key: cord-0911863-ioksta3j authors: Tasca, Chiara; Rossi, Roberta Simona; Corti, Silvia; Anelli, Gaia Maria; Savasi, Valeria; Brunetti, Federica; Cardellicchio, Manuela; Caselli, Emilio; Tonello, Cristina; Vergani, Patrizia; Nebuloni, Manuela; Cetin, Irene title: Placental Pathology in COVID-19 Affected Pregnant Women: a Prospective Case-Control Study date: 2021-05-05 journal: Placenta DOI: 10.1016/j.placenta.2021.04.002 sha: 0f91d722052626dc68f72ab31f47927a6bbc2a79 doc_id: 911863 cord_uid: ioksta3j INTRODUCTION: During pregnancy, SARS-CoV-2 infection may cause an abnormal development of the placenta, thus influencing maternal and fetal outcomes. Few studies have reported data on placental morphology and histology in infected pregnant patients, although not compared with carefully matched controls. The aim of this study is to compare placental morphology and histology of pregnant women affected by SARS-CoV-2 to non-infected controls. METHODS: This is a prospective multicenter case-control study on 64 pregnant women affected by SARS-CoV-2 who delivered at term or late-preterm. Data were collected about pregnancy course, maternal and fetal outcomes, placental biometry and macro- and microscopical morphology. 64 not-infected women were identified as controls, matched by age, body mass index and ethnicity. RESULTS: Cases and controls had similar fetal and maternal outcomes. No significant differences were observed in placental macro- or microscopical morphology between the two groups. In the cases treated with antivirals, chloroquine, LMWH or antibiotics, placentas were heavier but not more efficient than the non-treated, since the fetal/placental weight ratio did not differ. Moreover, delayed villous maturation was more frequent in treated women, although not significantly. The newborns whose mothers received oxygen therapy as treatment had higher levels of umbilical cord pO₂ at birth. DISCUSSION: In this prospective case-control study, SARS-CoV-2 infection during the third trimester did not influence placental histological pattern. Pharmacological and oxygen therapy administered to women affected by this viral infection could impact maternal and fetal outcomes and be associated to placental histological alterations. During pregnancy, SARS-CoV-2 infection may cause an abnormal development of the placenta, thus influencing maternal and fetal outcomes. Few studies have reported data on placental morphology and histology in infected pregnant patients, although not compared with carefully matched controls . The aim of this study is to compare placental morphology and histology of pregnant women affected by SARS-CoV-2 to non-infected controls. This is a prospective multicenter case-control study on 64 pregnant women affected by SARS-CoV-2 who delivered at term or late-preterm. Data were collected about pregnancy course, maternal and fetal outcomes, placental biometry and macro-and microscopical morphology. 64 not-infected women were identified as controls, matched by age, body mass index and ethnicity. Moreover, delayed villous maturation was more frequent in treated women, although not significantly. The newborns whose mothers received oxygen therapy as treatment had higher levels of umbilical cord pO₂ at birth. In this prospective case-control study, SARS-CoV-2 infection during the third trimester did not influence placental histological pattern. Pharmacological and oxygen therapy administered to women affected by this viral infection could impact maternal and fetal outcomes and be associated to placental histological alterations. The placenta represents a highly perfused compartment separating maternal and fetal 13 circulations. The infection with SARS-CoV-2 has the potential to increase inflammatory 14 and oxidative stress in the placenta, thus compromising both pregnancy evolution and fetal 15 development [1] . Indeed, pregnancies complicated by SARS-CoV-2 infection have an 16 increased risk of miscarriage, preterm birth, pre-eclampsia and stillbirth [2] [3] [4] . These 17 pregnancy-related pathologies have long been known to be associated with an abnormal 18 placental development. 