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© 2003 American Society for Clinical Oncology Pregnancy Outcome of Partners of Male Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study
From the Department of Pediatrics, Roswell Park Cancer Institute, and Department of Pediatrics, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY; Department of Biostatistics, Fred Hutchinson Cancer Research Center, and Department of Pediatrics, Children’s Hospital and Regional Medical Center, Seattle, WA; Department of Radiation Physics, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Division of Pediatric Epidemiology and Clinical Research, University of Minnesota, Minneapolis, MN; Department of Radiation Oncology, Stanford University Medical Center, Stanford, CA; Department of Pediatrics, Children’s Hospital of Columbus, Columbus, OH. Address reprint requests to Daniel M. Green, MD, Department of Pediatrics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263; email: daniel.green{at}roswellpark.org.
Purpose: This study was undertaken to determine the effect, if any, on pregnancy loss, live births, and birthweight of treatment for cancer diagnosed during childhood or adolescence. Patients and Methods: We reviewed pregnancy outcome among sexually active male Childhood Cancer Survivor Study (CCSS) participants who responded to a questionnaire before February 3, 2000. 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 radiotherapy. Results: There were 4,106 sexually active males; 1,227 reported they sired 2,323 pregnancies (69% live births, 1% stillbirths, 13% miscarriages, 13% abortions, 5% unknown or in gestation). The male-to-female ratio of the offspring of the partners of the male survivors was significantly different from that of the offspring of the partners of the male siblings of the survivors (1.0:1.03 v 1.24:1.0) (P = .016). The proportion of pregnancies of the partners of male survivors that ended with a liveborn infant was significantly lower than for the partners of the male siblings of the survivors who were the control group for comparison (relative risk = 0.77, P = .007). There were no significant differences in pregnancy outcome by treatment. Conclusion: This large study did not identify adverse pregnancy outcomes for the partners of male survivors treated with most chemotherapeutic agents. The reversal of the sex ratio and the association observed for procarbazine warrant further investigation.
THE TREATMENT of children and adolescents with cancer has become increasingly successful. Approximately 70% of all patients diagnosed before 15 years of age will survive for 5 years. The majority is expected to survive for many years after diagnosis.1–3 The treatment these patients receive may adversely affect their reproductive function. Prior studies of the offspring of patients treated for diverse types of childhood cancer did not identify an increase in the frequency of congenital anomalies in the offspring.4–8 All prior studies included too few offspring born to partners of men treated with chemotherapy to have the statistical power to exclude an effect of this prior treatment on pregnancy outcome. The present study was undertaken to evaluate the effect of prior treatment for childhood cancer with radiotherapy, chemotherapy, or both on pregnancy outcome among the partners of men treated for cancer during childhood and adolescence.
A cohort of 20,319 previously untreated patients who were less than 21 years of age at diagnosis, and were diagnosed with an eligible cancer between January 1, 1970 and December 31, 1986, was identified at the 25 participating institutions of the Childhood Cancer Survivor Study (CCSS). The study design and cohort characteristics are presented in detail elsewhere.9 Briefly, all members of the cohort or their proxy (if the cohort member was deceased) completed a baseline questionnaire that included items regarding sexual activity, attempts to become pregnant (sire a pregnancy), the occurrence of pregnancy, the age in years of the survivor at the beginning of the pregnancy (< 15, 15 to 20, 21 to 25, 26 to 30, 31 to 35, or > 35 years), the duration of the pregnancy (< 12, 12 to 24, 25 to 32, 33 to 37, 38 to 40, or > 40 weeks) and the outcome of pregnancy (medical abortion, miscarriage, stillbirth, live birth). The questionnaire (available at www.cancer.umn.edu/ccss) was returned by 14,008 of these individuals through February 3, 2000. The medical records of all members of the cohort were to be abstracted. Detailed data regarding the chemotherapeutic agents administered to the patient for treatment of the original cancer, and for 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 radiotherapy were recorded on the Medical Record Abstract Form (MRAF). The testes were classified as in, near, or out of the nearest radiation field, on the basis of a review of the radiotherapy record. "Near" was defined as within 5 cm of the field edge, in or out of the field. For irregular fields shaped with blocks, the testes were located in relation to the blocked edge of the field. No assessment of whether the testes were shielded (ie, clam shells on the testes), other than by blocks, or pinned outside the field (ie, oophoropexy) was made for the current analysis. The spine was classified as irradiated if any three-fourths of the spine was irradiated, and a cranial field was classified as irradiated if any part of the brain was irradiated. Permission was requested from a random sample of 50% of the cohort to contact their nearest-age sibling. Seven thousand thirty-nine patients were selected, of which 5,903 indicated that they had a full sibling who was alive. Permission to contact this sibling was given by 4,283 of the patients. Baseline questionnaires were sent to these siblings. Data from these siblings have been used as controls in some of the following analyses. This study was approved by the institutional review board at each participating institution, and informed consent for participation was obtained from all subjects who were 18 or more years of age, or their parents, if the subject was less than 18 years of age.
