Original Article

Congenital Anomalies in Children of Patients Who Received Chemotherapy for Cancer in Childhood and Adolescence

Daniel M. Green, M.D., Michael A. Zevon, Ph.D., Geoffrey Lowrie, M.A., Nina Seigelstein, B.S., and Brenda Hall, R.N., C.N.P.

N Engl J Med 1991; 325:141-146July 18, 1991DOI: 10.1056/NEJM199107183250301

Abstract

Abstract

Background.

Many patients who have been treated successfully for childhood cancer with regimens that contain one or more mutagenic chemotherapeutic agents are concerned that their own treatment during childhood or adolescence may adversely affect their children.

Full Text of Background....

Methods.

To determine the effect of chemotherapy for cancer during childhood and adolescence on the outcome of subsequent pregnancies, we reviewed the records of 306 men and women who had been treated for pediatric cancer and who responded to our questionnaire. One hundred of the 306 patients reported 202 pregnancies. Among the patients who had received chemotherapy as part of their treatment for cancer, 60 patients or wives of patients had had one or more pregnancies of 20 or more weeks' gestation. The 60 former patients had a total of 100 live-born and 2 stillborn children.

Full Text of Methods....

Results.

The frequency of congenital anomalies was 8.1 percent (5 of 62) among the live-born children of the women and 7.9 percent (3 of 38) among the live-born children of the men. Structural congenital cardiac defects were identified in 10.0 percent (2 of 20) of the children of women who had been treated with dactinomycin, as compared with 0.6 percent (144 of 24,153) among the children in a multicenter survey of fetal anomalies (P = 0.0126). We found no relation between the number of mutagens received or the cumulative dose of any agent received and the frequency of congenital anomalies in the children.

Full Text of Results....

Conclusions.

These data suggest that treatment of children and adolescents with mutagenic chemotherapeutic agents, in the dose ranges we examined, does not increase the frequency of congenital anomalies in the children subsequently born to the former patients. However, the possible adverse effect of dactinomycin on the children of such patients requires further study. (N Engl J Med 1991;325:141–6.)

Full Text of Conclusions....

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Media in This Article

Figure 1Relation between the Cumulative Doses of Chemotherapeutic Agents and the Presence of Congenital Anomalies in the Children of the Male Patients.

Figure 2Relation between the Cumulative Doses of Chemotherapeutic Agents and the Presence of Congenital Anomalies in the Children of the Female Patients.

Article Activity

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Article

CHEMOTHERAPEUTIC agents are used frequently in the treatment of children and adolescents with cancer. Many of these agents are mutagenic, with the potential to cause injury to germ-cell chromosomes. The possible results of this injury include an increase in the frequency of genetic diseases and congenital anomalies in the children subsequently born to patients successfully treated for cancer during childhood and adolescence.

Several studies of the children of patients previously treated for diverse types of childhood cancer identified no increase in the frequency of congenital anomalies in the children.1 2 3 Although previous reports of studies of the children of patients treated for cancer during childhood and adolescence identified the chemotherapeutic agents administered to the patients1 and evaluated the effect of infradiaphragmatic irradiation or treatment with alkylating agents on the frequency of congenital anomalies in the patients' children,3 the investigators did not evaluate the relation between the cumulative doses of mutagenic agents or the administration of mutagenic agents other than alkylating agents and the frequency of congenital anomalies in the children.

We undertook the present study in order to determine whether the frequency of congenital anomalies was increased in the children of former patients who had received treatment for cancer with one or more mutagenic agents during childhood and adolescence and to determine whether the increased risk of congenital anomalies, if any, was related to the cumulative dose of the mutagenic agents.

Methods

We abstracted the medical records of 1239 consecutive patients who were given a diagnosis of cancer between January 1, 1960, and December 31, 1984, and who were less than 20 years of age at the time of diagnosis. The hospital number, patient's name, date of birth, sex, race, diagnosis, date of diagnosis, primary tumor site, presence or absence of metastatic disease, treatment (surgery, radiation therapy, or chemotherapy), date of relapse, and date of death or most recent follow-up contact were entered into a computerized data base.

