Evidence of Placental Villous Inflammation and Apoptosis in Third-Trimester Symptomatic SARS-CoV-2 Maternal Infection

Overview

Journal Yonsei Med J

Specialty General Medicine

Date 2024 Mar 22

PMID 38515357

Authors

Manggala Pasca Wardhana

Kuntaman Kuntaman

Budi Utomo

Rozi Aditya Aryananda

Salsabila Nabilah Rifdah

Ifan Ali Wafa

Almira Aulia Shahnaz

Dahlia Ningrum

Nareswari Imanadha Cininta

Grace Ariani

Jan Mm Van Lith

Erry Gumilar Dachlan

Affiliations

Soon will be listed here.

Abstract

Purpose: In view of conflicting reports on the ability of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to infect placental tissue, this study aimed to further evaluate the impact of inflammation and placental damage from symptomatic third-trimester maternal COVID-19 infection.

Materials And Methods: This case-control study included 32 placenta samples each from symptomatic COVID-19 pregnancy and normal non-COVID-19 pregnancy. The villous placental area's inflammatory expression [angiotensin converting enzyme-2 (ACE-2), transmembrane protease serine-2 (TMPRSS2), interferon-γ (IFN-γ), interleukin-6 (IL-6), and SARS-CoV-2 spike protein] and apoptotic rate were examined using immunohistochemistry and Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assay. Comparison and correlation analysis were used based on COVID-19 infection, placental SARS-CoV-2 spike protein evidence, and maternal severity status.

Results: Higher expressions of TMPRSS2, IFN-γ, and trophoblast apoptotic rate were observed in the COVID-19 group (<0.001), whereas ACE-2 and IL-6 expressions were not significantly different from the control group (>0.05). Additionally, SARS-CoV-2 spike protein was detected in 8 (25%) placental samples of COVID-19 pregnancy. COVID-19 subgroup analysis revealed increased IFN-γ, trophoblast, and stromal apoptosis (<0.01). Moreover, the results of the current study revealed no correlation between maternal COVID-19 severity and placental inflammation as well as the apoptotic process.

Conclusion: The presence of SARS-CoV-2 spike protein as well as altered inflammatory and apoptotic processes may indicate the presence of placental disturbance in third-trimester maternal COVID-19 infection. The lack of correlation between placental disruption and maternal severity status suggests the need for more research to understand the infection process and any potential long-term impacts on all offsprings born to COVID-19-infected pregnant women.

References

Agostinis C, Toffoli M, Spazzapan M, Balduit A, Zito G, Mangogna A . SARS-CoV-2 modulates virus receptor expression in placenta and can induce trophoblast fusion, inflammation and endothelial permeability. Front Immunol. 2022; 13:957224. PMC: 9513489. DOI: 10.3389/fimmu.2022.957224. View

Shook L, Sullivan E, Lo J, Perlis R, Edlow A . COVID-19 in pregnancy: implications for fetal brain development. Trends Mol Med. 2022; 28(4):319-330. PMC: 8841149. DOI: 10.1016/j.molmed.2022.02.004. View

Hecht J, Quade B, Deshpande V, Mino-Kenudson M, Ting D, Desai N . SARS-CoV-2 can infect the placenta and is not associated with specific placental histopathology: a series of 19 placentas from COVID-19-positive mothers. Mod Pathol. 2020; 33(11):2092-2103. PMC: 7395938. DOI: 10.1038/s41379-020-0639-4. View

McDonald A, Mew E, Hawley N, R Lowe S . Anticipating the long-term neurodevelopmental impact of the COVID-19 pandemic on newborns and infants: A call for research and preventive policy. J Affect Disord Rep. 2021; 6:100213. PMC: 8417611. DOI: 10.1016/j.jadr.2021.100213. View

Algarroba G, Rekawek P, Vahanian S, Khullar P, Palaia T, Peltier M . Visualization of severe acute respiratory syndrome coronavirus 2 invading the human placenta using electron microscopy. Am J Obstet Gynecol. 2020; 223(2):275-278. PMC: 7219376. DOI: 10.1016/j.ajog.2020.05.023. View

Joshi B, Chandi A, Srinivasan R, Saini S, Prasad G, Puri G . The placental pathology in Coronavirus disease 2019 infected mothers and its impact on pregnancy outcome. Placenta. 2022; 127:1-7. PMC: 9293376. DOI: 10.1016/j.placenta.2022.07.009. View

