Is there evidence of a therapy-related increase in germ cell mutation among childhood cancer survivors?

Few studies have examined human population data for evidence of an association between environmental mutagens and genetic disease. Our objective was to determine whether study of pregnancies and offspring of childhood cancer survivors would show evidence that therapy potentially mutagenic to germ cells is associated with increased risk of miscarriage, serious congenital abnormalities, or altered sex ratio. We analyzed information from patients' general practitioners for 2286 survivors of childhood cancer (1049 females and 1237 males) who were exposed or not exposed to direct irradiation of the abdomen or gonads or treatment with an alkylating agent. In addition, external control data based on the general population were used for some of the comparisons relating to congenital abnormalities and sex ratio. Data on reproductive history were complete for 1037 female survivors, who had 944 completed pregnancies, and 1078 male survivors, who produced 537 offspring. For the female survivors given abdominal or gonadal irradiation, there was an excess of miscarriages for the total number of pregnancies (17%) and for first pregnancies (19%), compared with the proportion for the total number of pregnancies in the females with similar neoplasms who were not exposed to such therapy (9%) and for first pregnancies in these females (8%). These results show re-emergence of an association suggested in our previous report of an increased risk of miscarriage as well as low birth weight among off-spring of female survivors of childhood cancer who received abdominal irradiation. In that study, it was considered unlikely that the association was due to germ cell mutation. Data in the present study do not show an association of exposure to therapy potentially mutagenic to germ cells with sex ratio, or with occurrence of serious congenital abnormalities in the offspring of male or female survivors of such therapy. However, the question of a possible germ cell mutagenic effect of therapy will be adequately addressed only through an international collaborative effort.