In this population-based study, 15% of female childhood cancer survivors and 43% of cervical/genital carcinoma cases identified within the registry in each region had a live birth recorded within the same state during the study period (up to 28 years of follow-up). The childhood cancer survivors we identified with subsequent live births differ somewhat from all childhood cancer cases diagnosed in the study regions in that they were more often older at diagnosis (likely at least in part because more of them were of childbearing age during the years of data linkage). Genital carcinoma cases with subsequent deliveries were generally similar to all patients with the same diagnosis in the registries. Out-of-state migration of cases after diagnosis may lead to underestimation of the true proportion of young cancer patients who delivered infants. However, a separate linkage of Washington State birth certificates indicated that 17% of all girls born in that state in 1966 had a subsequent live born delivery in Washington during the years 1987-2006 (data not shown). Although this latter linkage included only women aged 21-37 years old at delivery, it suggests that any possible loss-to-follow up because of out migration among childhood cancer cases is similar to the general population. Finally, many of our cases were treated decades ago, so it also is possible that childbearing rates in more recent cohorts are greater due to development of therapies more likely to conserve fertility, and increased assisted fertilization options for survivors.
Approximately 30% of 6494 female childhood cancer survivors in the Childhood Cancer Survivor Study reported they became pregnant after diagnosis[8
], and 47% of 719 childhood and adolescent cancer survivors at risk of pregnancy (still menstruating) reported becoming pregnant in a province-wide cohort study in Ontario[9
]. Although a majority (76%) of childless individuals with a history of childhood cancer report a desire to parent[1
], the birth rate of female childhood cancer survivors is significantly lower than that of sibling controls[8
]. Nevertheless, there remains limited information about the proportion of childhood cancer survivors who ultimately bear children, and thus the extent to which our linkage may have underestimated the true proportion is unclear.
Overall, our results may be reassuring to female childhood cancer patients who subsequently bear children. Although offspring may be more likely to be preterm or of low birth weight, we observed no increased risk of SGA, malformations, or infant death, and no altered male:female sex ratio that might indicate increased germ cell mutagenicity. Our results related to malformations[11
] and sex ratio[8
] are consistent with recent previous reports. Although C-section deliveries were slightly more common among childhood cancer survivors, they were not consistently so. Among cervical/genital carcinoma patients, the majority of whom are treated surgically, we primarily observed an increased risk of preterm delivery. In a prior study, preterm delivery was associated with conization[15
], treatment information unavailable to us.
Studies in different countries using various methodology also have reported an increased risk of preterm delivery and low birth weight among female childhood cancer survivors[9
]. An increased risk of low birth weight and prematurity may be partly due to decreased uterine volume as a result of pelvic radiation[17
]. However, our observation of increased prematurity and/or low birth weight among cancer types typically not treated with pelvic radiation (such as leukemia or brain tumors) and among patients treated with chemotherapy only suggest that other factors may also contribute. Nevertheless, despite increased low birth weight and/or preterm delivery, risk of having SGA offspring has not been observed in our study and in a prior study[17
], suggesting that the observed decreases in birth weight are not severe enough to meet SGA criteria.
To our knowledge, preeclampsia has not been evaluated before among childhood cancer survivors. It is reassuring that the only increased risk we observed was a borderline finding among those who received chemotherapy, surgery, and radiation for their initial treatment. Although this may be a chance finding, it is plausible that respiratory/circulatory compromise secondary to cancer treatment may predispose towards a hypertension-related disorder during pregnancy, especially with reports of increased levels of hypertension among some childhood cancer survivors[20
]. Our finding of a nearly 5-fold increased occurrence of diabetes among childhood bone cancer survivors is without precedent and should be further explored.
Our study has several limitations. We did not have information about in- or out-of-state migration of subjects. However, the proportion of individuals 1 year or older who move out-of-state, at least in recent years, is <3% annually[22
], and migration is unlikely to have affected our comparison of outcomes unless cases who moved out of state differed from those who remained. It is also possible that our comparison group contained women diagnosed with childhood cancer in other states who then migrated into a study region. The misclassification of cancer cases among the comparison group (if a history of cancer indeed increases the risk of an adverse pregnancy outcome) would have biased our results towards the null.
Our study also was limited because we lacked information about fetal loss or childbearing intent, and thus our findings are relevant to women who were able to have live births, and to the first birth recorded after diagnosis. One advantage of our study, however, is its population-based nature. SEER registries have demonstrated nearly complete case ascertainment[23
], and non-response was not an issue. We also were not restricted to children and adolescents involved in clinical trials, which exclude some individuals identified by registries[24
]. However, we did not have detailed information about initial cancer treatment and thus were unable to evaluate radiation field location or specific chemotherapy exposures. It may be possible, however, for prospective studies with detailed treatment information to obtain comprehensive data about pregnancy, delivery, and infant outcomes as case cohorts mature and enter their reproductive years. This would allow closer examination of the maternal and pregnancy characteristics we evaluated. We also did not have information about treatments used for cancer relapse, and therefore there is likely some misclassification of treatment categories. However, given that any of the modalities evaluated are used for recurrent disease, it is difficult to predict the direction of bias introduced by such misclassification.
Birth records have been shown to be fairly accurate, with >95% sensitivity and specificity compared to medical records for delivery method, gravidity/parity, birth weight and gestational age[25
]. However, the recording of maternal conditions such as diabetes may be less sensitive, albeit highly specific[26
]. Although birth records are not subject to biases associated with self-report, bias may still occur if differential levels of screening are employed for cancer survivors versus comparison subjects. Differential monitoring of women with a cancer history could have resulted in the increased identification of some prenatal conditions such as preeclampsia, gestational diabetes, anemia, as well as infant malformations. However, the vast majority of both survivors and comparison women initiated prenatal care prior to the third trimester, and we observed no increased risk of malformations. One could speculate that care providers might be more likely to use C-section deliveries for women with cancer histories as a precaution, resulting in the modest borderline increased RRs observed. Bias secondary to differential monitoring would not have influenced gestational age or birth weight measurements.
For children and adolescents with cancer, it is reassuring that we did not find an increased risk of malformations or infant death among their first subsequent offspring. The increased occurrence of low birth weight and preterm delivery among childhood cancer cases, and of preterm delivery among young cervical/genital carcinoma cases that we and others have observed may indicate relatively less severe potential problems among offspring. However, these outcomes can still impact families greatly, are associated with significantly increased costs[27
], and indicate a need for close monitoring of pregnancies among childhood and adolescent cancer survivors.