Child development at 6 years after maternal cancer diagnosis and treatment during pregnancy

Tineke Vandenbroucke, Magali Verheecke, Mathilde van Gerwen, Kristel Van Calsteren, Michael J Halaska, Monica Fumagalli, Robert Fruscio, Amarendra Gandhi, Margreet Veening, Lieven Lagae, Petronella B Ottevanger, Jens-Uwe Voigt, Jorine de Haan, Mina M Gziri, Charlotte Maggen, Luc Mertens, Gunnar Naulaers, Laurence Claes, Frédéric Amant, International Network on Cancer, Infertility and Pregnancy (INCIP), Jeroen Blommaert, Jana Dekrem, Frederic Goffin, Vincent Rigo, Camilla Fontana, Fabio Mosca, Sofia Passera, Odoardo Picciolini, Giovanna Scarfone, Fedro Alessandro Peccatori, Maria Lucia Boffi, Martina Delle Marchette, Renata Nacinovich, Christianne Lok, Vera Wolters, Ingrid Boere, Els Witteveen, Carolina Schröder, Christianne de Groot, Martine van Grotel, Marry van den Heuvel-Eibrink, Anna Babkova, Vít Drochýtek, Tineke Vandenbroucke, Magali Verheecke, Mathilde van Gerwen, Kristel Van Calsteren, Michael J Halaska, Monica Fumagalli, Robert Fruscio, Amarendra Gandhi, Margreet Veening, Lieven Lagae, Petronella B Ottevanger, Jens-Uwe Voigt, Jorine de Haan, Mina M Gziri, Charlotte Maggen, Luc Mertens, Gunnar Naulaers, Laurence Claes, Frédéric Amant, International Network on Cancer, Infertility and Pregnancy (INCIP), Jeroen Blommaert, Jana Dekrem, Frederic Goffin, Vincent Rigo, Camilla Fontana, Fabio Mosca, Sofia Passera, Odoardo Picciolini, Giovanna Scarfone, Fedro Alessandro Peccatori, Maria Lucia Boffi, Martina Delle Marchette, Renata Nacinovich, Christianne Lok, Vera Wolters, Ingrid Boere, Els Witteveen, Carolina Schröder, Christianne de Groot, Martine van Grotel, Marry van den Heuvel-Eibrink, Anna Babkova, Vít Drochýtek

Abstract

Background: Data on the long-term effects of prenatal exposure to maternal cancer and its treatment on child development are scarce.

Methods: In a multicenter cohort study, the neurologic and cardiac outcomes of 6-year-old children born to women diagnosed with cancer during pregnancy were compared with the outcome of children born after an uncomplicated pregnancy. Assessment included clinical evaluation, comprehensive neuropsychological testing, electrocardiography and echocardiography.

Results: In total, 132 study children and 132 controls were included. In the study group, 97 children (73.5%) were prenatally exposed to chemotherapy (alone or in combination with other treatments), 14 (10.6%) to radiotherapy (alone or in combination), 1 (0.8%) to trastuzumab, 12 (9.1%) to surgery alone and 16 (12.1%) to no treatment. Although within normal ranges, statistically significant differences were found in mean verbal IQ and visuospatial long-term memory, with lower scores in the study versus control group (98.1, 95% confidence interval [CI]: 94.5-101.8, versus 104.4, 95% CI: 100.4-108.4, P = 0.001, Q < 0.001 [Q refers to the false discovery rate adjusted P value], and 3.9, 95% CI: 3.6-4.3, versus 4.5, 95% CI: 4.1-4.9, P = 0.005, Q = 0.045, respectively). A significant difference in diastolic blood pressure was found, with higher values in chemotherapy-exposed (61.1, 95% CI: 59.0 to 63.2) versus control children (56.0, 95% CI 54.1 to 57.8) (P < 0.001, Q < 0.001) and in a subgroup of 59 anthracycline-exposed (61.8, 95% CI: 59.3 to 64.4) versus control children (55.9, 95% CI: 53.6 to 58.1) (P < 0.001, Q = 0.02).

