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Effects of in-utero exposure to chemotherapy on fetal brain growth
  1. Sofia Passera1,
  2. Valeria Contarino2,
  3. Giovanna Scarfone2,3,
  4. Elisa Scola2,
  5. Camilla Fontana1,
  6. Fedro Peccatori4,
  7. Claudia Cinnante2,
  8. Serena Counsell5,
  9. Maneula Ossola2,
  10. Silvia Pisoni6,
  11. Nicola Pesenti7,
  12. Elena Grossi2,3,
  13. Frédéric Amant8,9,
  14. Fabio Mosca10,
  15. Fabio Triulzi2,11 and
  16. Monica Fumagalli2,10
  1. 1NICU, Clinica Mangiagalli, Milan, Italy
  2. 2Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
  3. 3Department of Obstetrics and Gynecology, University of Milan, Milan, Italy
  4. 4Fertility and Procreation Unit, Gynecologic Oncology Programme, European Institute of Oncology, Milan, Italy
  5. 5Centre for the Developing Brain, School of Bioengineering and Imaging Sciences, Kings College, London, UK
  6. 6Neonatology Unit, Mother and Child Department, Del Ponte Hospital, Azienda Socio Sanitaria Territoriale (ASST) Sette Laghi, Varese, Italy
  7. 7Division of Biostatistics, Epidemiology and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
  8. 8Centre for Gynaecologic Oncology Amsterdam, Antoni van Leeuwenhoek—Netherlands Cancer Institute, and Amsterdam University Medical Centres, Amsterdam, The Netherlands
  9. 9Department of Oncology, Katholieke Universiteit Leuven, Loeven, Belgium
  10. 10Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
  11. 11Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
  1. Correspondence to Dr Camilla Fontana, NICU, Clinica Mangiagalli, Milan, Italy; camilla.fontana{at}mangiagalli.it

Abstract

Objective Children exposed to chemotherapy in the prenatal period demonstrate normal neurocognitive development at 3 years but concerns regarding fetal brain growth remain high considering its vulnerability to external stimuli. Our aim was to evaluate the impact of in-utero chemotherapy exposure on brain growth and its effects on neurodevelopmental outcome.

Methods The protocol was approved by the local ethics committee. Brain regional volumes at term postmenstrual age were measured by MRI in children exposed to in-utero chemotherapy and compared with normal MRI controls. Brain segmentation was performed by Advanced Normalization Tools (ANTs)-based transformations of the Neonatal Brain Atlas (ALBERT). Neurodevelopmental assessment (Bayley-III scales) was performed at 18 months corrected age in both exposed infants and in a group of healthy controls. Multiple linear regressions and false discovery rate correction for multiple comparisons were performed.

Results Twenty-one newborns prenatally exposed to chemotherapy (epirubicin administered in 81% of mothers) were enrolled in the study: the mean gestational age was 36.4±2.4 weeks and the mean birthweight was 2,753±622 g. Brain MRI was performed at mean postmenstrual age of 41.1±1.4 weeks. No statistically significant differences were identified between the children exposed to chemotherapy and controls in both the total (398±55 cm3 vs 427±56 cm3, respectively) and regional brain volumes. Exposed children showed normal Bayley-III scores (cognitive 110.2±14.5, language 99.1±11.3, and motor 102.6±7.3), and no significant correlation was identified between the brain volumes and neurodevelopmental outcome.

Conclusion Prenatal exposure to anthracycline/cyclophosphamide-based chemotherapy does not impact fetal brain growth, thus supporting the idea that oncological treatment in pregnant women seems to be feasible and safe for the fetus.

  • gynecology
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Footnotes

  • Contributors SP participated to the design of the work and she managed the enrollment of patients (newborns) and the neonatal data collection and she gave substantial contribution to the analysis and interpretation of data. She coordinated the communication between the different participants. She wrote the first draft of the paper, she gave final approval of the version published, and she ensured that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved. VC performed the volumetric analysis of the MRI scans. She wrote the first draft of the paper and she gave final approval of the version published ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved. GS participated in the enrollment of patients (mothers) at moment of cancer diagnosis and was involved in the management of maternal treatment. She gave substantial contributions to the analysis and interpretation of data, especially those regarding the maternal therapy. She revised the work with important intellectual content, giving final approval of the version published. ES performed and assessed the MRI scans. She gave technical support to Contarino V regarding the volumetric analysis. She gave substantial contributions to the analysis and interpretation of data, especially those regarding brain morphometry. She revised the work with important intellectual content, giving final approval of the version published. CF participated in enrollment of patients (newborns) and performed the neurodevelopment assessments. She gave substantial contributions to the analysis and interpretation of data, especially those regarding the follow-up of the children. She revised the work with important intellectual content, giving final approval of the version published. FP contributed to the design of the clinical protocol. He participated in the management of maternal treatment. He gave substantial contributions to the analysis and interpretation of data, especially those regarding the maternal therapy. He revised the work with important intellectual content, giving final approval of the version published. CC performed and assessed the MRI scans. She revised the work with important intellectual content, giving final approval of the version published. SC participated in finalizing the setting-up of the tools to perform the volumetric analysis. She revised the work critically for important intellectual content and she gave final approval of the version published, ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved. MO participated in the management of maternal treatment. She revised the work with important intellectual content, giving final approval of the version published. SP participated in enrollment of patients (newborns) and in the neonatal data collection. She revised the work with important intellectual content, giving final approval of the version published. NP performed the statistical analysis and gave a substantial contribution to the interpretation of data. He wrote and revised the work with important intellectual content and gave final approval of the version published. EG participated in the management of maternal treatment. She revised the work with important intellectual content, giving final approval of the version published. FA revised the work critically for important intellectual content and he gave final approval of the version published, ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved. FM gave a substantial contribution to the conception, design of the work, and interpretation of final data. He participated in the intellectual content revision of the work and he gave his final approval of the published version. FT gave a substantial contribution to the conception, design of the work, and interpretation of final data. He participated in the intellectual content revision of the work and he gave his final approval of the published version. MF was the project manager of the study. She coordinated and managed the whole project, contributing to the design of the clinical protocol. She gave substantial contribution to the acquisition, analysis, and interpretation of data. She contributed to writing the paper and revised the work critically for important intellectual content and she gave final approval of the version published, ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval All infants included were part of the INCIP follow-up research protocol approved by the local Ethics Committee-Comitato Etico Milano Area B on the 15 of July 2014. In accord with the protocol, they were assessed at 18 months of age using the Bayley Scales of Infant Neurodevelopment, third edition. At term equivalent age, they underwent brain MRI as part of the routine clinical care, and MRI scans were retrospectively analyzed after informed parental consent was signed.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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