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Underestimation of SARS-CoV-2 infection in placental samples [Letter]

Hanna, Nazeeh; Lin, Xinhua; Thomas, Kristen; Vintzileos, Anthony; Chavez, Martin; Palaia, Thomas; Ragolia, Louis; Verma, Sourabh; Khullar, Poonam; Hanna, Iman
PMID: 34297970
ISSN: 1097-6868
CID: 4954872

Placental extracellular vesicles-associated miRNA-519c mediates endotoxin adaptation in pregnancy

Tiozzo, Caterina; Bustoros, Mark; Lin, Xinhua; Manzano de Mejia, Claudia; Gurzenda, Ellen; Chavez, Martin; Hanna, Iman; Aguiari, Paola; Perin, Laura; Hanna, Nazeeh
BACKGROUND:Pregnancy represents a unique challenge for the maternal-fetal immune interface, requiring a balance between immunosuppression, which is essential for the maintenance of a semi-allogeneic fetus, and pro-inflammatory host defense to protect the maternal-fetal interface from invading organisms. Adaptation to repeated inflammatory stimuli (endotoxin tolerance) may be critical in preventing inflammation-induced preterm birth resulting from exaggerated maternal inflammatory responses to mild/moderate infections that are common during pregnancy. However, the exact mechanisms contributing to the maintenance of tolerance to repeated infections are not completely understood. miRNAs play important roles in pregnancy, with several miRNAs implicated in gestational tissue function, as well as in pathologic pregnancy conditions. miRNA-519c, a member of the C19MC cluster, is a human-specific miRNA mainly expressed in the placenta. However, its role in pregnancy is largely unknown. OBJECTIVES/OBJECTIVE:To explore the role of "endotoxin tolerance" failure in the pathogenesis of an exaggerated inflammatory response often seen in inflammation-mediated preterm birth. In this study, we investigated the role of miRNA-519c, a placenta-specific miRNA, as a key regulator of endotoxin tolerance at the maternal-fetal interface. STUDY DESIGN/METHODS:-trimester placentas were treated with LPS. After 24 hours, the conditioned media was collected for analysis, and the placental explants were re-exposed to repeated doses of LPS for 3 days. The supernatant was analyzed for inflammatory markers, presence of extracellular vesicles (EVs) and microRNAs. To study the possible mechanism of action of the microRNAs, we evaluated the phosphodiesterase 3 B (PDE3B) pathway involved in TNF-α production using a miRNAs mimic and PDE3B siRNA transfection. Finally, we analyzed human placental samples from different gestational ages and from women affected by inflammation-associated pregnancies. RESULTS:Our data showed that repeated exposure of the human placenta to endotoxin challenges induced a tolerant phenotype characterized by decreased TNF-α and upregulated IL-10 levels. This reaction was mediated by the placenta-specific miRNA-519c packaged within placental EVs. LPS treatment increased the EVs that were positive for the exosome tetraspanin markers, namely CD9, CD63, and CD81, and secreted primarily by trophoblasts. Primary human trophoblast cells transfected with miR-519c mimic decreased PDE3B. While lack of PDE3B, achieved by siRNA transfection, resulted in a decreased TNF-α production. These data supported the hypothesis that the anti-inflammatory action of miRNA-519c was mediated by a downregulation of the phosphodiesterase 3 B pathway, leading to inhibition of TNF-α production. Furthermore, human placentas from normal and inflammation-associated pregnancies demonstrated that decreased placental miRNA-519c level was linked to infection-induced inflammatory pathologies during pregnancy. CONCLUSION/CONCLUSIONS:We identified miRNA-519c, a human placenta-specific miRNA, as a novel regulator of immune adaptation associated with infection-induced preterm birth at the maternal-fetal interface. Our study can serve as a basis for future experiments to explore the potential use of miRNA-519c as a biomarker for infection-induced preterm birth.
PMID: 34181894
ISSN: 1097-6868
CID: 4926282

Combined Medical and Minimally Invasive Robotic Surgical Approach to the Treatment and Repair of Cesarean Scar Pregnancies [Case Report]

