Main findings
In the largest U.S. cohort of births to female AYA cancer survivors to date, this study shows modestly increased risks of preterm birth and severe maternal morbidity in singleton births to AYA cancer survivors compared to those births to females without cancer, findings which support overall reassuring maternal and offspring outcomes of pregnancies after cancer. AYA cancer survivors had more comorbidities before and during pregnancy. As results suggest that approximately 30% of preterm birth and SMM may be due to maternal comorbidities, the findings shed light on the potential mechanisms through which these adverse perinatal outcomes occur and demonstrate a heightened need for clinical screening and prevention of comorbidities before and during pregnancy in reproductive-aged cancer survivors.
Assessment of comorbidities prior to and during pregnancy in this study provided new information on perinatal risks after cancer and is important because these conditions are determinants of SMM and mortality.37 Nearly all maternal comorbidities before and during pregnancy occurred more frequently in AYA cancer survivors than females without cancer, including cardiopulmonary and renal diseases that are known late effects of some cancer treatments.14 Indeed, we observed that prior chemotherapy (but not radiation) was significantly associated with higher comorbidity index (data not shown). Because mediation analysis suggests that maternal comorbidities are in the pathway between prior cancer and preterm births, the clinical implication of our work is the need for fidelity to preconception and prenatal surveillance (e.g., for hypertension38 and renal disease39) and/or interventions (e.g., aspirin for pre-eclampsia prevention40) in AYA cancer survivors.
Severe maternal morbidity, which comprises life-threatening labor and delivery outcomes that result in significant short- or long-term consequences to a female’s health, occurred at a 1.4-fold higher frequency in births to AYA cancer survivors than those to females without cancer. The single additional report on SMM in childhood and adolescent cancer survivors and matched females without cancer from the Ontario cancer and obstetrical registries, observed a relative risk of 2.3 (95% CI 1.5-3.6).41 Beyond this, little is known about the incidence of this CDC-defined composite maternal outcome in AYA cancer survivors, but increased risks in AYA cancer survivors is consistent with the attribution of rising rates of SMM in the U.S. to increasing incidence of chronic diseases in females.42Because absolute rates are low, we are limited in further delineation of cancer treatment-related risks of severe maternal morbidity, which will require pooling large datasets such as the one used in the current study.
Our observation of increased preterm birth risk is consistent with but of a lower magnitude than prior studies in female childhood and AYA cancer survivors. In a meta-analysis of cohorts from Europe, Australia and the U.S.,8 preterm birth rates globally are highly variable, supporting generating evidence by geographic population. We compare our findings to the two other population-based U.S. cohorts. Linked North Carolina cancer registry and birth certificate data showed a prevalence ratio of 1.52 (95% CI 1.34-1.71) comparing 2,598 singleton births to AYA cancer survivors with 12,990 singleton births to women without cancer, while linked Massachusetts cancer registry and vital records showed a relative risk of 1.2 (95% CI 1.07-1.32) comparing nearly 3,000 births to cancer survivors of unspecified diagnosis age to births in females without cancer.11
As expected, multiple births resulted in significantly higher risks of adverse perinatal outcomes, but this was not different by cancer status. While ART use did not modify the association between AYA cancer and adverse perinatal outcomes, ART was a significant contributor to multiple births. As ART techniques improve over time, guideline-based clinical practice43 needs to continue to improve on single embryo transfers to decrease the known complications of multiple birth.44