Impact of SARS-CoV-2 Infection on Unvaccinated Pregnant Women: Non-Reassuring Fetal Heart Rate Tracing Because of Placentitis.

In 2020, a new coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China. SARS-CoV-2 infection has been shown to be highly morbid in pregnant women, being a risk factor for several obstetric conditions leading to increased maternal and neonatal mortality. A few studies since 2020 have shown SARS-CoV-2 maternal-fetal transmission and noted placental abnormalities grouped under the term placentitis. We hypothesized that these placental lesions could be responsible for abnormalities in placental exchange and therefore abnormalities in cardiotocographic monitoring, leading to premature fetal extraction. The objective is to identify the clinical, biochemical, and histological determinants associated with the occurrence of non-reassuring fetal heart rate (NRFHR) outside labor in fetuses of SARS-CoV-2-infected mothers. We conducted a retrospective multicenter case series of the natural history of maternal SARS-CoV-2 infections resulting in fetal delivery outside labor due to NRFHR. Collaboration was sought with the maternity hospitals in the CEGORIF, the APHP and Brussels hospitals. The investigators were contacted by e-mail on three successive occasions over a period of one year. Data from 17 mothers and 17 fetuses were analyzed. Most women had a mild SARS-CoV-2 infection; only two women presented severe infection. No woman was vaccinated. We found a substantial proportion of maternal coagulopathy at birth: elevation of APTT ratio (62%), thrombocytopenia (41%) and liver cytolysis (58.3%). Iatrogenic prematurity was noted in 15 of 17 fetuses, and 100% were born by cesarean delivery due to emergency criteria. One male neonate died on the day of birth due to peripartum asphyxia. Three cases of maternal-fetal transmission were recorded following WHO criteria. Placental analysis in 15 cases revealed eight cases of SARS-CoV-2 placentitis, causing placental insufficiency. In total, 100% of the placentas analyzed showed at least one lesion suggestive of placentitis. SARS-CoV-2 maternal infection during pregnancy is likely to generate neonatal morbidity in relation to placental damage resulting in placental insufficiency. This morbidity may be the consequence of induced prematurity as well as acidosis in the most severe situations. Placental damage occurred in unvaccinated women and in women with no identified risk factor, in contrast to severe maternal clinical forms.

Hofbauer Cells and COVID-19 in Pregnancy.

CONTEXT.­: 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 SARS-CoV-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 is 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 were present in all 22 placentas (100%). SARS-CoV-2 was identified in Hofbauer cells from 4 of 22 placentas (18.2%). Villous capillary endothelial staining was positive in 2 of 22 cases (9.1%), both of which also had viral positivity in Hofbauer cells. Syncytiotrophoblast staining occurred in 21 of 22 placentas (95.5%). Hofbauer cell hyperplasia was present in 3 of 22 placentas (13.6%). In the 7 cases having documented transplacental infection of the fetus, 2 (28.6%) 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.

Chronic Histiocytic Intervillositis With Trophoblast Necrosis Is a Risk Factor Associated With Placental Infection From Coronavirus Disease 2019 (COVID-19) and Intrauterine Maternal-Fetal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Transmission in Live-Born and Stillborn Infants.

CONTEXT.­: The number of neonates with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is increasing, and in a few there are reports of intrauterine infection. OBJECTIVE.­: To characterize the placental pathology findings in a preselected cohort of neonates infected by transplacental transmission arising from maternal infection with SARS-CoV-2, and to identify pathology risk factors for placental and fetal infection. DESIGN.­: Case-based retrospective analysis by a multinational group of 19 perinatal specialists of the placental pathology findings from 2 cohorts of infants delivered to mothers testing positive for SARS-CoV-2: live-born neonates infected via transplacental transmission who tested positive for SARS-CoV-2 after delivery and had SARS-CoV-2 identified in cells of the placental fetal compartment by molecular pathology, and stillborn infants with syncytiotrophoblast positive for SARS-CoV-2. RESULTS.­: In placentas from all 6 live-born neonates acquiring SARS-CoV-2 via transplacental transmission, the syncytiotrophoblast was positive for coronavirus using immunohistochemistry, RNA in situ hybridization, or both. All 6 placentas had chronic histiocytic intervillositis and necrosis of the syncytiotrophoblast. The 5 stillborn/terminated infants had placental pathology findings that were similar, including SARS-CoV-2 infection of the syncytiotrophoblast, chronic histiocytic intervillositis, and syncytiotrophoblast necrosis. CONCLUSIONS.­: Chronic histiocytic intervillositis together with syncytiotrophoblast necrosis accompanies SARS-CoV-2 infection of syncytiotrophoblast in live-born and stillborn infants. The coexistence of these 2 findings in all placentas from live-born infants acquiring their infection prior to delivery indicates that they constitute a pathology risk factor for transplacental fetal infection. Potential mechanisms of infection of the placenta and fetus with SARS-CoV-2, and potential future studies, are discussed.

Transplacental transmission of SARS-CoV-2 infection.

SARS-CoV-2 outbreak is the first pandemic of the century. SARS-CoV-2 infection is transmitted through droplets; other transmission routes are hypothesized but not confirmed. So far, it is unclear whether and how SARS-CoV-2 can be transmitted from the mother to the fetus. We demonstrate the transplacental transmission of SARS-CoV-2 in a neonate born to a mother infected in the last trimester and presenting with neurological compromise. The transmission is confirmed by comprehensive virological and pathological investigations. In detail, SARS-CoV-2 causes: (1) maternal viremia, (2) placental infection demonstrated by immunohistochemistry and very high viral load; placental inflammation, as shown by histological examination and immunohistochemistry, and (3) neonatal viremia following placental infection. The neonate is studied clinically, through imaging, and followed up. The neonate presented with neurological manifestations, similar to those described in adult patients.