Hoffmann, Eva; Vahanian, Sevan; Martinelli, Vanessa T; Chavez, Martin; Mesbah, Michael; Nezhat, Farr R
Background and Objectives/UNASSIGNED:The rise in cesarean deliveries, has led to increase in maternal complications in subsequent pregnancies such as abnormal placental implantation, uterine rupture, hemorrhage and, less commonly, cesarean scar pregnancies (CSP). Our objective was to describe patient characteristics following a combined medical and surgical treatment approach to first trimester cesarean scar pregnancies. Methods/UNASSIGNED:This was a case series approved by the Institutional Review Board of cesarean scar pregnancies over a two-year period at a single academic institution. The study included five patients with diagnosed cesarean scar pregnancies opting for pregnancy termination with the desire for fertility preservation. Medical treatment involved intra-gestational sac injection of lidocaine followed by systemic injection of methotrexate. At a minimum of two months later, surgical resection of cesarean scar pregnancy and repair of the uterus was performed. Results/UNASSIGNED:Median patient age was 36 (range 34 - 42) years, with 4 (3 - 10) prior pregnancies and 2 (1 - 3) prior cesarean deliveries. 40% (2/5) were Hispanic, 20% (1/5) Caucasian, 20% (1/5) African-American, and 20% (1/5) South Asian. After medical intervention, patients waited on average 4.6 ± 2.3 months before surgery. No post-intervention complications or recurrences occurred. Two patients had a subsequent pregnancy. Conclusion/UNASSIGNED:This case series demonstrates an ideal management of cesarean scar pregnancy using combined medical and surgical approach in treating current ectopic pregnancy and repairing the uterine defect successfully without recurrence.
PMID: 34456552
ISSN: 1938-3797
CID: 5011242

Use of Cervical Elastography at 18 to 22 Weeks Gestation in the Prediction of Spontaneous Preterm Birth

Patberg, Elizabeth; Wells, Matthew; Vahanian, Sevan; Zavala, Jose; Bhattacharya, Sarmistha; Richmond, Diana; Akerman, Meredith; Demishev, Michael; Kinzler, Wendy; Chavez, Martin R; Vintzileos, Anthony
OBJECTIVES/OBJECTIVE:To develop standard cervical elastography nomograms for singleton pregnancies at 18-22 weeks gestation using the E-cervix ultrasound application; assess intra-observer reliability of the E-cervix elastography parameters; and determine if these cervical elastography measurements can be used in the prediction of spontaneous preterm birth. METHODS:This was a prospective cohort study of pregnant women undergoing cervical length screening assessment via transvaginal ultrasound examination at 18 - 22 weeks gestation. A semi-automatic, cervical elastography application (E-cervix) was utilized during the transvaginal examination to calculate five quantitative parameters (Internal Os Stiffness, External Os Stiffness, Internal to External Os Stiffness Ratio, Hardness Ratio, Elasticity Contrast Index) and create a standard nomogram for each one of them. The intra-observer reliability was calculated using Shrout-Fliess reliability. Cervical elastography parameters were compared between those who delivered preterm (<37 weeks) spontaneously versus full term. A multivariable logistic regression model was performed to determine the ability of the cervical elastography parameters to predict spontaneous preterm birth. RESULTS:742 women were included of which 49 (6.6%) had a spontaneous preterm delivery. A standard nomogram was created for each of the cervical elastography parameters from those who had a full term birth in the index pregnancy (n=693). Intra-observer reliability was good or excellent (intraclass correlation (ICC) = 0.757 - 0.887) for each of the cervical elastography parameters except External Os Stiffness which was poor (ICC = 0.441). In univariate analysis, none of the cervical elastography parameters were associated with a statistically significant increased risk of spontaneous preterm birth. In a multivariable model adjusting for history of preterm birth, gravidity, ethnicity, cervical cerclage and vaginal progesterone use, increasing Elasticity Contrast Index was significantly associated with an increased risk of spontaneous preterm birth (OR 1.15, 95%CI [1.02, 1.30]; P=0.02). CONCLUSIONS:Cervical elastography parameters are reliably measured and are stable across 18-22 weeks gestation. Based on our findings, the Elasticity Contrast Index was associated with an increased risk for spontaneous preterm birth and may be the parameter useful for future research.
PMID: 34051170
ISSN: 1097-6868
CID: 4890612

