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© 2002 American Society for Clinical Oncology Pregnancy Outcome After Treatment for Wilms Tumor: A Report From the National Wilms Tumor Study GroupByFrom the Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, NY; School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY; Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Radiation Oncology, Northwestern University, Chicago, IL; and Department of Biostatistics, University of Washington, Seattle, WA. Address reprint requests to Daniel M. Green, MD, Department of Pediatrics, Roswell Park Cancer Institute, Elm and Carlton Sts, Buffalo, NY 14263; email: daniel.green{at}roswellpark.org
PURPOSE: This study was undertaken to determine the effect, if any, of prior treatment with radiation therapy or chemotherapy for Wilms tumor diagnosed during childhood or adolescence on live births, birthweight, and the frequency of congenital malformations. PATIENTS AND METHODS: We reviewed pregnancy outcomes among survivors of Wilms tumor treated with or without irradiation to the flank or tumor bed on National Wilms Tumor Studies 1, 2, 3, and 4 using a maternal questionnaire and review of both maternal and offspring medical records. RESULTS: We received reports regarding 427 pregnancies with duration of 20 weeks or longer, including 409 liveborn singletons for whom 309 sets of medical records were reviewed. Malposition of the fetus and early or threatened labor were more frequent among irradiated women. Both were more frequent among women who received higher radiation therapy doses. The offspring of the irradiated female patients were more likely to weigh less than 2,500 g at birth and to be of less than 36 weeks gestation, with both being more frequent after higher doses of radiation. An increased percentage of offspring of irradiated females had one or more congenital malformations. CONCLUSION: Women who receive flank radiation therapy as part of their treatment for Wilms tumor are at increased risk of fetal malposition and premature labor. The offspring of these women are at risk for low birthweight, premature (< 36 weeks gestation) birth, and the occurrence of congenital malformations. These risks must be considered in the obstetrical management of female survivors of Wilms tumor.
THE TREATMENT OF childhood cancer has become increasingly successful. Approximately 70% of all patients1-3 and 90% of those with Wilms tumor2-8 survive for 5 years. Treatment with radiation therapy to the whole abdomen or only to the tumor bed may adversely affect reproductive function. Several studies demonstrated an increased risk of fetal death in women who received abdominal irradiation.9-13 All studies included too few offspring born to women treated with chemotherapy or lower radiation therapy doses to have the statistical power to exclude an effect of this treatment on pregnancy outcome.14-18 The present study was undertaken to evaluate the effect of prior treatment with lower doses of flank radiation therapy or combination chemotherapy on the risk of pregnancy complications, stillbirth, premature birth, and the health of offspring of women and the partners of men treated for Wilms tumor during childhood.
The National Wilms Tumor Study Group (NWTSG), formed in 1969, completed four studies that evaluated various doses of radiation therapy and several different combination chemotherapy regimens for the treatment of children with various stages of Wilms tumor.4-8 The NWTSG undertook a rigorous evaluation of the late effects of therapy in successfully treated patients (long-term follow-up study). Patients become eligible for the long-term follow-up study when they have completed 5 years of follow-up from the date of diagnosis of Wilms tumor. Six thousand four hundred eighty-four patients treated on NWTS 1 through 4 are eligible. Nine hundred eighty-six are known to have died. Three thousand two hundred fifty-nine are in active follow-up, and 703 are not in active follow-up by the original treating institution and permission to transfer follow-up to the NWTSG Data and Statistical Center (DSC) has been requested from the institution. Eight hundred thirteen are in tracking, 357 have been located but have not returned completed questionnaires, 158 are lost to follow-up, and 181 have had follow-up discontinued. A total of 3,514 of the 5,471 patients known not to be dead by the end of 1999 also had their 15th birthday before December 31, 1999. We have received responses to follow-up questionnaires from 81% (1,339 of 1,646) of the males and 82% (1,528 of 1,868) of the females in this subgroup of patients known not to be dead and to have had their 15th birthday before December 31, 1999. Follow-up is maintained by the original treating institution or by the NWTSG DSC. A Questionnaire for Mother, which covers items about the hospital where the birth took place, pregnancy complications and outcome, birth defects, childhood illnesses, and survival in the offspring, and an authorization for release of medical records on mother and child are mailed to the NWTSG patient as soon as the DSC learns about a pregnancy or birth. Medical conditions, such as pregnancy complications, identified in NWTSG survivors, and congenital malformations and medical conditions identified in the offspring generate a computer record that includes the 5-digit International Classification of Disease (ICD-9) code. All pregnancy complications and congenital anomalies were abstracted from medical records and reviewed by one of the investigators (D.M.G.). Congenital anomalies were evaluated using the method used by the Metropolitan Atlanta Congenital Defects Program, which excludes some of the anomalies using ICD-9-CM codes 740 to 759.19 This study is limited to pregnancies of patients or partners of patients who received either no abdominal irradiation or only flank irradiation (renal fossa/tumor bed) as part of the initial course of treatment. Estimates of the scattered dose to the ovaries and uterus of a 2-year-old and 7-year-old female were prepared by one of the investigators (J.A.K.) using the PLATO treatment planning software (Nucletron, Veenendaal, The Netherlands) assuming ovarian positioning at the lower border of the sacroiliac joint, as previously published.20