We identified a subgroup of this population (n = 383) made up of former patients who were currently 18 years of age or older in whom cancer had been diagnosed five or more years earlier; these patients were asked to complete a questionnaire that covered marital status, employment, health and life insurance, family and reproductive history, and the use of alcohol, tobacco, and prescription medications during pregnancy. The questionnaire was either completed at the time of the patient's annual evaluation in the Long-Term Follow-Up Clinic of Roswell Park Cancer Institute or completed and returned by mail by those who were no longer followed up.4 The questionnaire was completed by 306 of the former patients.

One hundred of the respondents reported that they or their wives or sexual partners had become pregnant one or more times since the completion of their treatment for cancer. The 202 pregnancies ended in 17 spontaneous abortions, 4 therapeutic abortions, 1 ectopic pregnancy, 4 stillbirths, 13 premature deliveries, and 163 full-term live births. Hospital nursery records were obtained for 81 percent of the live-born children. The presence of congenital structural cardiac defects was confirmed by a review of pediatric cardiology records and, in one case, review of autopsy records. We have previously reported the outcomes of 27 pregnancies that occurred after treatment for acute lymphoblastic leukemia.5

We did not analyze the effect of previous treatment on the frequency of spontaneous abortion because of the general inaccuracy of recalled information about such events6 and the possible effect of therapeutic abortion in lowering the frequency of spontaneous abortion.

Pregnancies of at least 20 weeks' gestation were reported in 60 of the respondents who received chemotherapy as part of their treatment for cancer or in their wives. The treatment records of these 60 patients were reviewed, the recorded drug dosages were normalized for body-surface area, and the cumulative doses of drug were determined.

Chemotherapeutic agents were classified as mutagenic or nonmutagenic on the basis of the results of testing with the Ames salmonella—microsome assay. Agents that are mutagenic according to the Ames salmonella—microsome assay include doxorubicin, daunorubicin, cyclophosphamide, ifosfamide, lomustine, carmustine, dacarbazine, cisplatin, chlorambucil, mechlorethamine, etoposide, and mercaptopurine.7 8 9 10 11 12 13 14 Procarbazine was classified as a mutagen on the basis of the results of a modified salmonella—microsome assay.15 Agents that are not identified as mutagenic in the Ames salmonella—microsome assay include vincristine, vinblastine, methotrexate, thioguanine, asparaginase, dactinomycin, and cytarabine.7 8 9 ^, 16

Statistical Analysis

The relation between the presence of congenital anomalies in the children and specific characteristics of the parents and children was assessed with a stepwise logistic-regression analysis. The statistical criterion for the entrance of a variable into the model was a P value less than 0.05. The use of a forward stepwise-regression procedure allowed us to evaluate the independent contribution of each variable to the model.

A binomial analysis was performed to determine whether the rate of anomalies observed in the study sample differed significantly from the rate in the general population. Depending on the number of subjects, chi-square analysis or Fisher's exact test was used to assess the relation between specific chemotherapeutic agents and the presence of an anomaly.

Results

Men

Twenty-five male patients reported the birth of 39 children (16 boys and 23 girls), including one stillbirth. These births occurred 113 to 8154 days after the completion of treatment in the fathers. The cumulative doses of the chemotherapeutic agents are shown in Table 1Table 1Treatment Received by Male Patients and Congenital Anomalies Reported in Their Children. and Figure 1Figure 1Relation between the Cumulative Doses of Chemotherapeutic Agents and the Presence of Congenital Anomalies in the Children of the Male Patients..

Two of the live-born children had birthmarks, and one had a skin tag on the hand (Table 2Table 2Characteristics of Parents Who Had Children with Anomalies.). These minor anomalies (7.9 percent) occurred in infants born 1940 to 3553 days after the completion of the father's chemotherapy.

