Tag Archives: placenta

Common mechanisms of placental dysfunction in preeclampsia, gestational diabetes, and COVID-19 in pregnant women

S. G. Vari1*, O. Shevchuk2, A. Boychuk3, S. Kramar4,
Z. Nebesna4, Y. Yakymchuk5, L. Kobylinska6, V. Chernyshenko7,
D. Korolova7, A. Gaspar-Suranyi8, T. Altorjay8, R. Gaspar9

1International Research and Innovation in Medicine Program, Cedars-Sinai Medical Center, Los Angeles, California, USA;
2Department of Pharmacology and Clinical Pharmacology, I. Horbachevsky Ternopil National Medical University, Ukraine;
3Department of Obstetrics and Gynecology, I. Horbachevsky Ternopil National Medical University, Ukraine;
4Department of Histology and Embryology, I. Horbachevsky Ternopil National Medical University, Ukraine;
5Department of Therapeutics and Family Medicine, I. Horbachevsky Ternopil National Medical University, Ukraine;
6Department of Biochemistry, Danylo Halytsky Lviv National Medical University, Ukraine;
7Department of Protein Structure and Function, Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
8Department of Obstetrics and Gynecology, Albert Szent-Györgyi Medical School, University of Szeged, Hungary;
9Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical School, University of Szeged, Hungary;
*e-mail: sandor.vari@cshs.org

Received: 13 June 2023; Revised: July 2023;
Accepted: July 2023; Available on-line: 11 July 2023

COVID-19 infection, preeclampsia and gestational diabetes mellitus in pregnancy cause similar changes in the placenta and influence development of the fetus between conception and birth in gestation. Proper uterine and placental vascularization is essential for normal fetal development. The transplacental exchange is regulated and maintained by the placental endothelium. During placental implantation, the trophoblast differentiates into two distinct layers, the inner cytotrophoblast and outer syncytiotrophoblast, which are key elements of the human placental barrier. Proinflammatory cytokines exacerbate ischemic events and create an upward spiral of an inflammatory reaction in the placenta. Placental pathology in gestational COVID-19 shows desquamation and damage of trophoblast and chronic histiocytic intervillositis. Similar lesions also occur in gestational diabetes mellitus and preeclampsia. The systemic inflammatory response of the mother, the increased inflammation in the placenta and cytokine production by placental trophoblasts should be monitored throughout pregnancy. Placental angiogenesis can be evaluated by serum vascular endothelial growth factor, Annexin A2, placental growth factor or sclerostin. Tissue damage can be assessed by measuring levels of serum lactate dehydrogenase and myeloperoxidase. Blood flow can be monitored with three-dimensional Doppler and pathological changes can be documented with paraffin-embedded tissue sections stained with hematoxylin and eosin, and electron microscope images as well as immunohistochemistry tests for vascular endothelial growth factor, placental growth factor, sclerostin and Annexin A2. The damage of maternal and fetal vascular perfusion (villitis and fibrin deposition) is a common mechanism of gestational diseases. The placenta lesions liberate anti-endothelial factors that lead to anti-angiogenic conditions and are the common mechanism of maternal placental vascular malperfusion in gestational diseases.

Inflammation is the common mechanism of diseases (CMD) in COVID-19 disease during pregnancy and in gestational diabetes mellitus

Sandor G. Vari

Cedars-Sinai Medical Center, International Research and Innovation in Medicine Program, Los Angeles, California, United States

The Regional Cooperation for Health, Science and Technology (RECOOP HST) Consortium, led by Cedars-Sinai Medical Center was formed in 2006, was transformed into an Association in 2012 and includes 17 universities and academic organizations from eight countries: seven in Central and Eastern Europe (Croatia, Czech Republic, Hungary, Poland, Romania, Slovakia, Ukraine) and the United States. RECOOP builds multinational, multidisciplinary collaborations, and assists as well as coordinates the research activities of the sixteen research groups that are the Cedars-Sinai Medical Center – RECOOP Research Centers (CRRCs). https://www.cedars-sinai.org/research/administration/recoop.html.
Implementations of RECOOP’s strategic goals enable diverse talents geared towards integration of new knowledge derived from multiple specialties to investigate Common Mechanism of Diseases (CMD). While some may consider RECOOP’s CMD research strategy unorthodox, recent and timely scientific evidence shows that inflammation is the triggering event in the change of vascularization and it is the common mechanism of these two diseases: COVID-19 Disease during pregnancy and gestational diabetes mellitus (GDM).
Binding of the SARS-CoV-2 virus to the ACE2 receptor and its entrance into endothelial cells plays a role in vascular thrombosis but has a lesser effect placental endothelial dysfunction. The latter is induced by inflammation and exacerbated by proinflammatory cytokines, resulting in ischemic events and creating an upward spiral of an inflammatory reaction in pregnant women, accompanied by similar conditions in the placenta that will ultimately affect fetal development. In mild or moderate COVID-19 disease, changes in placental vascularization and blood flow have similarities to comorbidities in pregnancy such as GDM. However, during severe or critical stages of COVID-19 Disease, the changes could be harsher than those observed in GDM.
In COVID-19 Disease and GDM the immune status of pregnant women and consequently the newborn is altered due to inflammation and characterized by changes in levels of C-reactive protein (CRP), immunoglobulins (IgG, IgM, IgA) and proinflammatory cytokines that are detectable in maternal and umbilical cord blood and in mother milk.
To examine changes and monitor placental angiogenesis it is necessary to measure Vascular Endothelial Growth Factor (VEGF), Placental Growth Factor (PLGF), and Umbilical Cord Blood Sclerostin (UCBS) in maternal and umbilical cord blood serum. The angiogenic activity of sclerostin must be validated with the well-known marker VEGF, which is a proven indicator for changes in vascularization. The morphology of the vascular tree and blood flow in the placenta could be evaluated with three-dimensional power Doppler. The proinflammatory and ischemic effects in the placenta should be quantified with histopathology and immunohistochemistry. Changes in blood flow in the placenta and the morphology of the vascular tree in COVID-19 Disease during pregnancy may have similarities to those observed in GDM.
In summary, to improve maternal and fetal outcomes it is imperative to formulate better strategies for managing pregnancies during COVID-19 Disease and comorbidities like GDM. VEGF, PLGF and UCBS could be predictors of placental weight, birth weight, and fetal outcomes. In addition, further studies are needed to investigate the effects, if any, of proinflammatory and anti-inflammatory cytokines on postnatal development.