Statistical Methods
The patients reported 427 pregnancies of 20 weeks or longer gestation. There was one miscarriage, one elective abortion, four stillbirths, 409 liveborn singleton infants, and 12 liveborn infants from twin gestation. Medical records of 309 pregnancies of 20 weeks or longer duration were reviewed. Complications of pregnancy and labor, including hypertension complicating pregnancy (ICD 642), early or threatened labor (ICD 644), malposition of fetus (ICD 652), obstructed labor (ICD 660), abnormality of forces of labor (ICD 661), and umbilical cord complications (ICD 663), were examined. None of these were significantly more frequent among the partners of men who were treated with flank radiation compared with those who were not. However, early or threatened labor (P = .030) and malposition of the fetus (P = .007) were more frequent among irradiated women (Table 1). The trend test result suggested that both complications were more frequent among women treated with higher radiation doses. The OR of early or threatened labor was 2.36 (95% CI, 0.93 to 6.02) among those who received greater than 25 Gy compared with the unirradiated females, and the OR of malposition of the fetus was 6.26 (95% CI, 1.50 to 36.57) among those who received 25 Gy or greater compared with the unirradiated females. The increased risk of malposition of the fetus remained significant in a multivariate model that included gestational age (P = .028).
There was no difference in the frequency of early or threatened labor (P = .676) or malposition of the fetus (P = .756) in the group of women treated with dactinomycin only or vincristine and dactinomycin compared with the group treated with vincristine, dactinomycin, and doxorubicin. The mean gestational age of the offspring of the irradiated females was 37.23 (± 4.00) weeks, compared with 38.47 (± 2.95) weeks for those of the unirradiated females (P = .005). The mean gestational age of the offspring of the irradiated (39.23 ± 2.09 weeks) and that of the offspring of the unirradiated (39.48 ± 1.92 weeks) males did not differ (P = .59). There was an excess of infants born before 36 weeks of gestation to women (P = .0005), but not to the partners of men, who received flank irradiation. The excess was greatest among women who had received flank radiation doses exceeding 25 Gy (Table 2). The OR of birth before 36 weeks of gestation was 4.07 (95% CI, 1.74 to 9.90) among the offspring of the females who received 25 Gy or greater compared with the offspring of the unirradiated females. There was no difference in the percentage of infants born before 36 weeks of gestation (P = .322) in the group of offspring of women treated with dactinomycin only or vincristine and dactinomycin compared with the group treated with vincristine, dactinomycin, and doxorubicin.
The mean birthweight of the offspring of the irradiated females was 3,036 ± 805 g, compared with 3,245 ± 620 g for the offspring of the unirradiated females (P = .02). The mean birthweight of the offspring of the irradiated (3,466 ± 451 g) and unirradiated (3,475 ± 794 g) males did not differ (P = .94). There was an excess in the percentage of infants with a birthweight less than 2,500 g born to women (P = .017), but not the partners of men, who received flank radiation. The proportion of infants with a birthweight less than 2,500 g was greater among the offspring of women who received flank radiation therapy doses greater than 25 Gy (Table 3). Most of the low-birthweight infants had weights that were appropriate for their gestational age (Fig 1). There was no difference in the percentage of infants with a birthweight less than 2,500 g (P = .129) in the group of offspring of women treated with dactinomycin only or vincristine and dactinomycin compared with the group treated with vincristine, dactinomycin, and doxorubicin.
Twenty of 309 singleton infants for whom medical records were reviewed had a total of 32 congenital malformations. Twelve had a single congenital malformation, five had two, two had three, and one had four congenital malformations. Congenital malformations were more frequent among the offspring of women who received flank radiation therapy (P = .054, Table 4). No such increase was observed for irradiated males (P = 1.0). Most malformations were isolated (Table 5). The specific anomalies are listed in Table 6. There was no difference in the percentage of infants with no versus one or more congenital anomalies (P = .757) in the group of offspring of women treated with dactinomycin only or vincristine and dactinomycin compared with the group treated with vincristine, dactinomycin, and doxorubicin.
