key: cord-338775-gh3a0wuf
authors: Gulersen, Moti; Prasannan, Lakha; Tam, Hima Tam; Metz, Christine N.; Rochelson, Burton; Meirowitz, Natalie; Shan, Weiwei; Edelman, Morris; Millington, Karmaine A.
title: Histopathological evaluation of placentas after diagnosis of maternal SARS-CoV-2 infection
date: 2020-08-15
journal: Am J Obstet Gynecol MFM
DOI: 10.1016/j.ajogmf.2020.100211
sha: 
doc_id: 338775
cord_uid: gh3a0wuf

Abstract Background The impact of maternal SARS-CoV-2 infection on placental histopathology is not well known. Objectives To determine if significant placental histopathological changes occur after diagnosis of SARS-CoV-2 infection in pregnancy and whether these changes are correlated with the presence or absence of symptoms associated with infection. Study Design Retrospective cohort study of women diagnosed with SARS-CoV-2 infection who delivered at a single center from April 9th to April 27th, 2020, and had placental specimens reviewed by pathology. Women with singleton gestations and laboratory-confirmed SARS-CoV-2 infection were eligible for inclusion. Historical controls selected from a cohort of women who delivered 6 months prior to the study period were matched in a 1:1 fashion by week of gestation at delivery. Histopathological characteristics were evaluated in each placenta and the incidence of these findings were compared between placentas after diagnosis of maternal SARS-CoV-2 infection and historical controls, as well as between placentas from patients with or without typical symptoms related to infection. Statistical analysis included use of Wilcoxon rank sum test and Fisher’s exact test for comparison of categorical and continuous variables. Statistical significance was defined as P value < 0.05. Results A total of 50 placentas after diagnosis of maternal SARS-CoV-2 infection and 50 historical controls were analyzed. Among placentas from patients diagnosed with SARS-CoV-2 infection, 3 (6%) were preterm (33 3/7, 34 6/7 and 36 6/7 weeks of gestation), 16 (32%) were from patients with typical symptoms related to infection and 34 (68%) were from patients without typical symptoms related to the infection. All patients had diagnosis of SARS-CoV-2 infection in the third trimester. Decidual vasculopathy was not visualized in any of the placentas from patients diagnosed with SARS-CoV-2 infection. There was no statistically significant difference in placental histopathological characteristics between the groups. SARS-CoV-2 testing for all neonates at 24 hours of life was negative. Conclusions Based on our data, there are no significant placental histopathological changes that occur after diagnosis of SARS-CoV-2 infection in the third trimester of pregnancy compared to a gestational age-matched historical control group. Similar incidences of histopathological findings were also discovered when comparing placentas from patients with SARS-CoV-2 infection with or without the presence of symptoms typically related to infection.

with SARS-CoV-2 infection have been reported thus far, including miscarriage 2,3 , intrauterine 98 fetal demise 4 , preeclampsia 5,6 , preterm delivery 7-9 , maternal critical illness 7-10 and death 11 , as well 99 as neonatal death 12, 13 . Evidence regarding the occurrence of antepartum or peripartum vertical 100 transmission has been conflicting to date. 14-18 101

The placenta represents a highly specialized organ that is crucial for maintaining an optimal 102 environment for fetal development. 19,20 Placental evaluation after delivery provides useful 103 information such as the identification of disease processes in the mother or infant that require 104 attention or diagnoses that provide a specific explanation for an adverse outcome. 21 105

Characteristic histopathological findings in placentas from mothers with viral infections have 106 been reported. 22-25 However, reports on placental evaluation in women with SARS-CoV-2 107 infection have been limited to few case series [26] [27] [28] [29] and the association between infection and 108 abnormal placental findings is not well known. Therefore, the objective of this study was to 109 determine if any significant placental histopathological changes occur after diagnosis of SARS-110

CoV-2 infection in pregnancy and whether these changes are correlated with the presence or 111 absence of symptoms typically related to infection. 112

This was a retrospective cohort study with historical controls. Cases included placentas from all 116 women diagnosed with SARS-CoV-2 infection and delivered at a single center (Long Island 117

