key: cord-1024579-jdvu0a0a
authors: Kotiloglu-Karaa, Esin; Kele, Beatrix; Kulasegaran-Shylini, Raghavendran; Broad, Claire E; Owoyemi, Dola; Martin, Joanne; MacPhail, Graham; Iliodromiti, Stamatina; Riddell, Anna; Alexander, Eliza; Cutino-Moguel, Teresa
title: SARS-CoV-2 placental infection is associated with massive perivillous fibrin deposition at the maternal-fetal interface: a preliminary study"
date: 2022-03-02
journal: Clin Infect Dis
DOI: 10.1093/cid/ciac173
sha: 18d1962fc29ac6fc8a1cd2a0f31c4e4633f5e8d6
doc_id: 1024579
cord_uid: jdvu0a0a

We observed an increased frequency of massive perivillous fibrin deposition (MPFD) ,during the second COVID-19 pandemic wave dominated by the alpha variant of SARS-CoV-2. MPFD associated with 100% RT-PCR positivity for SARS-CoV-2 and detection by immunohistochemistry. The alpha variant was identified in all placentas with MPFD that could be sequenced.

M a n u s c r i p t

The prevalence of COVID-19 in East London during December 2020 and January 2021 reached 7022 per 100,000 with 86% thought to be alpha variant (6) . Our population's annual birth rate is ~16,000 births (2018-2019). During 2020, 1190 pregnant women had a positive SARS-CoV-2 swab on admission to labour wards in Barts Health of which 293 were during the second pandemic wave in December 2020.

During the second pandemic wave, there was an increase in the number of placentas referred with massive perivillous fibrin deposition (MPFD) associated with histiocyte-rich intervillous inflammation on microscopy. MPFD is a rare lesion of uncertain aetiology reported in <1% of all pregnancies (1, 2) . Perivillous fibrin deposition is postulated to be a reaction to trophoblast necrosis where exposure of chorionic villous stroma to maternal blood stimulates the maternal clotting cascade (3). A case report by Linehan et al terms this entity 'SARS-CoV-2 placentitis' (4) and Marton et al described it as an emerging complication of SARS-CoV-2 infection, along with chronic histiocytic intervillositis (CHI), that causes placental insufficiency leading to poor pregnancy outcomes including severe intrauterine growth restriction (IUGR) and stillbirth (5) .

We evaluated the presence of SARS-CoV-2 in placental tissue (and its lineage) and correlated with histopathological findings and clinical outcomes.

Each year, >1500 placentas are referred to our histopathology department. Indications for referral include stillbirth, late miscarriage, neonatal admission to intensive care, premature birth, severe IUGR, and maternal severe pre-eclampsia.

During December 2020 and January 2021, 224 placentas were referred for histopathological assessment. Amongst these, 11 (5%) cases of MPFD were identified. This compared to zero cases in 199 placentas referred during the same months in the previous year (December 2019 and January 2020), and one case out of 160 placentas (0.6%) referred two years earlier (December 2018 and January 2019). Until December, there had been no cases of MPFD out of 1140 placentas referred for examination in 2020. Amongst the 11 placentas with MPFD there were six live births and 5 stillbirths: seven placentas were associated with birthweight < 10 th centile. Severity of COVID-19 (7) was not associated with MPFD findings. Thrombophillia screening was not performed for the most patients as not clinically indicated. Classically MPFD is associated with low birth weight and significant recurrence risk in subsequent pregnancies. The main aetiology is thought to be immunologic with increased risk in women with autoimmune diseases (8) . An infectious aetiology has been reported, including coronaviruses (8, 9, 10) . As the amount of tissue used in RT-PCR is not standardised, comparing CT values is of limited utility. Nevertheless, the mean CT values in MPFD placentas, compared with non-MPFD and normal placentas from COVID-19 positive mothers were 10 CTs lower suggestive of more viral RNA being present in the MPFD placental tissue. When normal placentas and non-COVID-19 pregnancies were excluded, there as a significantly higher incidence of stillbirth amongst pregnancies with MPFD (Fischer exact test The Fischer two-tailed p = 0.0265) vs pregnancies with other non-MPFD abnormalities. This increase in stillbirth remained significant when all cases in the series were included (p = 0.0274). This contrasts with reports of no increases in the rate of stillbirth in England during the first pandemic wave (13) .

Limitations of our study include small case numbers and selection bias as we specifically selected all MPFD cases for molecular testing. IHC detecting other viral proteins like nucleoprotein are necessary to rule out false negative results (14) .Due to the retrospective nature of this study, women have not been recalled for thrombophilia screening or additional testing.

A c c e p t e d M a n u s c r i p t

Our results suggest that SARS-CoV-can cause MPFD. During the alpha wave of the pandemic, we observed an increase in MPFD cases. We believe alpha may present a higher risk for MPFD. However, we have not been able to confirm this. Future studies should include SARS-CoV-2 negative patients as disease controls and placental tissue from patients infected with different variants of SARS-CoV-2 to allow direct comparison of MPFD with alpha versus other variants.

Disease progression in the placenta seems similar to other organs, particularly the lungs. As placenta is an easily retrievable organ, future mechanistic studies could allow better understanding of the pathophysiology of COVID-19 infection. Standardization of RT-PCR in placental tissue will also allow for better estimation of viral load.

The risk to pregnancies posed by emerging SARS-CoV-2 variants like Omicron must be explored further.

Sampling and definitions of Placental Lesions: Amsterdam Placental Workshop Group Consensus statement

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