Placental Contributions to Pregnancy Outcomes in the Townes Mouse Model of Sickle Cell Disease

Abstract Background With the growing adoption of improved care plans along with increased availability of interventions such as hydroxyurea, blood transfusion therapy, and recent disease modifying therapeutics the overall health and survival of individuals with SCD has improved significantly, allowing more women to reach sexual maturity and consider reproduction. However, women with sickle cell disease (SCD) face severely increased risk for adverse pregnancy outcomes, including preeclampsia, intrauterine growth restriction, venous thromboembolism, pre-term birth, and maternal and fetal mortality. Through these studies, we assessed the ability of the Townes humanized mouse model to recapitulate phenotypes analogous to those observed in human pregnancy. This model is well established for its use in studying various SCD phenotypes and is particularly useful in our case as it circumvents investigation in pregnant women until preclinical evaluations are complete. The Townes model has long served as the gold standard for pre-clinical research in SCD. Though not previously used for reproductive studies, many of the pathology we have identified are highly reflective of human outcomes in SCD. This includes gross pregnancy outcomes and placental vascular impairments which are highly implicated in adverse pregnancy events. This study aimed to characterize pregnancy outcomes in the SCD mouse model while identifying relevant clinical correlates and biological contributors. Methods Townes SS (sickle hemoglobin) and AA (normal hemoglobin) mice underwent timed breeding to produce pregnant dams which were housed under normal conditions until 18.5 days post conception (dpc). They were then subject to high-resolution ultrasound analysis, post-mortem analysis of pregnancy outcomes, and placental tissue collection. Included in this report are gross pregnancy outcomes, histological assessments of the placenta, and ultrasound analysis including 3-D volume measures, placental vascularization renders, and pulse-wave assessment of uterine and umbilical artery blood flow. Results We identified several pregnancy outcomes analogous to those occurring in humans, including reduced litter sizes (AA 6.86 ± 1.51 vs SS 5.18 ± 1.25 embryos**), fetal weight (AA 0.49 ± 0.14g vs SS 0.38 ± 0.16g**), viability of embryos (AA 100.00% IQR 0.0 vs SS 20.00% IQR 33.33****), and maternal mortality (AA 0.00% (0/27) vs SS 7.14% (2/28) OR = 4.82 ns). We further examined the impact of placental-vascular abnormalities, noting significantly reduced vascular density, increased presence of large avascular areas within SCD placentae, and histopathology consistent with ischemic injury and vascular trauma. High-resolution ultrasound analysis also revealed impaired uterine and umbilical artery blood flow. Conclusions Overall, 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 highlight both the utility and limitations of the model for translational investigations, emphasizing the need for continued clinical assessment.