The impact of cancer and chemotherapy during pregnancy on child neurodevelopment: A multimodal neuroimaging analysis

Abstract

Background This study applies multimodal MRI to investigate neurodevelopment in nine-year-old children born to cancer-complicated pregnancies. Methods In 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. Findings Forty-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 (p FDR ≤ 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. Interpretation Prenatal 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. Funding This 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 Flander...

Long-Term Neurodevelopmental Outcome of Children after in Utero Exposure to Chemotherapy

“…A summary of the studies describing the type of maternal cancer and the chemotherapy schemes administered during pregnancy while evaluating the neurodevelopmental outcome of children in utero exposed to chemotherapy is demonstrated in Tables 1 and 2. [16] Acute leukemia (7) Non-Hodgkin's lymphoma (18) Hodgkin's lymphoma (14 Acute leukemia (14) Non-Hodgkin's lymphoma (25) Hodgkin's lymphoma (19) COPA (6 Breast cancer (26) Ovarian cancer (4) Hodgkin's lymphoma (4) Acute leukemia (1) [27] and Van Gerwen et al, 2020 [28] Breast cancer (69) Hematological malignancy (20) Cervical cancer 10Ovarian cancer (10) Brain cancer (4) Oral cavity and oropharyngeal cavity cancer 4Nasopharyngeal cancer (1) Gastric cancer 2Colon cancer 1Melanoma 2 Breast cancer and hematological cancer (e.g., acute leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma) were the most frequently diagnosed malignancies during gestation [13][14][15][16][17][18][19][20][21][22][23][25][26][27][28][29]. Additionally, several cases of cervical, ovarian, brain and gastric cancer were also reported [13,14,[20][21][22]24,[26][27][28][29...…”

“…Additionally, several cases of cervical, ovarian, brain and gastric cancer were also reported [13,14,[20][21][22]24,[26][27][28][29]. Some studies focused on a single type of pregnancy-related cancer analyzing its treatment along with the maternal and the fetal outcomes [15][16][17][18][23][24][25], whereas other studies integrated data regarding multiple cancer types, as shown in Table 1 [13,14,[20][21][22][26][27][28][29]. Furthermore, various chemotherapy regimens were administered during the course of pregnancy, depending on the type of maternal cancer diagnosed; a combination of anthracycline-based regimens was most commonly used [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28].…”

“…Some studies focused on a single type of pregnancy-related cancer analyzing its treatment along with the maternal and the fetal outcomes [15][16][17][18][23][24][25], whereas other studies integrated data regarding multiple cancer types, as shown in Table 1 [13,14,[20][21][22][26][27][28][29]. Furthermore, various chemotherapy regimens were administered during the course of pregnancy, depending on the type of maternal cancer diagnosed; a combination of anthracycline-based regimens was most commonly used [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. Cyclophosphamide, 5-fluorouracil, taxanes, and platinum derivatives were also regularly administered [13][14][15][16][17][18][19][20][21][22][23][24][2...…”

“…Furthermore, various chemotherapy regimens were administered during the course of pregnancy, depending on the type of maternal cancer diagnosed; a combination of anthracycline-based regimens was most commonly used [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. Cyclophosphamide, 5-fluorouracil, taxanes, and platinum derivatives were also regularly administered [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. In the majority of the studies included in the review, the antineoplastic agents were administered in the second and third trimester of pregnancy [13,14,[20][21][22][23][24][25][26][27][28][29]; however, in all studies mainly investigating hematological malignancies, chemotherapy was administered in the first trimester as well [15]…”

“…Cyclophosphamide, 5-fluorouracil, taxanes, and platinum derivatives were also regularly administered [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. In the majority of the studies included in the review, the antineoplastic agents were administered in the second and third trimester of pregnancy [13,14,[20][21][22][23][24][25][26][27][28][29]; however, in all studies mainly investigating hematological malignancies, chemotherapy was administered in the first trimester as well [15][16][17][18][19].…”