Purpose: Preconception radiation and chemotherapy have the potential to produce germ cell mutations leading to genetic disease in the next generation. Dose-response relationships were evaluated between cancer treatments and untoward pregnancy outcomes. Patients and Methods: A case-cohort study was conducted involving 472 Danish survivors of childhood and adolescent cancer and their 1,037 pregnancies. Adverse outcomes included 159 congenital malformations, six chromosomal abnormalities, seven stillbirths, and nine neonatal deaths. Preconception radiation doses to the gonads, uterus, and pituitary gland and administered chemotherapy were quantified based on medical records and related to adverse outcomes using a generalized estimating equation model. Results: No statistically significant associations were found between genetic disease in children and parental treatment with alkylating drugs or preconception radiation doses to the testes in male and ovaries in female cancer survivors. Specifically, the risk of genetic disease was similar among the children of irradiated survivors when compared with nonirradiated survivors (relative risk [RR], 1.02; 95% CI, 0.59 to 1.44; P = .94). A statistically significant association between abdomino-pelvic irradiation and malformations, stillbirths, and neonatal deaths was not seen in the children of female survivors overall (P = .07) or in the children of mothers receiving high uterine doses (mean, 13.5 Gy; max, 100 Gy; RR, 2.3; 95% CI, 0.95 to 5.56). Conclusion: Mutagenic chemotherapy and radiotherapy doses to the gonads were not associated with genetic defects in children of cancer survivors. However, larger studies need to be conducted to further explore potential associations between high-dose pelvic irradiation and specific adverse pregnancy outcomes.

Survivors of childhood cancer are at increased risk for a wide range of late effects. However, no large population-based studies have included the whole range of somatic diagnoses including subgroup diagnoses and all main types of childhood cancers. Therefore, we aimed to provide the most detailed overview of the long-term risk of hospitalisation in survivors of childhood cancer. From the national cancer registers of Denmark, Finland, Iceland, and Sweden, we identified 21,297 5-year survivors of childhood cancer diagnosed with cancer before the age of 20 years in the periods 1943–2008 in Denmark, 1971–2008 in Finland, 1955–2008 in Iceland, and 1958–2008 in Sweden. We randomly selected 152,231 population comparison individuals matched by age, sex, year, and country (or municipality in Sweden) from the national population registers. Using a cohort design, study participants were followed in the national hospital registers in Denmark, 1977–2010; Finland, 1975–2012; Iceland, 1999–2008; and Sweden, 1968–2009. Disease-specific hospitalisation rates in survivors and comparison individuals were used to calculate survivors’ standardised hospitalisation rate ratios (RRs), absolute excess risks (AERs), and standardised bed day ratios (SBDRs) based on length of stay in hospital. We adjusted for sex, age, and year by indirect standardisation. During 336,554 person-years of follow-up (mean: 16 years; range: 0–42 years), childhood cancer survivors experienced 21,325 first hospitalisations for diseases in one or more of 120 disease categories (cancer recurrence not included), when 10,999 were expected, yielding an overall RR of 1.94 (95% confidence interval [95% CI] 1.91–1.97). The AER was 3,068 (2,980–3,156) per 100,000 person-years, meaning that for each additional year of follow-up, an average of 3 of 100 survivors were hospitalised for a new excess disease beyond the background rates. Approximately 50% of the excess hospitalisations were for diseases of the nervous system (19.1% of all excess hospitalisations), endocrine system (11.1%), digestive organs (10.5%), and respiratory system (10.0%). Survivors of all types of childhood cancer were at increased, persistent risk for subsequent hospitalisation, the highest risks being those of survivors of neuroblastoma (RR: 2.6 [2.4–2.8]; n = 876), hepatic tumours (RR: 2.5 [2.0–3.1]; n = 92), central nervous system tumours (RR: 2.4 [2.3–2.5]; n = 6,175), and Hodgkin lymphoma (RR: 2.4 [2.3–2.5]; n = 2,027). Survivors spent on average five times as many days in hospital as comparison individuals (SBDR: 4.96 [4.94–4.98]; n = 422,218). The analyses of bed days in hospital included new primary cancers and recurrences. Of the total 422,218 days survivors spent in hospital, 47% (197,596 bed days) were for new primary cancers and recurrences. Our study is likely to underestimate the absolute overall disease burden experienced by survivors, as less severe late effects are missed if they are treated sufficiently in the outpatient setting or in the primary health care system. Childhood cancer survivors were at increased long-term risk for diseases requiring inpatient treatment even decades after their initial cancer. Health care providers who do not work in the area of late effects, especially those in primary health care, should be aware of this highly challenged group of patients in order to avoid or postpone hospitalisations by prevention, early detection, and appropriate treatments.

Purpose: Radiation induces germ-cell mutations in experimental animals that result in adverse pregnancy outcomes, as does uterine damage caused by high-dose radiotherapy. We assessed the risks for spontaneous abortion and stillbirths among cancer survivors who received radiotherapy and subsequently became pregnant. Patients and Methods: We identified 1,688 female survivors of childhood cancer in the Danish Cancer Registry. Radiation doses to the ovary and uterus were characterized as high to low. The pregnancy outcomes of survivors, 2,737 sisters, and 16,700 comparison women in the population were identified from nationwide registries. The proportions of pregnancies among survivors that resulted in a livebirth, stillbirth, or abortion were compared with the equivalent proportions among the two comparison groups, and proportion ratios (PRs) were computed with sisters as referent. Results: More than 34,000 pregnancies were evaluated, 1,479 of which were among cancer survivors. No significant differences were seen between survivors and comparison women in the proportions of livebirths, stillbirths, or all types of abortions combined. Survivors, however, had a 23% excess risk for spontaneous abortion (PR, 1.23; 95% CI, 1.0 to 1.5), related primarily to prior radiation treatments (PR, 1.58; 95% CI, 1.2 to 2.2) and especially high-dose radiotherapy to the ovaries and uterus (PR, 2.8; 95% CI, 1.7 to 4.7). Conclusion: The pregnancy outcomes of survivors were similar to those of comparison women. A slight excess risk for spontaneous abortion may have resulted from uterine damage after high-dose pelvic radiotherapy, consistent with previous studies, although radiation-induced germinal mutations or decreased hypothalamic-pituitary-ovarian function could not be ruled out.