Effects of prenatal exposure to cancer treatment on neurocognitive development: an MRI and ERP study

About 1 in 1000 pregnancies is complicated by maternal cancer, a diagnosis which confronts families and caregivers with difficult medical and ethical decisions, with potential long-lasting consequences for both mother and child. While studies have indicated reassuring outcomes for the child after different therapies during pregnancy, subtle differences in birthweight, cardiac functioning and neuropsychological outcome have raised questions on the long-term effects of prenatal exposure to maternal cancer and its treatment. The main aim of this thesis is to provide solid data on the long-term effects of prenatal exposure to cancer and its treatment on neurocognitive development, with particular focus on the use of chemotherapy during pregnancy. Furthermore, we want to explore which treatment-related and secondary factors might play a role in the observed neurodevelopmental effects. For instance, many children are born preterm after cancer-complicated pregnancies, which has been associated with lower IQ scores and an increased risk of behavioral and neurocognitive problems. Advanced multimodal neuroimaging techniques, measuring different functional and structural characteristics of the brain, are used to investigate the multifaceted nature of neurodevelopment in these children. This information is then combined with data on mother and child from the International Network on Cancer, Infertility and Pregnancy (INCIP) registration and follow-up studies, in order to relate neuroimaging findings to the oncological and obstetrical history, as well as to the neuropsychological outcome. First, we investigated the impact of chemotherapy on brain volume in a longitudinal cohort of 121 young and older, non-pregnant, women with breast cancer, of whom 72 treated with chemotherapy, alongside 59 controls. We observed age-dependent cognitive decline and white matter volume expansion, potentially caused by chemotherapy-induced neuroinflammatory processes, with younger patients showing less cognitive decline and more white matter volume increase. These results suggest the younger brain to have a neuroprotective response to chemotherapy-induced neurotoxicity. Next, we applied event-related potentials to evaluate the development of executive functioning in 20 nine-year-old children who were prenatally exposed to chemotherapy, comparing with controls who where matched on a 1:1 ratio based on age, sex and gestational age at birth. We found children with prenatal chemotherapy exposure to have an impacted development of response inhibition and spatial attention. Moreover, both prenatal chemotherapy exposure and prematurity were found to affect neurocognitive processes of conflict monitoring. These findings indicate that cancer and/or chemotherapy during pregnancy might indeed impact neurodevelopment of the child, not limited to the effect of prematurity. Finally, multimodal MRI techniques were used to assess structural and functional brain development of 42 children born to cancer-complicated pregnancies, compared to matched controls. Cancer during pregnancy was associated with local differences in grey and white matter structure, but was not found to significantly affect functional connectivity or brain organization. While platinum derivatives showed an increased impact on gyrification of the left superior temporal gyrus, chemotherapy during pregnancy in general was not associated with a worse outcome. In summary, the work of this thesis describes a subtle impact of maternal cancer and its treatment on neurodevelopment of the child at the age of nine years. Although we, as well as others, observed the neurotoxic impact of chemotherapy in cancer patients, chemotherapy during pregnancy showed only a limited effect on the neurodevelopment of the child. Secondary mechanisms, such as the psychosocial impact of a cancer diagnosis during pregnancy, might have large contributions to the observed neurodevelopmental differences, and have to be explored in future research. Balancing the benefits of treating cancer during pregnancy against the subtle neurocognitive impact observed in this thesis, the current data favour cancer treatment during pregnancy, including chemotherapy, when clinically indicated.publisher: Elsevier articletitle: Effects of prenatal exposure to cancer treatment on neurocognitive development, a review journaltitle: NeuroToxicology articlelink: http://dx.doi.org/10.1016/j.neuro.2016.02.013 content_type: article copyright: © 2016 Elsevier B.V. All rights reserved.nrpages: 11status: publishe