Abstract
BackgroundThis study applies multimodal MRI to investigate neurodevelopment in nine-year-old children born to cancer-complicated pregnancies.MethodsIn this cohort study, children born after cancer-complicated pregnancies were recruited alongside 1:1 matched controls regarding age, sex and gestational age at birth (GA). Multimodal MRI was used to investigate whole-brain and subcortical volume, cortical structure (using surface-based morphometry), white matter microstructure (using fixel-based analysis) and functional connectivity (using resting-state blood-oxygen-level-dependant signal correlations). Graph theory probed whole-brain structural and functional organization. For each imaging outcome we conducted two group comparisons: 1) children born after cancer-complicated pregnancies versus matched controls, and 2) the subgroup of children with prenatal chemotherapy exposure versus matched controls. In both models, we used the covariate of GA and the group-by-GA interaction, using false-discovery-rate (FDR) or family-wise-error (FWE) correction for multiple comparisons. Exploratory post-hoc analyses investigated the relation between brain structure/function, neuropsychological outcome and maternal oncological/obstetrical history.FindingsForty-two children born after cancer-complicated pregnancies were included in this study, with 30 prenatally exposed to chemotherapy. Brain organization and functional connectivity were not significantly different between groups. Both cancer and chemotherapy in pregnancy, as compared to matched controls, were associated with a lower travel depth, indicating less pronounced gyrification, in the left superior temporal gyrus (pFDR ≤ 006), with post-hoc analysis indicating platinum derivatives during pregnancy as a potential risk factor (p = .028). Both cancer and chemotherapy in pregnancy were related to a lower fibre cross-section (FCS) and lower fibre density and cross-section (FDC) in the posterior corpus callosum and its tapetal fibres, compared to controls. Higher FDC in the chemotherapy subgroup and higher FCS in the whole study group were observed in the anterior thalamic radiations. None of the psycho-behavioural parameters correlated significantly with any of the brain differences in the study group or chemotherapy subgroup.InterpretationPrenatal exposure to maternal cancer and its treatment might affect local grey and white matter structure, but not functional connectivity or global organization. While platinum-based therapy was identified as a potential risk factor, this was not the case for chemotherapy in general.FundingThis project has received funding from the European Union's Horizon 2020 research and innovation program (European Research council, grant no 647,047), the Foundation against cancer (Stichting tegen kanker, grant no. 2014–152) and the Research Foundation Flanders (FWO, grants no. 11B9919N, 12ZV420N)
Highlights
Cancer complicates about one in 1000 pregnancies [1]
In the regions where we observed significantly lower Fibre Density and Cross-section (FDC) in prenatally chemotherapy exposed children compared to matched controls (Fig. 2:D), the FDC was less reduced for anthracyclines, compared to other chemotherapeutic agents (p = .048,U = 40, Fig. 3:B). This is the first study applying multimodal magnetic resonance imaging (MRI) to assess brain structure and function in children born of cancer-complicated pregnancies
We found macro- and microstructural differences within the white matter (WM) and grey matter (GM) between children born to women with cancer compared to matched controls, but no significant differences in functional connectivity or whole-brain organization were observed
Summary
Cancer complicates about one in 1000 pregnancies [1]. This diagnosis unavoidably leads to difficult medical and ethical decisions [2]. For each imaging outcome we conducted two group comparisons: 1) children born after cancer-complicated pregnancies versus matched controls, and 2) the subgroup of children with prenatal chemotherapy exposure versus matched controls. In both models, we used the covariate of GA and the group-byGA interaction, using false-discovery-rate (FDR) or family-wise-error (FWE) correction for multiple comparisons. Brain organization and functional connectivity were not significantly different between groups Both cancer and chemotherapy in pregnancy, as compared to matched controls, were associated with a lower travel depth, indicating less pronounced gyrification, in the left superior temporal gyrus (pFDR 006), with post-hoc analysis indicating platinum derivatives during pregnancy as a potential risk factor (p = .028).
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