Statistical Methods To allow for the fact that a CCSS patient can become pregnant several times, and thus be responsible for several pregnancy outcomes, estimates of relative risk (RR) were determined using generalized estimating equation models.10,11 A binary distribution of each outcome (whether a pregnancy ended in a live birth, and so on) was modeled. Risks for each exposure are relative to sibling controls, except for drug dose and radiation exposure, for which risks are relative to members of the CCSS cohort who were not exposed. Ongoing pregnancies, pregnancies with unknown outcomes, or unknown cancer treatment data were excluded from the regression models. The RRs reported are for univariate analyses unless otherwise specifically stated to be the result of a multivariate analysis.
A baseline questionnaire was returned by 7,514 males. Of the 7,033 male survivors, 4,122 (59%) who answered the question indicated that they had been sexually active. An MRAF was completed for 3,472 (84.2%) of the sexually active male survivors; 1,227 sexually active males reported they sired 2,323 pregnancies.
Sex Ratio The sex ratio of the offspring, by treatment received, was surgery only, 1.19:1.0 (64:54) (number of male offspring to number of female offspring); radiotherapy only, 1.75:1.0 (7:4); chemotherapy only, 1.0:1.13 (16:18); surgery and radiotherapy, 1.0:1.08 (109:118); surgery and chemotherapy, 1.14:1.0 (124:109); radiotherapy and chemotherapy, 1.07:1.04 (29:27); surgery, radiotherapy, and chemotherapy, 1.0:1.22 (199:242); and unknown 1.05:1.0 (100:95). The RR of a male offspring following treatment with the following chemotherapeutic agents was carmustine (BCNU), RR = 0.77 (P = .33); lomustine (CCNU), RR = 0.64 (P = .32); chlorambucil, RR = 2.18 (P = .29); cyclophosphamide, RR = 1.25; (P = .08); nitrogen mustard, RR = 0.81 (P = .44); and procarbazine, RR = 1.02 (P = .93).
Pregnancy Outcome in Relation to Nontreatment Factors
The distribution of pregnancy outcome of the partners of the male patients, by diagnosis, in comparison to the outcomes of the pregnancies of the partners of the male siblings of the survivors, is shown in Table 1
Pregnancy Outcome in Relation to Specific Treatment The distribution of pregnancy outcome of the partners of the male patients, by treatment, is shown in Table 2  . Although the RR for a live birth was decreased if the male survivor was treated with surgery and chemotherapy with or without radiotherapy, when compared with the pregnancies of the partners of the male siblings, there were no significant differences in the frequency of live birth when the pregnancies of the partners of the male survivors were compared within the survivor cohort by the survivor’s treatment (data available at www.cancer.umn.edu/ccss).
Possible Effects of Testicular Irradiation The partners of male survivors whose testes were in the radiotherapy field, near the radiotherapy field, or were shielded had very few live births. The rate of stillbirth or miscarriage was not increased among the partners of male survivors whose testes were not irradiated or who received no radiotherapy (Table 3 ).
Possible Effects of Cranial or Spinal Irradiation The frequency of miscarriage among the partners of the male survivors was not increased if the survivor had received cranial irradiation, craniospinal irradiation, spinal irradiation only, no cranial or spinal irradiation, or no irradiation (Table 4 ).
Possible Effects of Chemotherapy The rate of live births (Table 5 ) was significantly lower among the partners of male survivors treated with dactinomycin (RR = 0.68; 95% CI, 0.49 to 0.94; P = .02). The rates of live birth (Table 5) and of stillbirth (data available at www.cancer.umn.edu/ccss) were not different for offspring of the partners of male survivors treated with any other particular chemotherapeutic agent. The rates of live birth and miscarriage were not different for offspring of the partners of male survivors when analyzed according to the tertile of the cumulative dose received of each chemotherapeutic agent (data available at www.cancer.umn.edu/ccss).