Jewish Medical Center -Northwell Health, Queens, NY) from April 9 th to April 27 th , 2020 118 (during the peak of the pandemic in New York). The Northwell Health Institutional Review 119

Board approved this study as minimal-risk research using data collected for routine clinical 120 practice and waived the requirement for informed consent. Women with singleton gestations 121 who had laboratory-confirmed SARS-CoV-2 infection during their pregnancy were eligible for 122

inclusion. Diagnosis of SARS-CoV-2 infection was confirmed using qualitative real-time 123 polymerase chain reaction (PCR) on maternal nasopharyngeal swab specimens. Prior to the study 124 period, universal testing for SARS-CoV-2 infection had been implemented for all obstetrical 125 patients admitted to Labor and Delivery. After delivery, placentas were submitted to the 126 Pathology Department for evaluation. Placentas from women with a high clinical suspicion for 127 placenta accreta diagnosed during the antepartum period, on either ultrasound or magnetic 128 resonance imaging, were excluded. Placental specimens from cases with accreta had morbidly 129 adherent uterus. As a result, several gross examination characteristics, such as placental weight, 130 could not be obtained, and standardized sampling of each placenta for histologic evaluation 131

would not be consistent with that of other placentas in the study. 132

Historical controls were selected from a cohort of women who had placentas submitted to the 133 Pathology Department (including specimens obtained from delivery at North Shore University 134

Hospital -Northwell Health) during November 2019, at least 3 months prior to the first reported 135 case of SARS-CoV-2 infection in New York. The decision for pathological examination at that 136 time was at the discretion of the delivery physician. However, suggested criteria provided by the 137 Pathology Department were generally consistent with the College of American Pathologists 138 guidelines. 30 Historical controls were used, as placentas from patients who tested negative for 139 SARS-CoV-2 infection during the study period may not have represented an appropriate control 140 group due to reported high false negative rates. 31 Controls were matched in a 1:1 fashion by 141

week of gestation at delivery. Gestational age at delivery was selected as the matching variable 142 Health. 33 Mild cases were defined as those who have symptoms typically related to SARS-CoV-172 2 infection, but without dyspnea or abnormal imaging. Moderate cases were defined as those 173 who had evidence of lower respiratory disease by clinical assessment or imaging and a blood 174 oxygen saturation > 93% on room air. Severe cases were defined as those with respiratory rate ≥ 175 30 breaths per minute, blood oxygen saturation ≤ 93% on room air, partial pressure of arterial 176 oxygen to fraction of inspired oxygen < 300 and/or lung infiltrates > 50%. Critical cases were 177 defined as those that exhibited respiratory failure, septic shock and/or multiple organ dysfunction 178 or failure. 179

Two comparative analyses evaluating histopathological characteristics of placentas were 180 performed. The first comparison was between placentas from women after diagnosis of SARS-symptoms related to the infection and those who did not have such typical symptoms. Statistical 184 analysis included use of Wilcoxon rank sum test and Fisher's exact test for comparison of 185 categorical and continuous variables. Statistical significance was defined as P value < 0.05. 186

During the study period, a total of 52 placentas from singleton gestations diagnosed with SARS-189

CoV-2 infection were submitted to the Pathology Department. Two cases with placenta accreta 190 were excluded from the analysis. Therefore, the study cohort included 50 placentas after CoV-2 testing via PCR for all neonates at 24 hours of life was negative. 201

Maternal age, race/ethnicity, parity, gestational age at delivery, mode of delivery, neonatal 202 birthweight, and the number of antepartum or intrapartum complications were similar between 203 patients with SARS-CoV-2 infection and historical controls (Table 1) . Histopathological findings 204 such as accelerated villous maturation or decidual vasculopathy were not visualized in any of the 205 placentas from patients with SARS-CoV-2 infection. There was no statistically significant 206 difference in maternal vascular malperfusion histopathological characteristics such as distal 207 villous hypoplasia (4% vs. 2%), excessive infarction (8% vs. 8%) and old hemorrhage in 208 membranes (2% vs. 4%) between the two groups (Table 2 ). There was also no statistically 209 significant difference in fetal vascular malperfusion (8% vs. 12%), increased perivillous fibrin 210 (12% vs. 14%), intervillous thombi (26% vs. 16%), chorangiosis (6% vs. 2%) or presence of 211 meconium staining (18% vs. 10%) between the two groups ( Table 2) . 212