We undertook this study to evaluate the effect of treatment for Wilms tumor on complications of pregnancy and pregnancy outcome. Prior studies suggested that there was an increased risk of low birthweight among the offspring of irradiated female survivors of Wilms tumor.9-13 No prior study evaluated the frequency of risk factors for complications of pregnancy, such as fetal malposition, hypertension during pregnancy, premature labor, or umbilical cord abnormalities. The pregnancies identified by this study ended with 409 liveborn singleton infants of known gestational age, of whom 309 were represented in the statistical analyses, representing the largest study conducted to date of offspring of patients with Wilms tumor.9-12,23 We did not evaluate the outcome of pregnancies of less than 20 weeks gestation because of the known inaccuracy of subjects’ recall of such events.24,25 The rate of therapeutic abortion increased from 1970 through 1980, and then declined between 1987 and 1995,26,27 a societal trend that has a perturbing effect on the rate of spontaneous pregnancy loss before 20 weeks of gestation. For these reasons, we cannot comment on the possible relation between the rate of spontaneous pregnancy loss before 20 weeks of gestation, a potential marker for lethal X-linked mutations, and prior treatment for Wilms tumor. The subjects included in our study had all undergone at least a unilateral nephrectomy. Previous NWTSG studies suggested that hypertension may be more frequent,28 although renal failure was infrequent,29 in long-term survivors of unilateral Wilms tumor. Pregnancy associated hypertension (pre-eclampsia [eclampsia without chronic hypertension] and transient hypertension) occurred in 15% of unirradiated, compared to 19% of irradiated, female survivors of Wilms tumor. These rates are consistent with those reported for indigent women (13%)30 and nulliparous women (10% to 20%)31-34 but are higher than those reported by the National Center for Health Statistics (3.9%).35 Malposition of the fetus increased from 3.2% (three of 95) in unirradiated to 4.0% (three of 75) in lightly irradiated (0.01 to 25 Gy) and 16.9% (10 of 59) in heavily irradiated (25.01+ Gy) female survivors of Wilms tumor. Malpresentations, including breech presentation, face presentation, brow presentation, shoulder presentation, and compound presentations, occur in approximately 4% of all pregnancies.35 Breech presentations are more frequent in low-birthweight (< 2,500 g) infants, whereas cephalopelvic disproportion is more frequent in brow presentation.36 In this study, 5 of the 17 cases of malposition occurred among 28 pregnancies of less than 36 weeks of gestation (17.9%), whereas 12 cases of malposition were reported among 202 full-term pregnancies (5.9%). After adjustment for the confounding effects of gestational age, each additional 10 Gy of flank irradiation was estimated by logistic regression to increase the risk of malposition in female survivors of Wilms tumor by half (P = .028), an effect primarily attributable to the 10 cases of malposition observed in women who had received greater than 30 Gy of flank irradiation. Additional pregnancies will need to be ascertained to definitively exclude an effect on fetal malposition of flank irradiation at the lower doses now used in most treatment protocols. Umbilical cord complications were reported in 11% of unirradiated compared with 19% of irradiated female survivors of Wilms tumor. Umbilical cord complications, including true knots, nuchal coils, and cords around the body were reported in 27.7% of 17,190 deliveries ascertained at 15 institutions in the Collaborative Study of Cerebral Palsy, Mental Retardation and Other Neurological and Sensory Disorders of Infancy and Childhood.37 Nuchal cords were the most frequent abnormality (24.6% of all deliveries). The frequency was lower in infants weighing less than 2,000 g than in those weighing more than 2,000 g.37 We did not identify any effect of flank radiation therapy of male patients with Wilms tumor on the outcome of pregnancies of their partners. This finding is consistent with the results of several previous studies.9-13 The offspring of women who received flank irradiation as a component of their protocol therapy for Wilms tumor were significantly more likely to have a birthweight of less than 2,500 g than were those born to women whose protocol treatment for Wilms tumor did not include flank irradiation. This finding confirms those of several previous studies,9-12 including that of Chiarelli et al,38 who reported an increased relative risk of low-birthweight offspring among women treated with greater than 25 Gy of abdominal-pelvic radiation. None of these studies estimated the different doses received by the musculoskeletal structures, uterus, or ovaries from the various treatment volumes included in their analyses. The present study considered only patients who received flank or tumor bed irradiation. The radiation dose received by the spine, upper pelvis, abdominal musculature, and abdominal cavity of the irradiated flank can be assumed to be the prescribed treatment dose. Using computed tomography scan–based estimates for two females of different ages, we estimated the ipsilateral ovary, contralateral ovary, and uterine doses to be 4% to 7%, 2% to 5%, and 2% to 4% of the prescribed dose. However, actual dosimetry must be performed to accurately estimate the ovarian and uterine doses received by the patients included in the present study. The mechanism responsible for low birthweight is unknown. The studies of Critchley et al39,40 suggest that damage to both the uterine vasculature and myometrium contribute. These investigators demonstrated that uterine length was significantly less in 10 women with ovarian failure who had been treated with whole abdomen irradiation. Endometrial thickness did not increase in response to hormone replacement therapy in three women who underwent weekly ultrasound examination. No flow was detectable with Doppler ultrasound through either uterine artery of five women and through one uterine artery in three additional women.