The rate of miscarriage was higher for the partners of male survivors treated with more than 5,000 mg/m2 of procarbazine than for those treated with 0 to 5,000 mg/m2 of procarbazine (RR = 2.44, 95% CI, 1.28 to 4.67, P = .007) (Table 6 ). The rate of live birth was not decreased and the rate of miscarriage was not increased among the offspring of the partners of male survivors treated with various doses of cyclophosphamide (data available at www.cancer.umn.edu/ccss).
Birthweight There was no difference in the distribution of birthweights of offspring of the partners of male survivors who had or had not been treated with an alkylating agent (RR = 1.62; 95% CI, 0.84 to 3.11; P = .15) (Fig 1 ), whose partner smoked during pregnancy (RR = 1.64, 95% CI, 0.76 to 3.53, P = .21) (Table 7), or who had or had not received pelvic irradiation (RR = 1.51; 95% CI, 0.61 to 3.74; P = .38) (Fig 2). The offspring of male survivors who were treated with nonalkylating agent chemotherapy (RR = 3.03; 95% CI, 1.15 to 7.98; P = .025) (Fig 3) were more likely to weigh less than 2,500 g.
The survival rate of pediatric cancer patients improved dramatically during the last 2 decades.2 Because radiotherapy and many of the chemotherapeutic agents used in successful cancer treatment programs for children and adolescents are mutagenic, long-term survivors are concerned about the potential effect of the treatment they received on their fertility and the health of their offspring. These effects may be manifest as an increase in the rate of miscarriage or stillbirth, a change in the sex ratio of live-born infants, an increase in the frequency of congenital malformations, or an increase in the risk of cancer in the offspring. We undertook this study to determine what effect, if any, prior cancer therapy of males treated during childhood or adolescence had on the outcome of pregnancy. The frequency of congenital malformations and cancer in offspring will be the subject of future investigations. This study evaluated a cohort of consecutive, previously untreated male children and adolescents with specific cancer types diagnosed between January 1, 1970, and December 31, 1986, who were treated at 25 pediatric cancer centers. All drug and radiotherapy exposure data were abstracted to allow evaluation of the relationships among the exposures and pregnancy outcome reported by the survivors. Independent verification of pregnancy outcome, by review of obstetrical or newborn nursery records, was not obtained. Pregnancies that resulted from assisted technology were excluded because it was not known whether the pregnancy used the male survivor’s sperm. The sex ratio (M to F) was 1.00:1.03 among the offspring of the partners of the male survivors. This figure is different from United States population trends,12 and was significantly lower than the M to F ratio among the offspring of the partners of the male siblings of the survivors. This raises the possibility of a deficit of male infants among the offspring of the partners of male survivors. Our results do not support the hypothesis that exposures of the male survivors might generate an abnormal paternal X-chromosome with a lethal mutation, as was postulated before studies of the reproductive outcome following exposure to the atomic bombs at Hiroshima and Nagasaki.13 The present data are most consistent with those reported after some occupational exposures. Potashnik et al14 reported a significant decrease in the sex ratio of offspring of males conceived 3 or more months following initiation of exposure to dibromochloropropane. Mocarelli et al15 reported that the sex ratio of offspring of males exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) was significantly decreased. The effect was most significant among those males with the highest serum concentrations of TCDD, and among those males who were 19 years of age or less when the initial exposure occurred. Rogan et al16 were unable to demonstrate an effect on the sex ratio of offspring of Taiwanese women exposed to TCDD through cooking oil contamination. This is consistent with the data of Mocarelli,15 who also failed to demonstrate an effect among exposed women, unless the male was also exposed. The exposure status of the partners of the Taiwanese women was not reported. The mechanism proposed for modification of the sex ratio following exposure to these agents is one of lowering of the testosterone level,17 an effect that was demonstrated among male workers recruited from two of 12 National Institute for Occupational Safety and Health cohorts of workers exposed to dioxin.18 We cannot exclude the possibility that our finding is the result of chance because we performed multiple comparisons in analyzing our data set, and did not initially hypothesize the direction of the sex ratio among the offspring of the male survivors. This finding needs to be confirmed in one or more additional cohorts of offspring of childhood cancer survivors. However, the outcome is plausible because subclinical Leydig cell deficiency has been identified in male