The experience with SARS-CoV and MERS-CoV showed different pregnancy outcomes, ranging from mild consequences to high pressure, PE, acute renal failure for pregnant women; from no consequences, to
intrauterine growth restriction (IUGR) and pre-term birth (PTB)
[35][36] to death for newborns
[37]. Despite the wide body of clinical and molecular evidence (see above) that underpins an interrelationship between COVID-19 and PE a causative role for SARS-CoV-2 in the development of pre-eclamptic conditions has still to be clearly demonstrated. However, it has been reported that in SARS-CoV-2-positive pregnant women, the incidence of PE was 15.7% with respect to 9.3% of non-COVID-19 pregnancies
[38]. This may depend on potential intrauterine SARS-CoV-2 infection, leading to the increased expression of ACE2 and elevated AngII levels in placental villi with subsequently vasoconstriction and restricted fetal blood flow, all phenomena typical of early-onset PE
[39]. Data related to SARS-CoV-2 entry molecules ACE2 and TMPRSS2 expression in the human placenta are contradictory. Indeed, ACE2 has been reported to be widely expressed in the human placenta, in particular in syncytiotrophoblasts, cytotrophoblasts, vascular cells of villi (ECs and smooth muscle cells (SMCs)) in the decidua and even in ECs and SMCs of umbilical cord
[40][41]. Furthermore, a cytokine proinflammatory profile (IL-2, IL6, IL-7, and TNF-α) is found both in SARS-CoV2-infected and pre-eclamptic pregnant women, as well as ferritin plasma and low platelet count
[31][42]. In particular, a low platelet count (<100,000/mL) is an independent risk factor used to determine the severity in PE
[43], but it is also a useful parameter to determine COVID-19 severity
[31]. Mendoza et al. report that six out of eight COVID-19 pregnant women with severe pneumonia revealed laboratory test results and biophysical and biochemical parameters typically occurring in late-onset pre-eclamptic women
[44]. Moreover, a case report related to the analysis of the placenta of a COVID-19-affected pregnant woman with hypertension, coagulopathy, and PE, who underwent pregnancy termination of pre-viable pregnancy, by dilation and evacuation, at 22 weeks of gestation, demonstrated SARS-CoV-2 infection of the placenta—especially in syncytiotrophoblasts, overlapping ACE2 expression
[41]—and the umbilical cord, both by real-time PCR and electron microscopy. Fetal tissues were, however, negative for SARS-CoV-2 at the molecular testing
[45], confirming those reports assessing no vertical transmission of the infection. Other studies on the morphological characteristics of placentas derived from COVID-19-affected pregnant women testify a gross malfunctioning of the local vasculature, with diffuse fetal thrombi, arteriopathy of the decidua, and villitis of unknown etiology with respect to normal pregnancies
[46]. These findings, together with the demonstration of the direct placenta infection by SARS-CoV-2, may suggest an involvement of ACE2/Ang1-7/Mas axis in determining the vascular pathology of COVID-19 placentas and in the SARS-CoV-2-dependent onset of early onset PE, which, as stated above, is characterized by decreased levels of Ang1-7
[28]. An interesting analysis of the expression of ACE2 and TMPRSS2 in placental tissues derived from non-COVID-19 affected women at different time of gestation and with different pathological features demonstrated an increase in ACE2 and TMPRSS2 in placentas from the first pregnancy trimester, to decline at later stages, suggesting a major susceptibility to SARS-CoV-2 infection early during pregnancy. No changes in the expression of these two SARS-CoV-2 entry molecules—which were barely detectable—have been found at the decidual interface in PTB and pre-eclamptic pregnancies, compared to uncomplicated pregnancies
[47]. However, a decrease in ACE2 mRNA was detected in the uterus of a rat model of pregnancy-induced hypertension, when compared to control pregnant rats
[48]. Studies on the human placenta performed at the single cell level gave opposite results. In fact, Li et al. observed 32 cell types within a population of 65,000 cells, 4 of which expressed ACE2 at considerable levels, including decidual stromal and perivascular cells, cytotrophoblasts in villi, and syncytiotrophoblasts in placenta. Co-expression of ACE2 and TMPRSS2 was also observed in villous cytotrophoblasts and syncytiotrophoblasts, although TMPRSS2 was found at low levels in these latter
[49]. Conversely, another publication reported negligible co-expression of these two molecules both at the single cell level and at single nuclear level in placental cells
[50]. However, recently, another work confirmed the expression of both ACE and TMPRSS2 in human placenta at the single cell level, but most importantly, also at the protein level, by immunohistochemical analyses of placental tissues, with different degrees of expression according to the trimester of pregnancy and the cell type evaluated
[51]. This last report suggests that, although limited, a vertical transmission of SARS-CoV-2 infection is possible, as recently described
[52].
A computational comparison between differentially expressed genes by SARS-CoV-2 infection and PE associated genes
[53][54][55] reported that SARS-CoV-2 modulates the expression of several genes typical of pre-eclamptic conditions. Intriguingly,
Gene Set Enrichment Analyses (GSEA) showed that one of the most affected pathways is related to defective vascular response. Indeed, many angiogenic/antiangiogenic and vasoactive molecules have been found to be deregulated by SARS-CoV-2
[53]. Of note, among them sFlt-1 and
endoglin (ENG), two antiangiogenic molecules contributing to PE development, are upregulated by SARS-CoV-2. As stated above, sFlt-1 act as a decoy for PlGF, preventing its binding to membrane-bound Flt-1
[56] and impairing its angiogenic function. ENG impairs
Vascular Endothelial Growth Factor (VEGF) and PlGF activity, cooperating with sFlt-1
[57][58]. Moreover, vasoconstrictive (Urotensin-2, Angioteninogen, Endothelin-1) and pro-thrombotic peptides (e.g., Thrombomodulin, Plasminogen Activator Inhibitor-1,
Sigma-1 ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP)) are also deregulated
[59], possibly suggesting at least one of the molecular mechanism–besides RAS dysfunction-for the vascular malformations detected in COVID-19 pregnant patients.
Another issue to take into account is the presence of genetic polymorphisms predisposing one either to PE or SARS-CoV-2 infection. To date, the one linked to the risk both to develop PE and COVID-19 is the
ACE I/D (insertion/deletion) polymorphism. This polymorphism consists in the insertion or deletion of a 287 bp sequence in the intron 16 of
ACE gene. The DD genotype results in higher ACE levels and risk to develop hypertension
[60] due to an increase in AngII levels, whereas the II genotype is characterized by low ACE. Despite controversial results, some reports established a relationship between the DD ACE genotype and PE
[61]. Intriguingly, the II ACE genotype is inversely correlated both to COVID-19 incidence and mortality
[62], suggesting the DD genotype as a predisposing factor to develop the disease and confirming hypertension as an underlying clinical condition contributing to the pathogenesis of both COVID-19 and PE.