Characterizing pregnancy outcomes in a humanized mouse model of sickle cell disease

Although increased risk for adverse pregnancy outcomes has been well characterized in women with sickle cell disease (SCD), there remains unexplored value in the characterization of a preclinical model which could minimize human risk. This study aimed to characterize pregnancy outcomes in the SCD mouse model with emphasis on analogous clinical correlates and biological contributors. As such, we identified worsened outcomes including reduced litter sizes (haemoglobin HbSS (SS) 5.18 ± 1.25 embryos vs. haemoglobin HbAA (AA) 6.86 ± 1.51**), fetal weight (SS 0.38 ± 0.16 g vs. AA 0.49 ± 0.14 g**), viability of embryos (SS 20.00% interquartile range (IQR) 33.33 vs. AA 100.00% IQR 0.0***) and maternal mortality (SS 7.14% (2/28) vs. AA 0.00% (0/27) odds ratio (OR) = 4.82 ns). We further noted a significant reduction in vascular density and impaired uterine and umbilical artery blood flow within SCD placentae. Assessments of soluble growth factors revealed evidence of angiogenic dysregulation but maintained limited translational utility due to the multiparous nature of mouse pregnancy. These results serve as a cornerstone characterization of pregnancy outcomes in the SCD mouse model while highlighting the implications of placental vascular insufficiency. They further demonstrate both the utility and limitations of the model, emphasizing the need for continued clinical assessment.