19 To date, a viral infection of the placenta by SARS-CoV-2 has been suggested in small 20 case series [5] [6] [7] [8] . Our group has recently described the SARS-CoV-2 genome in two term 21 placentas out of 31 pregnancies with COVID [9]. In that study, three cases of vertical issues however still need to be effectively addressed to make this evidence strong. Placental morphological and histological examination may contribute significant clues 28 about placental viral exposure and its consequences. However, as of today, limited data 29 are available from infected pregnant patients, mainly in severe cases not compared with 30 carefully matched controls. In particular, placentas from SARS-CoV-2 positive neonates 31 showed chronic intervillositis together with macrophages CD68+ infiltration and SARS- 32 CoV-2 spike protein's mRNA in placental syncytiotrophoblast cells [14] . rate >30/minute or pneumonia involving more than 50% of the lungs' volume at X-ray 84 scan. Neonatal data were also collected: umbilical arterial pH and pO₂ at delivery, neonatal 87 weight, APGAR score at 5 minutes, NICU admission. Cases underwent a clinical evaluation of vital signs and symptoms, and a radiological 89 chest x-ray when required. Pharmacological management before and/or after delivery 90 (antivirals, hydroxychloroquine, LMWH, antibiotics or their combinations, oxygen) was 91 recorded to be included in our analysis. All placentas, both from cases and controls, were stored and analyzed at the 'Pathology The criteria used for grading and staging were applied for each category. After removing both the maternal decidua and all the fetal membranes, the umbilical cord 119 was trimmed from the placental disc. Then histological multiple samples were collected as 120 follows: two samples were trimmed from the membranes, three from the umbilical cord, Wallis test) or among two independent study groups (Mann-Whitney U test). 150 Chi-square analyses were performed to compare among groups the ethnicity, parity, 151 pregnancy onset, pregnancy related diseases, delivery mode, induction of labor, APGAR 152 score at 5 minutes <7, NICU admission data and the placental histological diagnoses, 153 applying the Yates continuity correction. A two-way between-group ANOVA (ANalysis Of VAriance) was conducted to explore the Oxygen supplementation was required for the 3 severe cases and for one moderate case. 247 We also compared placental biometry and histology and cord pO₂ levels between cases 248 treated with any pharmacologic therapy to those who did not receive drugs (Table 3) . Placentas of treated women were significantly heavier (506.1 ± 85.5 vs. 453.6 ± 69.5, p= 254 0.032) but not more efficient since the fetal/placental weight ratio did not differ significantly. No relevant differences resulted from the histological diagnoses between these two 256 groups. The delayed villous maturation was more frequent in treated women, approaching 257 statistical significance (23.5% vs. 4.3%, p= 0.051). From the PCR analysis performed on 47 placentas, only seven were found positive. When comparing SARS-CoV-2 PCR positive versus negative placentas, we found no and severe groups). Therefore we may hypothesize that placental oxygen exchange was 327 preserved in these placentas. This prospective study has made benefit of a specialized team of pathologists that made Placental pathology in COVID-19 Outcome of coronavirus spectrum infections COVID-19-positive mothers Disorders of coagulation in pregnancy Placental Pathology in Covid-19 Positive Mothers: Preliminary 403 A mechanistic analysis placental intravascular 405 thrombus formation in COVID-19 patients SARS-CoV-2 infection of the placenta CoV-2-Positive Women Sampling and definitions of placental 420 lesions: Amsterdam placental workshop group consensus statement. Archives of 421 pathology & laboratory medicine Placental Pathology Findings during and after 423 Epub ahead of print SARS-CoV-2 in the context of past 430 coronaviruses epidemics: Consideration for prenatal care Clinical Characteristics of Coronavirus Disease Pregnancy and postpartum outcomes in a 437 universally tested population for SARS-CoV-2 in New York City: a prospective cohort 438 study Detection of severe acute respiratory syndrome 440 coronavirus 2 in placentas with pathology and vertical transmission Histopathologic evaluation of placentas 443 after diagnosis of maternal severe acute respiratory syndrome coronavirus 2 infection A structured review of placental morphology and 446 histopathological lesions associated with SARS-CoV-2 infection Placenta Hospitalized Pregnant Women With Coronavirus Disease 2019 (COVID-19) Analysis of SARS-CoV-2 vertical transmission during 453 pregnancy Methodology for Biometrical Analysis of the 459 Placenta: Feasibility and Reproducibility Acknowledgements: we are particularly grateful to all the pregnant women that