Brum A, Vain N . Impact of perinatal COVID on fetal and neonatal brain and neurodevelopmental outcomes. Semin Fetal Neonatal Med. 2023; 28(2):101427. PMC: 9991322. DOI: 10.1016/j.siny.2023.101427. View

Ouyang Y, Bagalkot T, Fitzgerald W, Sadovsky E, Chu T, Martinez-Marchal A . Term Human Placental Trophoblasts Express SARS-CoV-2 Entry Factors ACE2, TMPRSS2, and Furin. mSphere. 2021; 6(2). PMC: 8546705. DOI: 10.1128/mSphere.00250-21. View

Bwire G, Majigo M, Njiro B, Mawazo A . Detection profile of SARS-CoV-2 using RT-PCR in different types of clinical specimens: A systematic review and meta-analysis. J Med Virol. 2020; 93(2):719-725. PMC: 7404904. DOI: 10.1002/jmv.26349. View

10.

Soullane S, Spence A, Abenhaim H . Association of placental pathology and gross morphology with autism spectrum disorders. Autism Res. 2021; 15(3):531-538. DOI: 10.1002/aur.2658. View

11.

Faure-Bardon V, Isnard P, Roux N, Leruez-Ville M, Molina T, Bessieres B . Protein expression of angiotensin-converting enzyme 2, a SARS-CoV-2-specific receptor, in fetal and placental tissues throughout gestation: new insight for perinatal counseling. Ultrasound Obstet Gynecol. 2020; 57(2):242-247. PMC: 7461228. DOI: 10.1002/uog.22178. View

12.

Di Girolamo R, Khalil A, Alameddine S, DAngelo E, Galliani C, Matarrelli B . Placental histopathology after SARS-CoV-2 infection in pregnancy: a systematic review and meta-analysis. Am J Obstet Gynecol MFM. 2021; 3(6):100468. PMC: 8379009. DOI: 10.1016/j.ajogmf.2021.100468. View

13.

Argueta L, Lacko L, Bram Y, Tada T, Carrau L, Rendeiro A . Inflammatory responses in the placenta upon SARS-CoV-2 infection late in pregnancy. iScience. 2022; 25(5):104223. PMC: 8996470. DOI: 10.1016/j.isci.2022.104223. View

14.

Remmele W, Stegner H . [Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue]. Pathologe. 1987; 8(3):138-40. View

15.

Bugra A, Das T, Arslan M, Ziyade N, Buyuk Y . Postmortem pathological changes in extrapulmonary organs in SARS-CoV-2 rt-PCR-positive cases: a single-center experience. Ir J Med Sci. 2021; 191(1):81-91. PMC: 8104039. DOI: 10.1007/s11845-021-02638-8. View

16.

Heerema-McKenney A . Defense and infection of the human placenta. APMIS. 2018; 126(7):570-588. DOI: 10.1111/apm.12847. View

17.

Rebutini P, Zanchettin A, Stonoga E, Pra D, Luiz Parmegiani de Oliveira A, da Silva Deziderio F . Association Between COVID-19 Pregnant Women Symptoms Severity and Placental Morphologic Features. Front Immunol. 2021; 12:685919. PMC: 8187864. DOI: 10.3389/fimmu.2021.685919. View

18.

Juttukonda L, Wachman E, Boateng J, Jain M, Benarroch Y, Taglauer E . Decidual immune response following COVID-19 during pregnancy varies by timing of maternal SARS-CoV-2 infection. J Reprod Immunol. 2022; 151:103501. PMC: 8867981. DOI: 10.1016/j.jri.2022.103501. View

19.

Mullins E, Evans D, Viner R, OBrien P, Morris E . Coronavirus in pregnancy and delivery: rapid review. Ultrasound Obstet Gynecol. 2020; 55(5):586-592. DOI: 10.1002/uog.22014. View

20.

Hosier H, Farhadian S, Morotti R, Deshmukh U, Lu-Culligan A, Campbell K . SARS-CoV-2 infection of the placenta. J Clin Invest. 2020; 130(9):4947-4953. PMC: 7456249. DOI: 10.1172/JCI139569. View