) have examined associations between paternal cancer history and subsequent pregnancy complications among female partners and outcomes among offspring outside of malformations or cancer. In this study of a relatively contemporary cohort of male childhood cancer survivors, partners and progeny of cancer survivors were not at increased risk of most complications examined. However, we did observe an increased risk of low birth weight and preeclampsia associated with some treatment characteristics.
Based on self-reported outcomes of more than 1500 live births, the North American Childhood Cancer Survivor Study reported a 3-fold increased risk of low birth weight progeny among male childhood survivors treated with nonalkylating chemotherapy compared with siblings(14
). Risk estimates associated with pelvic radiation and alkylating chemotherapy (RR 1.5−1.6) were not significantly increased, but were similar in magnitude to ours. Gestational age was not examined in this study. A registry-based study examining several hundred Norwegian male cancer survivors diagnosed between 15 to 35 years of age did not report an increased risk of low birth weight progeny(15
). However, given that our estimates were greatest for males diagnosed <15 years of age, differences in the study populations and their exposures may account for this discrepancy. Nevertheless, in neither study was there a consistent risk of progeny being delivered preterm.
Both maternal and paternal contributions to birth weight have been reported in the general population. Parents who were themselves low birth weight infants tend to give birth to low birth weight infants independent of environmental factors(16
). Although we did not know parental birth weights, there is no reason to suspect that male cancer survivors or their partners would more likely have been low birth weight infants themselves. Aside from hepatoblastoma (there were no cases in this study), low birth weight has not been associated consistently with an increased risk of childhood cancers(18
). Additional maternal demographic and environmental factors associated with low birth weight include nulliparity, very young or older maternal age, prior low birth weight infant, lower socioeconomic status, and substance use including tobacco exposure(19
). We attempted to adjust for many of these factors, but it is possible residual confounding exists as childhood cancer survivors, particularly central nervous system tumor patients, are more likely to be unmarried(20
) and unemployed(21
), though less likely to smoke(22
). Nevertheless, it is interesting that risk was increased after exposure to chemotherapy and radiotherapy, but not to surgery alone. Compared with maternal associations, any paternal influence on infant birth weight is more likely to be genetic rather than environmental(17
). There is evidence that the imprinting of fetal genes can affect fetal growth and adult health(24
), although there is no evidence that prior cancer therapy in the father affects imprinting of germ line cells, particularly as epigenetic therapies would not have been widely used during the study period.
It is unclear why preeclampsia was associated with central nervous system tumors, and to a lesser degree, leukemias. Although we examined maternal factors that can be associated with preeclampsia in our analysis such as age, nulliparity, and diabetes, it is possible these findings could still reflect residual confounding, or be due to chance. Prior studies generally have not examined preeclampsia among partners of male cancer survivors. One study of male hematopoietic cell transplant survivors found that 6% of partners (n=4) experienced preeclampsia(25
), similar to the prevalence in our study but also within estimated population rates(26
). A paternal contribution to preeclampsia has been reported in the general population, suggesting that paternally-derived fetal genes are involved in pathogenesis(27
). The mechanism by which paternal genes affect preeclampsia is unclear, although a role for paternally imprinted alleles also has been hypothesized(27
). However, as with low birth weight, it is unclear if cancer therapy affects germ line imprinting. Although loss of imprinting is an increasingly recognized phenomena among pediatric and adult cancers, these changes typically are restricted to tumor cells with the exception of certain rare cancer predisposition syndromes(29
Previous studies have investigated possible mutagenic effects of cancer therapy on germ cells as manifested by an altered male:female progeny sex ratio, malformations, and miscarriages or stillbirths. In our study, the male:female progeny sex ratio was slightly greater among survivors (1.09) compared with comparison subjects (1.04), and greatest among those with pelvic tumors and those exposed to any chemotherapy or radiotherapy (range 1.16−1.23). In comparison, over the past 50 years the U.S. ratio has been around 1.05(30
). Although our estimates did not reach statistical significance, this pattern supports the hypothesis that mutagenic therapies could result in an increased male:female progeny ratio among treated fathers due to dominant lethal X-chromosome mutations. However, male:female sex ratios have not been increased in other studies of male childhood cancer survivors(6
) and even significantly decreased in one(14
Most studies, including ours, have not reported increased risks of malformations (reviewed in Ref(32
)), although our use of birth registry data may under-ascertain more subtle defects not diagnosed at birth. One birth registry study did report a 50% increased risk of malformations among progeny of adolescent and young adult male cancer survivors compared with the general population(15
). An increased risk of miscarriage or stillbirths among partners of male cancer survivors(14
) also suggests the possibility that mutagenic exposures may affect viability of future offspring.
Our study has several limitations. Although SEER audits have shown that case ascertainment exceeds 95% and that tumor characteristics(33
) and broad treatment categories (e.g. chemotherapy, radiotherapy, and surgery) are accurately recorded(34
), our data were limited to initial cancer treatment. Information about treatment for relapse was not available and therefore our estimates for treatment categories contain some misclassification. The effects of this are difficult to predict as chemotherapy, radiotherapy, and surgery are all used for salvage treatments, but patients likely received more multi-modal therapy than shown.
Although >99% of births in the US are captured on birth records(35
), birth records have some limitations. Generally, paternal characteristics are not as thoroughly recorded as maternal characteristics, particularly if parents are unmarried(35
). As male cancer survivors were less likely to be currently married than comparison subjects, this may in part explain why the percentage of cancer survivors identified as fathers (6.7%) was lower than in other studies, although birth registries do attempt to record paternal information even if the couple is unmarried. Migration to other states would also decrease our cancer-birth registry linkages. However, at least for recent years, U.S. Census surveys report <3% of people who move, move out-of-state, and concern regarding health is rarely cited as the primary reason for moving(36
). Furthermore, migration would have affected our outcomes only if cases who moved out-of-state differed from those who remained, information we did not have access to. Finally, as the median age of survivors in this cohort was only 25 years, many survivors also are just entering reproductive age.
Nevertheless, for successful linkages, birth record characteristics such as gravidity/parity, delivery method, infant gender, birth weight, and gestational age are recorded accurately with sensitivity/specificity typically >95% when compared with medical records(37
). However, although the specificity of maternal comorbidities such as diabetes, preeclampsia, anemia, and tobacco exposure is typically high, sensitivity can be much more variable(37
). Overall, there is no reason to suspect that partners of male cancer survivors would have birth record data recorded differently than others; birth records should not be susceptible to response or recall biases.
Misattributed paternity may also be present within our population. Although one may hypothesize that use of donor sperm may be more prevalent among cancer survivors, there is little information about its prevalence and we did not have any data on use of assisted reproductive techniques. Furthermore, the direction of any bias arising from misattributed paternity is difficult to predict. Among the general population, non-paternity rates have varied greatly across populations and have been associated with different demographic factors in various studies(39
Lastly, differences may exist between this cohort and the overall population of male childhood cancer cases. Despite follow-up of up to 28 years, our study, like many other studies of childhood illnesses that attempt to examine outcomes in adulthood, our subjects include more individuals who were diagnosed in earlier time periods and who were older at diagnosis. Cancers with increased reproductive morbidity and mortality also would be less represented in any survivor cohort. Nevertheless, for male survivors identified as fathers in state birth records, the vast majority of associated pregnancies resulting in live births were not at significantly greater risk of complications versus comparison subjects. However, our finding of increased low birth weight and preeclampsia associated with some diagnostic groups raise the possibility that prior cancer therapy may affect male germ cells with effects on female partners and progeny of male survivors.