cancer survivors exposed to alkylating agents, including cyclophosphamide, nitrogen mustard, chlorambucil, and procarbazine.19–23 We were, however, unable to demonstrate a statistically significant change in the sex ratio when male survivor exposure to specific alkylating agents was evaluated. We were not able at this time to evaluate the relationship between mother’s age at the start of pregnancy and pregnancy outcome because this information was not ascertained with the baseline questionnaire. A separate pregnancy questionnaire that included a query regarding the mother’s age at the start of each pregnancy has been sent to all respondents who indicated that they had one or more pregnancies, but the return of this questionnaire is still incomplete. This finding is consistent with societal trends where the percentage of pregnancies that are terminated by an induced abortion is highest among those less than 15 years of age, and reaches a minimum value for those 25 to 29 years of age.24 The effect of previous treatment on the frequency of spontaneous abortion cannot be adequately analyzed because of the inaccuracy of recall in relation to such events25,26 and the perturbing effect of therapeutic abortion on the frequency of spontaneous abortion. We are unaware of any prior study that demonstrated an effect of chemotherapy treatment on the rate of stillbirth or miscarriage, or birthweight.27,29 However, none of the prior studies has included a large enough number of chemotherapy-exposed parents to exclude, with adequate statistical power, an effect of prior chemotherapy treatment on the frequency of stillbirth or miscarriage, or birthweight. In the present study, prior treatment of males with more than 5,000 mg/m2 of procarbazine was associated with an increased risk of miscarriage by the male survivors’ partners. This finding requires additional evaluation. The results of this study are reassuring, and generally support the conclusion that prior treatment of male pediatric and adolescent cancer patients with chemotherapeutic agents does not adversely affect pregnancy outcome of their partner. The possible effect of childhood cancer or its treatment on the sex ratio of offspring of male survivors will require further analysis.
Supported by the National Cancer Institute (U24 CA55727) of the National Institutes of Health. Support provided to the University of Minnesota Cancer Center from the Children’s Cancer Research Fund. Presented in part at the XXXI Annual Meeting of the International Society of Paediatric Oncology, Montreal, Canada, September 13–18, 1999 (Med Pediatr Oncol 33:146, 1999).
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8. Green DM, Fiorello A, Zevon MA, et al: Birth defects and childhood cancer in offspring of survivors of childhood cancer. Arch Pediatr Adolesc Med 151:379–383, 1997 9. 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 38:229–239, 2002[CrossRef][Medline] 10. SAS/STAT Software: Changes and enhancements through release 6.12. Cary, NC: SAS Institute Inc, 1997
11. Liang KY, Zeger SL: Longitudinal data analysis using generalized linear models. Biometrika 73:13–22, 1986 12. Ventura SJ, Martin JA, Curtin SC, et al: Births: Final data for 1999. National Vital Statistics Report. Hyattsville, MD, National Center for Health Statistics, volume 49 number 1, 2001 13. Schull WJ: Effects of Atomic Radiation. A Half-Century of Studies from Hiroshima and Nagasaki. New York. Wiley-Liss, Inc., 1995. 14. Potashnik G, Goldsmith J, Insler V: Dibromochloropropane-induced reduction of the sex-ratio in man. Andrologia 16:213–218, 1984[Medline] 15. Mocarelli P, Gerthoux PM, Ferrari E, et al: Paternal concentrations of dioxin and sex ratio of offspring. Lancet 355:1858–1863, 2000[CrossRef][Medline] 16. Rogan WJ, Gladen BC, Guo Y-L, et al: Sex ratio after exposure to dioxin-like chemicals in Taiwan. Lancet 353:206–207, 1999[Medline] 17. James WH: Occupations associated with low offspring sex ratios. Am J Ind Med 25:607–608, 1994[Medline]
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22. Whitehead E, Shalet SM, Morris, Jones PH, et al: Gonadal function after combination chemotherapy for Hodgkin’s disease in childhood. Arch Dis Child 57:287–291, 1982 23. Shafford EA, Kingston JE, Malpas JS, et al: Testicular function following the treatment of Hodgkin’s disease in childhood. Br J Cancer 68:1199–1204, 1993[Medline] 24. Ventura SJ, Taffel SM, Mosher WD, et al: Trends in pregnancies and pregnancy rates by outcome: Estimates for the United Sates, 1976–1996. Vital and Health Statistics. Hyattsville, MD, National Center for Health Statistics, series 21, number 56, 2000
25. Wilcox AJ, Horney LF: Accuracy of spontaneous abortion recall. Am J Epidemiol 120:727–733, 1984 26. Wilcox AJ, Weinberg CR, O’Connor JF, et al: Incidence of early loss of pregnancy. N Engl J Med 319:189–194, 1988[Abstract] 27. Green DM, Fine WE, Li FP: Offspring of patients treated for unilateral Wilms’ tumor in childhood. Cancer 49:2285–2288, 1982[CrossRef][Medline]
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