The frequency of offspring with one or more congenital malformations increased from 3.2% (three of 93) for unirradiated to 10.5% (eight of 76) for lightly irradiated (0.01 to 25 Gy) and 10.0% (six of 60) for heavily irradiated ( Byrne et al16 reported no increase in the frequency of simple malformations among the offspring of female cancer survivors compared with the offspring of their siblings. They used subject report of congenital malformations, with medical record confirmation of reported conditions when possible. They did not analyze the relationship between maternal therapeutic irradiation and the risk of congenital malformations and did not report the percentage of females among the 87 survivors who received infradiaphragmatic irradiation. Chiarelli et al38 reported no increase in the risk of congenital anomalies among the offspring of females treated with abdominal or pelvic irradiation compared with those treated with surgery only, chemotherapy with an alkylating agent, or treatment with an alkylating agent and abdominal or pelvic irradiation. The number of exposed females in each group was not reported. They used responses to a mailed questionnaire but did not verify malformations through medical record review. Hawkins et al42 reported congenital anomalies in 3.6% of offspring born to women exposed to potentially mutagenic therapy (radiotherapy involving direct exposure of the abdomen or gonads or treatment with an alkylating agent) compared with 2.1% of offspring of unexposed women. Congenital malformations were ascertained by general practitioner report of a potentially lethal or handicapping malformation, but the presence of a malformation was not independently verified by review of medical records. Previous research evaluated the effect of gamma and neutron radiation on the mutation frequency in the offspring of Japanese populations exposed to atomic bombs. No evidence of an effect of radiation on the frequency of mutation in the offspring of proximally exposed subjects was identified.43,44 Using assays of the frequency of mutation of the glycophorin A locus45-48 or the hypoxanthine-guanine phosphoribosyl transferase locus,48,49 several investigators confirmed that mutational injury could be identified years after exposure to gamma or neutron irradiation. Such injury was identified in adult cancer patients after treatment with radiation therapy or chemotherapy,50-52 survivors of Hodgkin’s disease treated during childhood with combination chemotherapy,53 survivors of diverse types of cancer treated during childhood,54 and survivors of acute leukemia treated during childhood.55 The present results suggest that prior flank radiation may increase the risk of congenital malformations, a finding supported by the increased frequency of congenital malformations with increased flank radiation therapy dose. We need to estimate ovarian radiation doses to strengthen the suggestion that prior flank radiation therapy increased the risk of congenital malformations. Our study was limited by the use of a mailed questionnaire for the ascertainment of pregnancy. The questionnaire asked for events that occurred since the time of last contact. This wording resulted in incomplete reporting of pregnancies that occurred between the last contact of the patient with the original treating institution and the first direct contact between the patient and the NWTSG DSC. Our results may be confounded by ascertainment bias, with women whose pregnancies were complicated by one or more of the analyzed end points or whose infant had one or more congenital malformations possibly being more likely to participate. We conclude that irradiated female survivors of Wilms tumor are at increased risk for early or threatened labor and fetal malposition, and their offspring are more likely to be premature (< 36 weeks gestation) and of low birthweight (< 2,500 g). The obstetrical management of the pregnancies of these women should take these elevated risks into consideration. In addition, our data suggest that the frequency of congenital malformations may be increased in the offspring of irradiated females. This possibility will require additional study. We will continue our study to determine if the pregnancies of survivors who received lower flank radiation therapy doses are less likely to be complicated by low birthweight or premature birth and if the offspring of women who received lower flank radiation therapy doses are less likely to have offspring with congenital malformations.
Supported in part by United States Public Health Service grant nos. CA-54498 and CA-42326. We thank the investigators of the Pediatric Oncology Group and the Children’s Cancer Group, the health professionals who managed the children entered onto the studies, Cynthia A. Moore, MD, and Diane Piacente.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) and irradiated female (
) patients with Wilms tumor.
25.01 Gy) females (P = .054). The figure for the United States population is 3.6%.