The male patients who fathered children with congenital anomalies had received one or more of the following nine drugs as part of the chemotherapy regimen: cytarabine, thioguanine, mercaptopurine, asparaginase, etoposide, doxorubicin, cyclophosphamide, vincristine, and methotrexate. There was no relation between the frequency of congenital anomalies in the children and the fathers' receipt of any of these chemotherapeutic agents. There was also no relation between the occurrence of congenital anomalies in the children of the male patients and either the fathers' ages at diagnosis or the length of time since the completion of treatment.

Women

Thirty-five female patients reported 63 births, including 1 stillbirth and 6 premature births (37 boys and 26 girls), occurring 396 to 8350 days after the mother's completion of chemotherapy. The cumulative doses of the chemotherapeutic agents received by the mothers are shown in Table 3Table 3Treatment Received by Female Patients and Congenital Anomalies Reported in Their Children. and Figure 2Figure 2Relation between the Cumulative Doses of Chemotherapeutic Agents and the Presence of Congenital Anomalies in the Children of the Female Patients..

Five of the live-born infants (8.1 percent) had congenital anomalies, including one each with a ventricular septal defect, the tetralogy of Fallot, an epidermal nevus, a hydrocele, and a hemangioma (Table 2). The anomalies occurred in children born 1125 to 4192 days after the completion of the mother's chemotherapy.

The proportion with ventricular septal defect as a single malformation was 3.85 percent (1 of 26; 95 percent confidence interval, 0.07 to 19.62 percent) among the female children of the white female former patients, as compared with 0.034 percent (3.42 per 10,000) among white female infants in the general population17 (P<0.001 by two-sided binomial probability analysis). The proportion with tetralogy of Fallot was 2.78 percent (1 of 36; 95 percent confidence interval, 0 to 15 percent) among the male offspring of the white female former patients, as compared with 0.024 percent (2.41 per 10,000) among white male infants in the general population17 (P<0.001 by two-sided binomial probability analysis). The proportion of structural congenital cardiac defects among the children of women treated with dactinomycin was 10 percent (2 of 20; 95 percent confidence interval, 2.0 to women who were treated with any of these agents and those who were not. No relation was identified between either the mother's age at diagnosis or the length of time since the completion of treatment.

Multivariate Analysis

Stepwise logistic-regression analysis was used to evaluate the relations between the occurrence of an 31.6 percent), as compared with 0.60 percent (144 of 24,153) among white infants in the general population17 (P = 0.0126 by two-sided binomial probability analysis). There was no history of congenital cardiac malformation in the family of either infant with this anomaly; neither mother took any prescription or nonprescription medication during the pregnancy.

The treatment of the women who gave birth to an infant with a congenital anomaly had included one or more of the following agents: procarbazine, chlorambucil, dactinomycin, vinblastine, vincristine, cyclophosphamide, asparaginase, mercaptopurine, and methotrexate. There were no significant differences in the frequency of congenital anomalies between the children of anomaly in a child and the parent's sex, his or her diagnosis, the length of time since the completion of treatment, treatment with surgery or radiation therapy (or both) in addition to chemotherapy, treatment with a mutagen (see above), and the sex and birth weight of the child. None of the variables we investigated were significantly associated with the frequency of anomalies among the children.

The association of specific chemotherapeutic agents with the presence of a congenital anomaly was also examined with the use of stepwise logistic-regression analysis. The cumulative doses of doxorubicin, cyclophosphamide, vincristine, procarbazine, chlorambucil, dactinomycin, and vinblastine were entered as covariates, with the presence of an anomaly as the outcome. We found no relation between the cumulative dose of any of these drugs and the frequency of anomalies among the children. There was no relation between the number of mutagens (zero, one, two, three, or four or more) received by the patient and the presence of an anomaly in his or her child.

Discussion

The survival rate of children with cancer has improved dramatically during the past two decades.18 Many former patients have now reached young adulthood and are beginning to make decisions about marriage and reproduction. Because many of the chemotherapeutic agents that are frequently used alone or in combination in successful treatment programs for a variety of cancers in children and adolescents are mutagenic, former patients are concerned about the potential effect of the treatment they received on their fertility and the health of their children.

