key: cord-0733476-lyod4u5x
authors: Vivanti, Alexandre J.; Vauloup-Fellous, Christelle; Escourrou, Guillaume; Rosenblatt, Jonathan; Jouannic, Jean-Marie; Laurent-Bellue, Astrid; De Luca, Daniele
title: Factors associated with SARS-CoV-2 transplacental transmission
date: 2022-05-11
journal: Am J Obstet Gynecol
DOI: 10.1016/j.ajog.2022.05.015
sha: 88f9614bd5e0f110584fe232945bd6bac6f968be
doc_id: 733476
cord_uid: lyod4u5x

nan

Transplacental transmission of SARS-CoV-2 is a rare event albeit severe cases have been described. 1 We know that the transmission may occur through Hofbauer cells in a minority of cases. 2 Therefore, other factors such as placental expression of viral receptors, viral load, degree of inflammation or some clinical features might be involved in the transmission. We investigate these as we hypothesized that they might play a relevant role.

We observed a series of six cases of SARS-CoV-2 transplacental transmissions; as we suspected that the first ascertained case of transplacental transmission 3 was linked to fetal distress, all these cases received fetal monitoring. These six cases presented placental positive RT-PCR. Then, we recruited other four women affected by COVID-19 during the third trimester with positive placental RT-PCR but without transplacental transmission: these six and four cases constitute the group of ten pregnancies complicated by COVID-19 and placental infection (C+P+; i.e.: the six transplacental transmissions were in this group). In the same period, we also recruited 10 women with COVID-19 during the third trimester and negative placental RT-PCR (C+P-; i.e.: pregnancies complicated by COVID-19 but without placental infection), and 11 healthy pregnant women without any SARS-CoV-2 infection (Controls). Clinical management of all studied patients is described in supplementary methods.

We performed a translational cohort study analyzing biological data (ELISA for viral receptors, RT-PCR with viral load estimation and gene sequencing, histology and immunohistochemistry; details available in supplementary methods) in placentas obtained from the three groups. 

Patients in C+P-and C+P+ groups had mild/moderate COVID-19. With the exception of two cases (one neonatal cerebral vasculitis 3 

Our findings suggest that: 1) viral load and expression of viral receptors are not linked to the transplacental transmission; 2) placental inflammation with a peculiar signature is evident in cases of transplacental transmission, which is associated with fetal distress, lower cord pH and NICU admission. Interestingly, all liveborn transmissions occurred in the setting of non-reassuring fetal heart tracings and/or prematurity. Fetal monitoring during mild-moderate COVID-19 is not firmly recommended but our findings raise the hypothesis that transplacental transmission might occur more often than thought. Maternal infection in proximity to delivery may be a risk factor for the J o u r n a l P r e -p r o o f transmission: this seems mainly due to the inflammatory placental damage, which is associated with immune response at the maternal-fetal interface and increasing cytokines in the fetal circulation. 4 This is a situation similar to the so called "cytokine storm" observed during severe SARS-CoV-2 pneumonia: this excessive local response might lead to placental insufficiency and transplacental transmission. 5 The knowledge accumulated so far has been provided mostly by case series: ours is the first controlled study about the mechanisms of SARS-CoV-2 transplacental transmission.

Limitations include the lack of data on viral variants and the small sample size possibly introducing type 2-error and selection bias (although groups were comparablesee supplementary results) and

limiting the possibility to study exposure time (i.e.: time from maternal infection to delivery) and viral receptors expression across gestational age.

Basic clinical data are considered in 6 cases of transplacental transmission (i.e.: those included in the C+P+ group), while perinatal outcomes are considered only in 5 surviving neonates (because one of these pregnancies ended in fetal demise and was not considered for this analysis). These pregnancies with transplacental transmission were compared with all patients from our dataset not experiencing a transplacental transmission: in other words the six transplacental transmissions were compared with 14 cases of COVID-19 during the third trimester without transplacental transmission (that is, all cases enrolled in the C+P-and C+P+ groups lacking transplacental transmission 

Synthesis and systematic review of reported neonatal SARS-CoV-2 infections

Hofbauer cells and coronavirus disease 2019 (COVID-19) in pregnancy: Molecular pathology analysis of villous macrophages, endothelial cells, and placental findings from 22 placentas infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with and without fetal transmission

Transplacental transmission of SARS-CoV-2 infection

Maternal respiratory SARS-CoV-2 infection in pregnancy is associated with a robust inflammatory response at the maternal-fetal interface

Authors are grateful to Prof. Alexandra Benachi and Prof. Sophie Prevot as well as Drs. Anne-Gael Cordier, Feriel Fortas, Marine Jeay, Barbara Loi and Melanie Vandekerckhove who helped in data collection.