Risk of COVID-19 maternofetal transmission at term: new evidence against placental infection by SARS-CoV-2

Objective The vertical transmission of SARS-CoV-2 has not been proven, but several cases of positive newborns have been reported. Combining clinical samples and cultures of primary human trophoblasts, this project aimed to determine if SARS-CoV-2 is able to infect the fetus by crossing the placental barrier and replicating inside the syncytium. Methods: Pregnant women tested positive by RT-PCR for SARS-CoV-2 at their admission for delivery in the Cliniques universitaires Saint-Luc (Brussels, Belgium) were included. Maternal/fetal plasma, vaginal/rectal swabs, maternal/fetal urine, placenta, amniotic membrane, fetal nasopharyngeal swabs, and maternal milk were collected to detect SARS-CoV-2 by RT-PCR, IHC and ISH. Trophoblasts isolated from normal term placentas were exposed to SARS-Cov-2 and viral replication assessed by RT-PCR and IF. The two main proteins mediating the entry of the SARS-CoV-2 (ACE2 and TMPRSS2) were studied in trophoblasts and normal placentas throughout gestation by RT-qPCR, WB, and IHC. Results: Between April 1 and November 1, 20 patients were included (10 asymptomatic, 9 mildly symptomatic, 1 ICU hospitalization). One patient gave birth prematurely and one fetus died in utero. All the babies were healthy and were tested negative for SARS-CoV-2. The virus was detected in the plasma of the hospitalized patient, confirming the rare viremia occurring in severely ill patients. In addition, SARS-CoV-2 was only evidenced in the placenta of the deceased fetus. Several mothers had SARS-CoV-2 IgM and/or IgG but their newborns only had IgG, which suggests that none of the fetuses were infected by SARS-CoV-2. In vitro, exposure of undifferentiated and differentiated trophoblasts to increasing MOI did not result in infection and viral replication, contrary to the positive control cells Vero E6. The mechanistic study revealed that the absence of infection is likely due to the very low co-expression of ACE2 and TMPRSS2 by the placenta. Conclusion: Altogether, these results underline that trophoblasts are not likely to be infected by SARS-CoV-2 at term. However, variable expression of ACE2 - TMPRSS2 by the placenta throughout gestation raises concern about infection before term, which could lead to dramatic pregnancy complications.

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Colson, A., Depoix, C., Dessilly, G., Baldin, P., Hubinont, C., Danhaive, O., Sonveaux, P., & Debiève, F. (2021). Risk of COVID-19 maternofetal transmission at term: new evidence against placental infection by SARS-CoV-2. IFPA Annual Meeting 2021, Virtual. https://hdl.handle.net/2078.5/269507