In the sample we studied, three minor congenital anomalies were identified among the children of the male patients. The frequency of single anomalies (7.9 percent) was not greater than that reported in the general population (13.0 percent [6906 of 53,257]).17 There was no relation between the occurrence of congenital anomalies in the children of the male patients and either the patient's age at diagnosis or the length of time since the completion of treatment.

Five congenital anomalies were identified among the children born to the female patients. The frequency of anomalies (8.1 percent) was not greater than that observed in the general population. No relation between the mother's age at diagnosis or the length of time since the completion of treatment and the presence of congenital anomalies was identified. Both cardiac defects, however, occurred in children of women who had been treated with dactinomycin. Although dactinomycin was not identified as mutagenic in the Ames salmonella—microsome assay, it is carcinogenic in murine systems.8 ^, 19

The present data are limited by the number of both survivors of cancer and children of such patients available for study and by the small number of anomalies reported. A small, although biologically significant, change in the mutation rate, manifested by a change in the frequency of recognizable single-gene defects,3 ^, 20 would not have been identified in our study because of the small size of our sample of children.

The results of this study suggest that one chemotherapeutic agent, dactinomycin, may be associated with an increased risk of a specific type of anomaly, congenital structural cardiac defects. Several previous studies that included patients treated with dactinomycin for diverse types of childhood cancer or gestational trophoblastic disease did not find heart murmurs or structural cardiac anomalies in their children.21 22 23 Other studies in which cardiovascular abnormalities were identified did not relate the abnormality in the children to the specific chemotherapeutic agents used to treat the parents,1 ^, 24 25 26 although tetralogy of Fallot was reported in children of women treated for gestational trophoblastic disease with dactinomycin in combination with other agents.24 Others have observed an increased incidence of cardiac septal defects in children with a variety of malignant tumors,27 but no previous study has suggested that the frequency of such abnormalities was increased in the children of successfully treated patients.

The effect of two mutagens, gamma radiation and neutron radiation, on the frequency of mutations among the children of Japanese exposed to the atomic bombs in Hiroshima and Nagasaki has been evaluated in detail in studies in which protein electrophoretic mobility or protein activity was used as a measure of mutational effects. No evidence was found of an effect of radiation on the frequency of mutation among the children of proximally exposed subjects.28 ^, 29 Using assays of the frequency of mutation of the glycophorin A locus30 ^, 31 or the hypoxanthine guanine phosphoribosyltransferase locus,32 however, several investigators have confirmed that mutational injury can be detected many years after exposure to gamma or neutron radiation. Such mutational injury has been identified in adult patients with cancer after treatment with radiation therapy, chemotherapy, or both.33

The results of our study generally support the conclusion that previous treatment with chemotherapeutic agents does not adversely affect the outcome of pregnancy. This finding may reflect more efficient repair of damage to DNA in germ cells than in somatic cells, or it may be an artifact of the relatively small number of pregnancies available for evaluation, especially in the cases of some of the chemotherapeutic agents included in this analysis. Our data suggest that one agent, dactinomycin, may have an adverse effect on the outcome of pregnancy. This finding must be further evaluated in a larger study.

Supported in part by a grant from the Association for Research of Childhood Cancer and a grant (CA-18201 –15 ) from the Cancer Education Program.National Cancer Institute.

We are indebted to Mrs. Diane Piacente for her assistance with our research.

Source Information

From the Departments of Pediatrics (D.M.G., B.H.) and Psychology (M.A.Z., G.L., N.S.), Roswell Park Cancer Institute, Buffalo, N. Y.; the Department of Pediatrics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo (D.M.G.); and the Department of Natural Sciences, Roswell Park Graduate Division, State University of New York at Buffalo (M.A.Z.). Address reprint requests to Dr. Green at the Department of Pediatrics, Roswell Park Cancer Institute, Elm and Carlton Sts., Buffalo, NY 14263.

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