The effect of the delta SARS-CoV-2 variant on maternal infection and pregnancy

Abstract

A greater proportion of pregnant women with COVID-19 have mild disease compared with their non-pregnant counterparts. Paradoxically, however, they are at higher risk of developing severe disease, requiring respiratory support and admission to intensive care. The delta SARS-Cov-2 variant is associated with increased risk of hospitalization and morbidity in unvaccinated pregnant populations. However, it is not known whether the worse pregnancy outcomes associated with the delta variant are due to a direct effect of the virus on the pregnancy, or whether this effect is mediated through more severe maternal infection. Here, we synthesize studies of COVID-19 pregnancies, focusing on the different routes of SARS-CoV-2 infection of lung and placenta, and the mechanisms of syncytial formation for each SARS-CoV-2 variant. To delineate COVID-19 complications in pregnant women, future studies should explore whether the delta variant causes greater placental infection compared to other variants and contributes to increased syncytial formation.

Keywords: Pregnancy; Virology.

Figure 1

Delta SARS-CoV-2 variant efficiently enters cells via binding to the ACE2 receptor and activating cell membrane fusion using the host cell-surface protease TMPRSS2 This specific mechanism of infection of cells bearing both the ACE2 and TMPRSS2 (double ACE2+ TMPRSS2+ cell infection) allows the delta virions to bypass the endosome and not be destroyed by the host cell. On the other hand, omicron may enter cells in both a TMPRSS2-dependent and independent manner, as it can avoid the endosome, and may also infect ACE2 cells. Omicron enters cells through endocytosis, as its spike proteins drive the fusion of viral and endosomal membranes to facilitate insertion of the viral genome into the cytoplasm. Once the cell is infected by omicron, the virions that are replicated inside are finally released to disseminate other cells. In the case of the delta variant, when the spike protein is expressed on the surface of infected cells, it may interact with the ACE2 receptors on neighboring cells and form syncytia.

Figure 2

Cytotrophoblasts fuse with the overlying giant multinucleated syncytiotrophoblasts and form the outer layer of the placental microvilli to render the tissue impermeable and enable mother–child immune tolerance The cytotrophoblasts may regenerate the syncytiotrophoblast if damaged, but if the process is significantly compromised, pathological conditions such as preeclampsia and intra-uterine fetal growth restriction (FGR) might ensue. Increased numbers of syncytial knots, as seen in the placenta under conditions of hypoxia, hyperoxia, or in the presence of reactive oxygen species (ROS), and in preeclampsia, were also observed with COVID-19. There may be small amounts of fibrin deposition in normal placentas, which is increased in hypertensive disorders of pregnancy. But massive intervillous fibrin deposition has also been reported as a hallmark of COVID-19 pregnancies. As systemic SARS-CoV-2 infection leads to hypoxia and reduced utero-placental perfusion, it induces focal necrosis and extensive fibrin deposition. This increased amount of intravillous and perivillous fibrin might result from impaired fibrinolytic capacity of the compromised maternal endothelium or from immune cell activation with subsequent pro-coagulation signals. As fibrin deposition further compromises maternal-fetal gas exchange, further research is needed to elucidate the underlying cellular and molecular mechanisms.