Stillbirth and neonatal death in relation to radiation exposure before conception: a retrospective cohort study.

BACKGROUND: The reproductive implications of mutagenic treatments given to children with cancer are not clear. By studying the risk of untoward pregnancy outcomes, we indirectly assessed the risk of transmission of germline damage to the offspring of survivors of childhood cancer who were given radiotherapy and chemotherapy.

METHODS: We did a retrospective cohort analysis, within the Childhood Cancer Survivor Study (CCSS), of the risk of stillbirth and neonatal death among the offspring of men and women who had survived childhood cancer. Patients in CCSS were younger than 21 years at initial diagnosis of an eligible cancer, were treated at 25 US institutions and one Canadian institution, and had survived for at least 5 years after diagnosis. We quantified the chemotherapy given to patients, and the preconception radiation doses to the testes, ovaries, uterus, and pituitary gland, and related these to the risk of stillbirth or neonatal death using Poisson regression analysis.

FINDINGS: Among 1148 men and 1657 women who had survived childhood cancer, there were 4946 pregnancies. Irradiation of the testes (16 [1%] of 1270; adjusted relative risk 0.8 [95% CI 0.4-1.6]; mean dose 0.53 Gy [SD 1.40]) and pituitary gland (17 [3%] of 510, 1.1 [0.5-2.4] for more than 20.00 Gy; mean dose 10.20 Gy [13.0] for women), and chemotherapy with alkylating drugs (26 [2%] of 1195 women, 0.9 [0.5-1.5]; ten [1%] of 732 men, 1.2 [0.5-2.5]) were not associated with an increased risk of stillbirth or neonatal death. Uterine and ovarian irradiation significantly increased risk of stillbirth and neonatal death at doses greater than 10.00 Gy (five [18%] of 28, 9.1 [3.4-24.6]). For girls treated before menarche, irradiation of the uterus and ovaries at doses as low as 1.00-2.49 Gy significantly increased the risk of stillbirth or neonatal death (three [4%] of 69, 4.7 [1.2-19.0]).

INTERPRETATION: Our findings do not support concern about heritable genetic changes affecting the risk of stillbirth and neonatal death in the offspring of men exposed to gonadal irradiation. However, uterine and ovarian irradiation had serious adverse effects on the offspring that were probably related to uterine damage. Careful management is warranted of pregnancies in women given high doses of pelvic irradiation before puberty.

FUNDING: Westlakes Research Institute, National Cancer Institute, and Children's Cancer Research Fund.