This is among the largest investigations of congenital anomalies in the offspring of childhood cancer survivors and, importantly, among the first to evaluate these outcomes using carefully reconstructed gonadal radiation and chemotherapy doses. With subjects from 26 institutions, the study was well powered (80%) to detect ORs of 1.7 to 2.2 for the effect of ovarian radiation dose more than 1.00 Gy, testicular radiation dose more than 0.10 Gy, and the highest cumulative exposure to alkylating agents. Yet over a wide range of exposures, we found no significant associations between these therapies and congenital anomalies in the offspring, providing evidence against adverse transgenerational effects. These findings have relevance for both male and female survivors and were supported by rigorous validation of self-reported outcomes.
For alkylating agents, there were no consistent associations with overall anomaly risk in relation to dose, although we noted a modestly elevated malformation risk with the lowest tertile exposure for men (OR = 1.47) and the highest tertile exposure for women (OR = 1.30), both nonsignificant. The former finding makes little intuitive sense and was likely a chance finding. The latter finding was based on malformations in 12 unrelated offspring, among whom there was no clear pattern of malformation type, which included those of the heart (n = 5), eye (n = 3), extremities (n = 1), skin (n = 1), genitalia (n = 1), and musculoskeletal system (n = 1). With few exceptions,13
alkylating agents have not been linked to malformations in the children of patients with cancer.14–18
Our findings should be interpreted cautiously given that malformations can also be of environmental origin, that ever use of alkylating agents showed no effect, and that the CIs for the AAD ORs were compatible with a null effect.
Our investigation follows earlier CCSS analyses, which found similar genetic disease occurrence for survivors' children and those of a sibling control group.19
Now with treatment dosimetry, we can focus specifically on individual exposure to mutagenic therapy, conduct dose-response evaluations, and thus confirm that even high-doses of gonadal irradiation are unassociated with future genetic disease risk. Our results strengthen the conclusions of at least a dozen studies that reported no increased risk of congenital anomalies in the children of cancer survivors.13–17,20–26
In contrast, two Scandinavian studies reported some positive associations, comparing offspring outcomes of cancer survivors with those of the general Norwegian27
populations. In these studies, differential clinical surveillance of cancer survivors' children compared with that of the general population may account for more defects being diagnosed in the former group.29
We believe our use of nonexposed cancer survivors as a referent resulted in groups with similar impetus to report offspring health problems and with similar health surveillance for their children.
Overall we found a congenital anomaly prevalence of 2.7% in the offspring, within the range of previous reports of childhood cancer survivors and their siblings,13,16,17,20–24,27,28
and consistent with US population estimates of approximately 3%.30
Our prevalence is slightly underestimated because we excluded defects related to known (eg, familial) causes, given the hypotheses being tested. Although heritable defects are present at birth, not all are diagnosed immediately. The average age of the children at the time when their parent provided data for this study was 4.6 years, which should have provided opportunity for most anomalies to be diagnosed. Moreover, the parents of children with and without anomalies had a comparable time period for potential diagnoses (average, 5.0 and 4.5 years, respectively). We noted a higher reported prevalence of anomalies among the children of female versus male survivors for reasons that are unclear but could involve underreporting by the fathers.
Sperm can be damaged by the therapies used for many cancers, resulting in abnormal numbers of chromosomes (aneuploidy) that underlie certain types of genetic disorders, such as Down syndrome, which were rare outcomes in our study.31–34
Although sperm DNA damage has been shown to persist for as long as 2 years after treatment,31
the effect generally seems to be transient without lasting damage to the spermatogonial stem cells.31–35
In our study, the children were born an average of 15.5 years after paternal irradiation. However, in a separate analysis (not shown, and including children not part of our main analysis because they were born before their parent achieved 5-year survivorship), no children born within 3 years after diagnosis to fathers exposed to testicular irradiation (mean dose, 1.35 Gy) had a reported congenital anomaly, although these results were based on a small number of children (n = 14). Similarly, there were no congenital anomalies reported among children born within 3 years after diagnosis to fathers exposed to alkylating agents.
We cannot rule out the possibility that cancer treatment resulted in inherited mutations, albeit ones not resulting in a recognized anomaly in the offspring. However, the search for such genetic damage has not been fruitful to date. Two recent studies in Denmark that included adult survivors of childhood cancer, their nonaffected partners, and their offspring demonstrated no indication of transmissible genomic instability in the offspring using chromosomal analysis36
and no evidence of germline minisatellite mutation rates being associated with radiotherapy.37
Our ability to fully evaluate this issue is likely to improve as genomic technologies improve,6
but given the current body of evidence, important increases in the risk of treatment-related genetic disease seem unlikely. As we reported previously in this population,8
induced abortions were not more frequently reported by male and female survivors with a history of high gonadal irradiation, limiting the possibility that pregnancy terminations of adversely affected fetuses obscured our results.
Our findings were based on 5-year childhood cancer survivors and thus are limited in their generalization outside this group. However, given the young ages of these patients, pregnancies would be unusual before 5-year survivorship, thus our findings should be relevant to the majority of childhood cancer survivors. Nonresponse to the questionnaires limited our inclusion of all potential offspring, and it is possible that nonresponse was related to the probability of offspring medical problems (either more likely if it provided impetus to respond, or less likely if competing parental responsibilities interfered with participation). Approximately 15% of the identified offspring also could not be included in our analyses because of missing treatment details for their parent. These exclusions, however, are unlikely to have affected our dose-response evaluations performed within the responder group with complete data. Finally, although our analyses were based on relatively complete treatment exposure data, information on behavioral confounders such as cigarette smoking or alcohol drinking were available for only approximately 60% of the subjects; although analyses on this subset suggested these factors were not necessary for our final models, we cannot rule out the possibility that uncontrolled confounding influenced our findings.
In conclusion, our findings offer strong evidence that the children of 5-year cancer survivors are not at increased risk for congenital anomalies stemming from their parent's exposure to mutagenic cancer treatments. Whether humans have the capacity to repair damage to germ cell DNA or whether the various processes of reproduction filter out such insults (eg, through early pregnancy losses or infertility) merit exploration. It is nevertheless reassuring that potential damage is not manifesting as recognized, genetic disease in the offspring. Such information is important for counseling cancer survivors planning to have children.