Evaluating chemotherapy-driven placental alterations and their impact on fetal development

Katrien De Clercq^1*Carolina Velazquez²Eleonora Persoons¹Vera Elena Renée Annechien Wolters³Marieke van de Ven⁴Ji-Ying Song⁵Frédéric Amant^2,3,6*

• ¹Implantation, Placentation and Pregnancy (POPPY) Research Group, Department of Development and Regeneration, KU Leuven, Herestraat 49 box 611, 3000 Leuven, Belgium, Leuven, Belgium
• ²Department of Oncology, KU Leuven, Leuven, Belgium, Leuven, Belgium
• ³Gynecologic Oncology, Netherlands Cancer Institute, Amsterdam, Anthony Van Leeuwenhoek, The Netherlands, Amsterdam, Netherlands
• ⁴Mouse Clinic for Cancer and Aging (MCCA), Preclinical Intervention Unit, Netherlands Cancer Institute, Amsterdam, The Netherlands, Amsterdam, Netherlands
• ⁵Department of Experimental Animal Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands, Amsterdam, Netherlands
• ⁶Department of Obstetrics and Gynecology, UZ Leuven, Leuven, Belgium, Leuven, Belgium

ABSTRACT Background: Chemotherapy during pregnancy presents a clinical challenge, balancing maternal treatment efficacy with fetal safety. While chemotherapy after the first trimester is generally considered safe, its impact on placental development remains underexplored. This study investigates the effects of commonly used chemotherapeutic agents (CAs), including anthracyclines, taxanes, and platinum-based compounds, on maternal, placental, and fetal outcomes using a mouse model. Methods: To model the chemotherapy exposure during pregnancy, pregnant mice received a single CA dose at embryonic day 13.5 (E13.5), equivalent to the beginning of the second trimester in human gestation. Placental and fetal outcomes were assessed at E15.5 and E18.5 using contrast-enhanced microtomography (micro-CT) and histopathological analyses to investigate the alterations associated to the exposure to differen CAs. Results: Platinum-based agents, particularly carboplatin, significantly reduced fetal and placental weights and altered placental morphology, with persistent effects observed at E18.5. Contrast-enhanced microtomography (micro-CT) and histopathological analyses revealed reduced placental volumes, in both the labyrinth and junctional zones, and increased signs of trophoblast degeneration. Despite these changes, embryonic viability and litter size remained unaffected, suggesting that fetal growth restriction may be driven by placental insufficiency rather than direct fetal toxicity. Conclusion: These findings underscore the importance of placental assessment in evaluating chemotherapy safety during pregnancy and highlight the potential long-term implications of platinum-based treatments on fetal development.