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