COVID-19 Infection and Placental Histopathology in Women Delivering at Term

Patberg, Elizabeth T; Adams, Tracy; Rekawek, Patricia; Vahanian, Sevan A; Akerman, Meredith; Hernandez, Andrea; Rapkiewicz, Amy V; Ragolia, Louis; Sicuranza, Genevieve; Chavez, Martin R; Vintzileos, Anthony M; Khullar, Poonam
BACKGROUND:- There is a paucity of data describing the effects of COVID-19, especially in asymptomatic patients, on placental pathology. Although the pathophysiology of COVID-19 is not completely understood, there is emerging evidence that it causes a severe systemic inflammatory response and results in a hypercoagulable state with widespread microthrombi. We hypothesized that it is plausible that a similar disease process may occur in the fetal-maternal unit. OBJECTIVE:- The aim of this study was to determine whether COVID-19 in term patients admitted to Labor and Delivery, including women without COVID-19 symptomatology, is associated with increased placental injury compared to a cohort of COVID-19 negative controls. STUDY DESIGN/METHODS:- This was a retrospective cohort study performed at NYU Winthrop Hospital between 3/31/2020 and 6/17/2020. During the study period all women admitted to Labor and Delivery were routinely tested for SARS-CoV-2 regardless of symptomatology. The placental histopathological findings of COVID-19 patients (n=77) who delivered a singleton gestation at term were compared to a control group of term patients without COVID-19 (n=56). Controls were excluded if they had obstetric or medical complications including fetal growth restriction, oligohydramnios, hypertension, diabetes, coagulopathy or thrombophilia. Multivariable logistic regression models were performed for variables that were significant in univariable analyses. A subgroup analysis was also performed comparing asymptomatic COVID-19 cases to negative controls. RESULTS:- In univariable analyses, COVID-19 cases were more likely to have evidence of fetal vascular malperfusion, i.e. presence of avascular villi and/or mural fibrin deposition (32.5% (25/77) vs. 3.6% (2/56), p<0.0001) and villitis of unknown etiology (20.8% (16/77) vs. 7.1% (4/56), p=0.030). These findings persisted in a subgroup analysis of asymptomatic COVID-19 cases compared to COVID-19 negative controls. In a multivariable model adjusting for maternal age, race/ethnicity, mode of delivery, preeclampsia, fetal growth restriction and oligohydramnios, the frequency of fetal vascular malperfusion abnormalities remained significantly higher in the COVID-19 group (OR= 12.63, 95% CI [2.40, 66.40]). While the frequency of villitis of unknown etiology was more than double in COVID-19 cases compared to controls, this did not reach statistical significance in a similar multivariable model (OR=2.11, 95% CI [0.50, 8.97]). All neonates of mothers with COVID-19 tested negative for SARS-CoV-2 by PCR. CONCLUSIONS:- Despite the fact that all neonates born to mothers with COVID-19 were negative for SARS-CoV-2 by PCR, we found that COVID-19 in term patients admitted to Labor and Delivery is associated with increased rates of placental histopathologic abnormalities, particularly fetal vascular malperfusion and villitis of unknown etiology. These findings appear to occur even among asymptomatic term patients.
PMID: 33091406
ISSN: 1097-6868
CID: 4642442

Coronavirus disease 2019 infection and placental histopathology in women delivering at term

Patberg, Elizabeth T.; Adams, Tracy; Rekawek, Patricia; Vahanian, Sevan A.; Akerman, Meredith; Hernandez, Andrea; Rapkiewicz, Amy V.; Ragolia, Louis; Sicuranza, Genevieve; Chavez, Martin R.; Vintzileos, Anthony M.; Khullar, Poonam
ISSN: 0002-9378
CID: 5016142

Confirmatory evidence of visualization of SARS-CoV-2 virus invading the human placenta using electron microscopy [Letter]

