Abstract Body: Introduction: Higher risks of preterm birth and fetal growth restriction are observed in COVID-19 pregnancies. The infection mechanism, linked to a potential depletion of the cardioprotective protein ACE2, which serves as a receptor for SARS-CoV-2, could pose additional risks for mothers and fetuses. An ACE2/ACE imbalance, favoring ACE, has been seen in hypertensive (HT) pregnancies and is linked to poor outcomes, including pre-eclampsia. This study aims to assess whether similar changes in ACE and ACE2 regulation in placentas and umbilical cord blood occur in COVID-19 compared to HT and healthy (Ctrl) pregnancies, and whether this imbalance is associated with impaired vascular structure.
Methods: A retrospective cohort study recruited 77 pregnancies (25 COVID-19, 16 HT, 36 Ctrl) at Montreal Hospital Sacré-Coeur. Placental infarction was assessed in histological sections, umbilical cord fibrosis by Masson's trichrome staining, and placental ACE2 content by immunohistochemistry. ACE and ACE2 activity were measured by fluorometric assay in umbilical cord plasma. Data are presented as mean 95% CI. Linear regression was used for correlations, Kruskal-Wallis and Mann-Whitney tests for group comparisons.
Results: Maternal age, gestational age, and the proportion of male/female fetuses were similar between groups. Ctrl group had lower rates of C-section delivery, obesity, and gestational diabetes compared to COVID-19 and HT pregnancies. Although ACE2 content in placentas was reduced in HT pregnancies, the COVID-19 group had significantly higher content compared to HT and Ctrl pregnancies (23.4 CI=20.4-26.4 vs. 15.5 CI=9.7-21.3 and 17.6 CI=15.1-20.1, respectively, p<0.01). The ACE2/ACE activity ratio in cord blood was significantly reduced in COVID-19 and HT groups compared to Ctrl (3.1 CI=2.4-3.6, 2.5 CI=1.7-3.1, and 4.1 CI=3.5-4.8, p<0.01), indicating an imbalance favoring ACE activity in HT and COVID-19 groups. The ACE2/ACE ratio negatively correlated with umbilical cord fibrosis (slope=-3.1 CI= -6.1 to -0.1, p=0.04) and was significantly lower in placentas with tissue infarction (2.5 CI=1.2-3.8 vs. 4.6 CI=3.8-5.3, p<0.01).
Conclusion: HT pregnancies have reduced ACE2 content and an ACE2/ACE activity imbalance in cord blood. COVID-19 pregnancies show a similar imbalance in cord blood but significantly higher ACE2 content in the placenta. This imbalance is associated with structural changes in fetal-placental vessels, suggesting a link to poor pregnancy outcomes.