1342–1346. [PubMed]
22. Wallace WHB, Shalet SM, Crowne EC, et al. Ovarian failure following abdominal irradiation in childhood: Natural history and prognosis. Clin Oncol (R Coll Radiol) 1989;1:75–79. [PubMed]
23. Scott JES. Pubertal development in children treated for nephroblastoma. J Pediatr Surg. 1981;16:122–125. [PubMed]
24. Shalet SM, Beardwell CG, Morris Jones PH, et al. Ovarian failure following abdominal irradiation in childhood. Br J Cancer. 1976;33:655–658. [PMC free article] [PubMed]
25. Hamre MR, Robison LL, Nesbit ME, et al. Effects of radiation on ovarian function in long-term survivors of childhood acute lymphoblastic leukemia: A report from the Children's Cancer Study Group. J Clin Oncol. 1987;5:1759–1765. [PubMed]
26. Wallace WHB, Shalet SM, Tetlow LJ, et al. Ovarian function following the treatment of childhood acute lymphoblastic leukemia. Med Pediatr Oncol. 1993;21:333–339. [PubMed]
27. Swift PGF, Kearney PJ, Dalton RG, et al. Growth and hormonal status of children treated for acute lymphoblastic leukemia. Arch Dis Child. 1978;53:890–894. [PMC free article] [PubMed]
28. Voorhess ML, Brecher ML, Glicksman AS, et al. Hypothalamic-pituitary function of children with acute lymphocytic leukemia after three forms of central nervous system prophylaxis: A retrospective study. Cancer. 1986;57:1287–1291. [PubMed]
29. Bath LE, Anderson RA, Critchley HO, et al. Hypothalamic-pituitary-ovarian dysfunction after prepubertal chemotherapy and cranial irradiation for acute leukaemia. Hum Reprod. 2001;16:1838–1844. [PubMed]
30. Stillman RJ, Schinfeld JS, Schiff I, et al. Ovarian failure in long-term survivors of childhood malignancy. Am J Obstet Gynecol. 1981;139:62–66. [PubMed]
31. Critchley HO, Wallace WH, Shalet SM, et al. Abdominal irradiation in childhood: The potential for pregnancy. Br J Obstet Gynecol. 1992;99:392–394. [PubMed]
32. Critchley HOD. Factors of importance for implantation and problems after treatment for childhood cancer. Med Pediatr Oncol. 1999;33:9–14. [PubMed]
33. Bath LE, Critchley HOD, Chambers SE, et al. Ovarian and uterine characteristics after total body irradiation in childhood and adolescence: Response to sex steroid replacement. Br J Obstet Gynaecol. 1999;106:1265–1272. [PubMed]
34. Holm K, Nysom K, Brocks V, Hertz H, Jacobsen N, Muller J. Ultrasound B-mode changes in the uterus and ovaries and Doppler changes in the uterus after total body irradiation and allogeneic bone marrow transplantation in childhood. Bone Marrow Transplant. 1999;23:259–263. [PubMed]
35. Hudson MM, Greenwald C, Thompson E, et al. Efficacy and toxicity of multiagent chemotherapy and low-dose involved-field radiotherapy in children and adolescents with Hodgkin's disease. J Clin Oncol. 1993;11:100–108. [PubMed]
36. Papadakis V, Vlachopapadopoulou E, Van Cyckle K, et al. Gonadal function in young patients successfully treated for Hodgkin disease. Med Pediatr Oncol. 1999;32:366–372. [PubMed]
37. Mackie EJ, Radford M, Shalet SS. Gonadal function following chemotherapy for childhood Hodgkin's disease. Med Pediatr Oncol. 1996;27:74–78. [PubMed]
38. Ortin TT, Shostak CA, Donaldson SS. Gonadal status and reproductive function following treatment for Hodgkin's disease in childhood: The Stanford experience. Int J Radiat Oncol Biol Phys. 1990;19:873–880. [PubMed]
39. Chapman RM, Sutcliffe SB, Malpas JS. Cytotoxic-induced ovarian failure in women with Hodgkin's disease: Hormone function. JAMA. 1979;242:1877–1881. [PubMed]
40. Schilsky RL, Sherins RJ, Hubbard SM, et al. Long-term follow-up of ovarian function in women treated with MOPP chemotherapy for Hodgkin's disease. Am J Med. 1981;71:552–556. [PubMed]
41. Waxman JHX, Terry Y, Wrigley PFM, et al. Gonadal function in Hodgkin's disease: Long-term follow-up of chemotherapy. BMJ. 1982;285:1612–1613. [PMC free article] [PubMed]
42. Santoro A, Bonadonna G, Valagussa P, et al. Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: Superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Clin Oncol. 1987;5:27–37. [PubMed]
43. Andrieu JM, Ochoa-Molina ME. Menstrual cycle, pregnancies and offspring before and after MOPP therapy for Hodgkin's disease. Cancer. 1983;52:435–438. [PubMed]
44. Devita VTJ, Serpick AA, Carbone PP. Combination chemotherapy in the treatment of advanced Hodgkin's disease. Ann Intern Med. 1970;73:881–895. [PubMed]
45. Schwartz CL, Constine LS. Current protocol and concepts for classical Hodgkin disease (HD) in the USA: A Children's Oncology Group (COG) report. Presented at the 7th International Symposium on Hodgkin Lymphoma; November 3-7, 2007; Cologne, Germany. p. 6.
46. Womer RB, West DC, Krailo MD, et al. Randomized comparison of every-two-week versus every-three-week chemotherapy in Ewing sarcoma family tumors (ESFTs) J Clin Oncol. 2008;26(suppl):554s. abstr 10504.
47. Chiarelli AM, Marrett LD, Darlington GA. Early menopause and infertility in females after treatment for childhood cancer diagnosed in 1964-1988 in Ontario, Canada. Am J Epidemiol. 1999;150:245–254. [PubMed]
48. Byrne J, Fears TR, Mills JL, et al. Fertility in women treated with cranial radiotherapy for childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2004;42:589–597. [PubMed]
49. Wilcox AJ, Weinberg CR, O'Connor JF, et al. Incidence of early loss of pregnancy. N Engl J Med. 1988;319:189–194. [PubMed]
50. Schover LR, Rybicki LA, Martin BA, et al. Having children after cancer: A pilot survey of survivors' attitudes and experiences. Cancer. 1999;86:697–709. [PubMed]
51. Zebrack BJ, Casillas J, Nohr L, et al. Fertility issues for young adult survivors of childhood cancer. Psychooncology. 2004;13:689–699. [PubMed]
52. Oosterhuis BE, Goodwin T, Kiernan M, et al. Concerns about infertility risks among pediatric oncology patients and their parents. Pediatr Blood Cancer. 2008;50:85–89. [PubMed]

Articles from Journal of Clinical Oncology are provided here courtesy of American Society of Clinical Oncology