Background: As cancer survival improves, preserving reproductive function is a growing survivorship priority. While chemotherapy-mediated ovarian damage is well-established(1), emerging clinical evidence suggests survivors experience higher prevalence of pregnancy complications, including preterm birth and intrauterine growth restriction(2). These complications persist even with existing fertility preservation strategies using cryopreserved oocytes/embryos collected before treatment(3). However, whether prior chemotherapy alters uterine function and placental development to drive these impacts remains unknown.
Method: Reproductively young female C57/Bl6 mice (n=10-12/group) received four clinically relevant doses of 5-florouracil used to treat colorectal and breast cancers prevalent in reproductive-aged women (50mg/kg), followed by a three-week recovery before uterine collection or mating. Pregnancies were assessed at embryonic day (E)12.5 and E18.5, with offspring analysed at postnatal day (PN)21. Fetal, placental and offspring growth, together with placental morphology, were evaluated.
Results: Uteri from exposed mice exhibited increased fibrosis (p<0.01). Litter size was unaffected between groups. However, 5-florouracil-exposed dams produced significantly female-biased litters (p<0.05). At E12.5, fetal and placental weights were increased (p<0.05), despite a reduced proportion of trophoblast within the placental labyrinth, the crucial site of maternal-fetal nutrient exchange (p<0.01). By E18.5, placental weight was significantly decreased (p=<0.0001), suggesting altered placental developmental progression. Labyrinth interhaemal membrane thickness was reduced at both gestational timepoints (p<0.001). Importantly, offspring from chemotherapy-exposed dams exhibited sustained postnatal growth retardation, with significantly reduced body weights at PN9, PN16, and PN21 in both females and males (p<0.0001).
Conclusion: This study provides the first evidence that 5-fluoruracil exposure before conception disrupts uterine architecture, placental developmental progression, and impairs offspring growth after treatment cessation. As women treated with 5-fluoruracil are not routinely offered fertility preservation(4), these findings reveal an important and previously unrecognised reproductive consequence with direct translational relevance for cancer survivorship. Ongoing studies are investigating cognitive development of offspring and mechanisms underpinning chemotherapy-mediated placental dysfunction.