Conclusions: Children prenatally exposed to maternal cancer and its treatment are at risk for lower verbal IQ and visuospatial long-term memory scores and for higher diastolic blood pressure, but other cognitive functions and cardiac outcomes were normal at the age of 6 years.

Clinical trial registration: The study is registered at ClinicalTrials.gov, NCT00330447.

Keywords: Antineoplastic agents; Child development; Follow-up studies; High risk; Infant; Pregnancy; Prenatal exposure delayed effects.

Conflict of interest statement

Conflict of interest statement None declared.

Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1
Fig. 1
Study design and recruitment. This cohort of 132 children evaluated at the age of 6 years includes 83 children who underwent cognitive evaluation and 28 children who underwent cardiac examinations in our previously published 1.5–3 years cohort study [6]. The results of 12 children at the age of 6 years were previously published [5], whereas 120 children underwent new testing. Longitudinal analyses will be performed when we reach our sample size in the oldest age group.
Fig. 2
Fig. 2
Cognitive outcome. (A) Comparison of the mean full scale IQ, verbal IQ, performance IQ and processing speed between the chemotherapy-exposed group and the control group. The mean of standardised IQ-scores is 100 with a standard deviation of 15 and scores between 90 and 110 are considered average. Higher scores indicate more advanced development. (B) The relation between full scale IQ and gestational age at birth (in weeks) for the chemotherapy-exposed and control group. Values of children from the chemotherapy-exposed group are represented by circles, and those of children from the control group are represented by crosses. Mean values (as calculated by linear regression) are indicated by a solid line for the chemotherapy-exposed group and a dashed line for the control group. (C) The relation between full scale IQ and the number of chemotherapy cycles administered during pregnancy. (D) Comparison of the raw memory scores from the subtests of the Children's Memory Scale between the chemotherapy-exposed group and the control group. Verbal memory was measured using the subtest numbers (range of scores between 0 and 14 for numbers forward [verbal memory span] and 0–12 for numbers backward [verbal working memory]). Visuospatial short- and long-term memory was measured using the subtest dot locations (range: 0–6). Visuospatial memory span was measured using the subtest picture locations (range: 0–30). Higher scores indicate more advanced memory skills. (E) Comparison of the standardised T-scores for internalising and externalising behaviour problems on the Child Behavior Checklist between the chemotherapy-exposed group and the control group. The mean of standardised T-scores is 50 with a standard deviation of 15. Higher scores indicate more behaviour problems. (A), (D), (E): The figures show estimated marginal means with standard errors of the means for each group and variable. Raw P values and false discovery rate adjusted P values (Q values) are presented.
Fig. 2
Fig. 2
Cognitive outcome. (A) Comparison of the mean full scale IQ, verbal IQ, performance IQ and processing speed between the chemotherapy-exposed group and the control group. The mean of standardised IQ-scores is 100 with a standard deviation of 15 and scores between 90 and 110 are considered average. Higher scores indicate more advanced development. (B) The relation between full scale IQ and gestational age at birth (in weeks) for the chemotherapy-exposed and control group. Values of children from the chemotherapy-exposed group are represented by circles, and those of children from the control group are represented by crosses. Mean values (as calculated by linear regression) are indicated by a solid line for the chemotherapy-exposed group and a dashed line for the control group. (C) The relation between full scale IQ and the number of chemotherapy cycles administered during pregnancy. (D) Comparison of the raw memory scores from the subtests of the Children's Memory Scale between the chemotherapy-exposed group and the control group. Verbal memory was measured using the subtest numbers (range of scores between 0 and 14 for numbers forward [verbal memory span] and 0–12 for numbers backward [verbal working memory]). Visuospatial short- and long-term memory was measured using the subtest dot locations (range: 0–6). Visuospatial memory span was measured using the subtest picture locations (range: 0–30). Higher scores indicate more advanced memory skills. (E) Comparison of the standardised T-scores for internalising and externalising behaviour problems on the Child Behavior Checklist between the chemotherapy-exposed group and the control group. The mean of standardised T-scores is 50 with a standard deviation of 15. Higher scores indicate more behaviour problems. (A), (D), (E): The figures show estimated marginal means with standard errors of the means for each group and variable. Raw P values and false discovery rate adjusted P values (Q values) are presented.

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