David A Schwartz1, Marcella Baldewijns2, Alexandra Benachi3, Mattia Bugatti4, Gaetano Bulfamante5, Ke Cheng6, Rebecca R J Collins7, Larisa Debelenko8, Danièle De Luca9, Fabio Facchetti10, Brendan Fitzgerald11, Daniel Levitan12, Rebecca L Linn13, Lukas Marcelis14, Denise Morotti15, Raffaella Morotti16, Luisa Patanè17, Sophie Prevot18, Bianca Pulinx19, Ali G Saad20, Sam Schoenmakers21, David Strybol22, Kristen Thomas23, Delfina Tosi24, Valentina Toto25, Lotte E van der Meeren26, Robert M Verdijk27, Alexandre J Vivanti28, Mehreen Zaigham29. 1. Department of Pathology, Medical College of Georgia, Augusta, GA. 2. Department of Pathology, University Hospitals Leuven, Leuven, Belgium. 3. Division of Obstetrics and Gynecology, Antoine Béclère Hospital, Paris Saclay University Hospitals, Clamart, France. 4. Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy. 5. Hospital Complex for Pathological Anatomy and Medical Genetics, ASST Santi Paolo e Carlo, Milan, Italy Department of Health Sciences, University of Milan, Milan, Italy. 6. HistoWiz, Inc., Brooklyn, NY. 7. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX. 8. Department of Pediatric and Perinatal Pathology, Columbia University Medical Center, New York, NY. 9. Neonatology Division of Pediatrics, Transportation and Neonatal Critical Care APHP, Paris Saclay University Hospitals, Medical Center "A.Béclère" & Physiopathology and Therapeutic Innovation Unit, Paris-Saclay University, Paris, France. 10. Pathology Unit, Department of Molecular and Translational Medicine, Università degli Studi di Brescia, Brescia, Italy. 11. Department of Pathology, Cork University Hospital, Wilton, Cork, Ireland. 12. Department of Pathology, SUNY Downstate Medical Center, Brooklyn, NY. 13. Department of Pathology & Lab Medicine, Perelman School of Medicine at the University of Pennsylvania & Children's Hospital of Philadelphia, Philadelphia, PA. 14. Department of Pathology, UZ Leuven, Leuven, Belgium. 15. Pathology Unit and Medical Genetics Laboratory, Papa Giovanni XXIII Hospital, Bergamo, Italy. 16. Department of Pathology and Pediatrics, Autopsy Service, Yale University School of Medicine, New Haven, CT. 17. Department of Obstetrics and Gynecology, Papa Giovanni XXIII Hospital, Bergamo, Italy. 18. Division of Pathology, Bicêtre Hospital, Paris Saclay University Hospitals, APHP, Le Kremlin-Bicêtre, France. 19. Department of Clinical Biology, Sint-Trudo Hospital, Sint-Truiden, Belgium. 20. Department of Pathology, University of Miami Miller School of Medicine/Jackson Health System/Holtz Children's Hospital, Miami, FL. 21. Department of Obstetrics and Gynaecology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands. 22. Department of Pathology, Sint-Trudo Hospital, Sint-Truiden, Belgium. 23. Department of Pathology, NYU Langone Health, Main Campus & Bellevue Hospital Center, New York University School of Medicine, New York, NY. 24. Department of Health Sciences, University of Milan, Milan, Italy. 25. Hospital Complex for Pathological Anatomy and Medical Genetics, ASST Santi Paolo e Carlo, Milan, Italy. 26. Department of Pathology, Leiden University Medical Center, and Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. 27. Department of Pathology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands. 28. Department of Obstetrics and Gynecology, Antoine Beclere Hospital, APHP, Université Paris Saclay, Clamart, France. 29. Obstetrics & Gynecology, Skåne University Hospital, Malmö, Sweden and Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
Abstract
CONTEXT: - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can undergo maternal-fetal transmission, heightening interest in the placental pathology findings from this infection. Transplacental SARS-CoV-2 transmission is typically accompanied by chronic histiocytic intervillositis together with necrosis and positivity of syncytiotrophoblast for SARSCoV-2. Hofbauer cells are placental macrophages that have been involved in viral diseases including HIV and Zika virus, but their involvement in SARS-CoV-2 in unknown. OBJECTIVE: - To determine whether SARS-CoV-2 can extend beyond the syncytiotrophoblast to enter Hofbauer cells, endothelium and other villous stromal cells in infected placentas of liveborn and stillborn infants. DESIGN: - Case-based retrospective analysis by 29 perinatal and molecular pathology specialists of placental findings from a preselected cohort of 22 SARS-CoV-2-infected placentas delivered to pregnant women testing positive for SARS-CoV-2 from 7 countries. Molecular pathology methods were used to investigate viral involvement of Hofbauer cells, villous capillary endothelium, syncytiotrophoblast and other fetal-derived cells. RESULTS: - Chronic histiocytic intervillositis and trophoblast necrosis was present in all 22 placentas (100%). SARS-CoV-2 was identified in Hofbauer cells from 4/22 placentas (18%). Villous capillary endothelial staining was positive in 2/22 cases (9%), both of which also had viral positivity in Hofbauer cells. Syncytiotrophoblast staining occurred in 21/22 placentas (95%). Hofbauer cell hyperplasia was present in 3/22 placentas (14%). In the 7 cases having documented transplacental infection of the fetus, 2 occurred in placentas with Hofbauer cell staining positive for SARS-CoV-2. CONCLUSIONS: - SARS-CoV-2 can extend beyond the trophoblast into the villous stroma, involving Hofbauer cells and capillary endothelial cells, in a small number of infected placentas. Most cases of SARS-CoV-2 transplacental fetal infection occur without Hofbauer cell involvement.
CONTEXT: - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can undergo maternal-fetal transmission, heightening interest in the placental pathology findings from this infection. Transplacental SARS-CoV-2 transmission is typically accompanied by chronic histiocytic intervillositis together with necrosis and positivity of syncytiotrophoblast for SARSCoV-2. Hofbauer cells are placental macrophages that have been involved in viral diseases including HIV and Zika virus, but their involvement in SARS-CoV-2 in unknown. OBJECTIVE: - To determine whether SARS-CoV-2 can extend beyond the syncytiotrophoblast to enter Hofbauer cells, endothelium and other villous stromal cells in infected placentas of liveborn and stillborninfants. DESIGN: - Case-based retrospective analysis by 29 perinatal and molecular pathology specialists of placental findings from a preselected cohort of 22 SARS-CoV-2-infected placentas delivered to pregnant women testing positive for SARS-CoV-2 from 7 countries. Molecular pathology methods were used to investigate viral involvement of Hofbauer cells, villous capillary endothelium, syncytiotrophoblast and other fetal-derived cells. RESULTS: - Chronic histiocytic intervillositis and trophoblast necrosis was present in all 22 placentas (100%). SARS-CoV-2 was identified in Hofbauer cells from 4/22 placentas (18%). Villous capillary endothelial staining was positive in 2/22 cases (9%), both of which also had viral positivity in Hofbauer cells. Syncytiotrophoblast staining occurred in 21/22 placentas (95%). Hofbauer cell hyperplasia was present in 3/22 placentas (14%). In the 7 cases having documented transplacental infection of the fetus, 2 occurred in placentas with Hofbauer cell staining positive for SARS-CoV-2. CONCLUSIONS: - SARS-CoV-2 can extend beyond the trophoblast into the villous stroma, involving Hofbauer cells and capillary endothelial cells, in a small number of infected placentas. Most cases of SARS-CoV-2 transplacental fetal infection occur without Hofbauer cell involvement.
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