On subgroup analysis, maternal age, race/ethnicity, parity, gestational age at delivery, mode of 213 delivery, neonatal birthweight, and the number of antepartum or intrapartum complications were 214 similar between patients with SARS-CoV-2 infection who had typical symptoms related to the 215 infection and those who did not have such typical symptoms (Table 3) . Time interval from 216 diagnosis of SARS-CoV-2 infection to delivery was significantly higher among patients who had 217 typical symptoms related to the SARS-CoV-2 infection compared to those who did not have such 218 typical symptoms (12.5 days vs. 0.5 days; P value < 0.001). There was no statistically significant 219 difference in maternal vascular malperfusion histological characteristics such as distal villous 220 hypoplasia (0% vs. 5.9%), excessive infarction (18.8% vs. 2.9%) and old hemorrhage in 221 membranes (6.2% vs. 0%) between the two groups (Table 4 ). There were also no statistically 222 significant differences in fetal vascular malperfusion (6.2% vs. 8.8%), increased perivillous 223 fibrin (12.5% vs. 11.8%), intervillous thombi (37.5% vs. 20.6%), chorangiosis (6.2% vs. 5.9%), 224 or presence of meconium staining (25% vs. 14.7%) between the two groups (Table 4) . 225

The results of our study did not demonstrate significant placental histopathological changes 229 occurring after diagnosis of SARS-CoV-2 infection in the third trimester of pregnancy compared 230 to a gestational-age-matched historical control group with a similar incidence of antepartum or Pathology for examination or due to history of melanoma. 26 Compared to all historical controls, 240 placentas from women infected with SARS-CoV-2 in their cohort showed a higher incidence of 241 decidual arteriopathy (47% vs. 16%; P value = 0.04), delayed villous maturation (27% vs. 4%; P 242 value < 0.001), chorangiosis (27% vs. 5%; P value = 0.001), and intervillous thrombi (40% vs. 243 9%; P = < 0.001). 26 Rates of delayed villous maturation, chorangiosis, and intervillous thrombi 244 were lower in our cohort of placentas from pregnancies with SARS-CoV-2 infection, and reassuring. However, in the absence of placental SARS-CoV-2 testing and standardized serology 294 testing for neonates, we cannot assume or refute vertical transmission. Furthermore, whether 295 these pathology findings would be similar after first or second-trimester SARS-CoV-2 infection 296 and whether earlier infection increases likelihood of vertical transmission is unknown and 297 requires further study. 298

There are several strengths to this study. To our knowledge, and based on a review of the 300 literature, this is the largest reported cohort of examined placentas from pregnancies with SARS-301

CoV-2 infection and first report comparing histopathological findings in women with and 302 without symptoms related to infection. Our control group was matched by gestational age and 303 had the same median maternal age, thus limited possible confounders. Our population is 304 diversified in terms of demographics and derived from New York, where the total number of 305 novel coronavirus infections is among the highest worldwide. Lastly, all placentas were reviewed 306 by one pathologist subsequent to the initial histopathologic examination, which reduced the 307 impact of interobserver variability. 308

There are also several limitations to this study. The pathologist was not blinded to the clinical 309 history or status of SARS-CoV-2 infection for each placenta examined, which may have 310 introduced bias regarding interpretation. This is unlikely since no pattern of significant 311 histopathological changes were found. Despite a larger sample size of cases relative to other 312 reports in the literature, several outcomes had relatively low frequencies. This may have limited 313 power to detect significant differences, particularly when histopathological characteristics in 314 placentas from infected patients with or without symptoms related to SARS-CoV-2 infection 315 were compared. We also utilized a historical control group with several clinical diagnoses that 316 may have contributed to the abnormal pathological findings, as placentas are not routinely sent 317 for examination at our institution. However, rates of these diagnoses were similar between cases 318 from infected pregnancies and controls. We did not test each placenta for the presence of SARS- 

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We would like to acknowledge the contributions of the Northwell Health COVID-19 Research 344Consortium. 345