Clinical and in Vitro Evidence against Placenta Infection at Term by Severe Acute Respiratory Syndrome Coronavirus 2

Abstract

Despite occasional reports of SARS-CoV-2 vertical transmission during pregnancy, the question of placental infection and its consequences for the newborn remain questionable. Here, we analyzed the placentas of 31 COVID-19-positive mothers by RT-PCR, immunohistochemistry and in situ hybridization. We only detected one case of placental infection, which was associated with intrauterine demise of the fetus. We then isolated and differentiated primary trophoblasts from non-pathological human placentas at term, and exposed them to SARS-CoV-2 virions. Unlike for positive control cells Vero E6, we were not able to detect the virus inside cytotrophoblasts and syncytiotrophoblasts or in the supernatant four days after infection. As a mechanism of defense, we hypothesized that trophoblasts at term do not express ACE2 and TMPRSS, the two main host membrane receptors for SARS-CoV-2 entry. The quantification of these proteins in the placenta during pregnancy confirmed the absence of TMPRSS2 at the surface of the syncytium. Surprisingly, a transiently induced experimental expression of TMPRSS2 did not allow the entry or replication of the virus in differentiated trophoblasts. Altogether, these results underline that trophoblasts are not likely to be infected by SARS-CoV-2 at term, but the reported case raises concern about preterm infection.

Meta-analysis on COVID-19-pregnancy-related placental pathologies shows no specific pattern

“…We identified a total of 1452 cases from 30 publications [ [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] ] ( Table 1 ). It should be taken into consideration that histological changes were not graded in all publications and even minor changes could have been summarized as “pathology”.…”

“… 64 (3) 0 [ 18 ] 19 1 mean 32 n.a. 18 (7) 1 (29th week) [ 17 ] 31 5 mean 31 15 male, 16 female 30 (n.a.) 1 (n.a.)…”

SARS-CoV-2 positivity in offspring and timing of mother-to-child transmission: living systematic review and meta-analysis

“… 27 Although we found evidence of SARS-CoV-2 positivity in various biological samples that could be associated with the potential for vertical infection—such as amniotic fluid, placenta, and vaginal secretions, finding a pathogen in such samples does not necessarily correlate with infection of the fetus. 9 10 11 Studies did not always report whether the maternal or fetal side of the placenta was swabbed, making it difficult to accurately determine placental infection.…”

“… 7 8 Detection of SARS-COV-2 in specimens from fetuses (eg, placental, amniotic fluid) or offspring (eg, nasopharyngeal or faecal) using reverse transcriptase polymerase chain reaction (RT-PCR) alone is not sufficient to diagnose fetal infection. 9 10 11 The accuracy of anti-SARS-CoV-2 IgM assays for serological diagnosis of congenital infection also varies. 12 13 Furthermore, as timing and route of infection may affect clinical outcomes, we need to be able to differentiate between intrapartum transmission of the virus and infection acquired soon after birth through contact with mother, caregivers, healthcare workers, or the neonate’s environment.…”

Cellular Complexity of Hemochorial Placenta: Stem Cell Populations, Insights from scRNA-seq, and SARS-CoV-2 Susceptibility

“…Indeed, clinical studies only support rare instances of vertical transmission of SARS-CoV-2, and most reported neonatal infections lack evidence of viral RNA in the fetal blood and amniotic fluid. A recent study by Colson et al 59 analyzed the placentas of 31 COVID-19-positive mothers and detected one case of placental infection. The authors further expanded the study with tractable in vitro experiments and did not detect the virus inside primary cytotrophoblasts or syncytiotrophoblasts exposed to SARS-CoV-2 virions.…”