Algarroba, Gabriela N; Hanna, Nazeeh N; Rekawek, Patricia; Vahanian, Sevan A; Khullar, Poonam; Palaia, Thomas; Peltier, Morgan R; Chavez, Martin R; Vintzileos, Anthony M
PMID: 32866527
ISSN: 1097-6868
CID: 4582852

Reply to the letter to the editor [Letter]

Algarroba, Gabriela N; Rekawek, Patricia; Vahanian, Sevan A; Khullar, Poonam; Palaia, Thomas; Peltier, Morgan R; Chavez, Martin R; Vintzileos, Anthony M
PMID: 32531214
ISSN: 1097-6868
CID: 4478702

Visualization of SARS-CoV-2 virus invading the human placenta using electron microscopy

Algarroba, Gabriela N; Rekawek, Patricia; Vahanian, Sevan A; Khullar, Poonam; Palaia, Thomas; Peltier, Morgan R; Chavez, Martin R; Vintzileos, Anthony M
PMID: 32405074
ISSN: 1097-6868
CID: 4431402

First trimester maternal serum alpha fetoprotein is associated with ischemic placental disease

Dinglas, Cheryl; Afsar, Nur; Cochrane, Elizabeth; Davis, Jay; Kim, Sara; Akerman, Meredith; Wells, Matthew; Chavez, Martin; Herrera, Kimberly; Heo, Hye; Vintzileos, Anthony
BACKGROUND:While elevated second trimester maternal serum alpha fetoprotein (msAFP) has been associated with adverse pregnancy outcomes, the utility of first trimester msAFP in predicting these outcomes is limited. Some laboratories have been including msAFP as part of the first trimester analyte screening for aneuploidy and preeclampsia, offering its potential utility in predicting pregnancy outcomes. OBJECTIVE:Our primary objective was to determine the association between elevated first trimester msAFP and preeclampsia, as well as ischemic placental disease (a composite of preeclampsia, fetal growth restriction and/or placental abruption). Secondary outcomes included early onset preeclampsia requiring delivery at <34 weeks gestation, fetal growth restriction, placental abruption, preterm delivery, fetal demise, and spontaneous abortion. STUDY DESIGN/METHODS:An IRB-approved multi-site retrospective cohort study was performed including all patients with first trimester msAFP as part of routine first trimester aneuploidy screening from April 2015-January 2017. Pregnancies with multiple gestations, known structural or chromosomal abnormalities, known malignancy, and incomplete delivery records were excluded. Delivery records were reviewed for baseline characteristics and adverse pregnancy outcomes. The optimal cut-off point for first trimester msAFP to predict these outcomes was assessed and an elevated msAFP was considered > 2.0 MoM. Fisher exact test and odds ratios were used to determine the association between elevated first trimester msAFP and adverse pregnancy outcomes. Spearman correlation coefficient assessed the relationship between first and second trimester msAFP. RESULTS:Of 1478 patients with first trimester msAFP, 1280 had complete records available for review (86.6%). There was no association demonstrated between elevated first trimester msAFP (> 2.0 MoM) and the primary outcome, overall preeclampsia (5.8% vs. 4.6%, OR 1.29, 95% CI 0.58, 2.91). However, there was an increased incidence of ischemic placental disease, 15.8% vs 7.7% (OR 2.26, 95% CI 1.33-3.87) in those with an elevated AFP. Also, elevated first trimester msAFP was associated with a higher incidence of fetal growth restriction (7.5% vs 2.3%, OR 3.40, 95% CI 1.56-7.42) and preterm birth (18.3% vs 10.3%, OR 1.95, 95% CI 1.18-3.21). Also, a positive correlation between first and second trimester msAFP was demonstrated (rho = 0.46, P< 0.0001). CONCLUSIONS:Elevated first trimester msAFP is associated with ischemic placental disease, fetal growth restriction, and preterm birth. This suggests that elevated msAFP may help to identify high risk pregnancies as early as the first trimester of pregnancy. Future studies are necessary to determine if addition of first trimester msAFP to existing algorithms can improve the early detection of ischemic placental disease.
PMID: 31794723
ISSN: 1097-6868
CID: 4252112