The placenta in fetal death: molecular evidence of dysregulation of inflammatory, proliferative, and fetal protective pathways - 12/08/24

Doi : 10.1016/j.ajog.2024.06.011

Eleonora Nardi, MD ^a, Isabelle Seidita, PhD ^b, Isabella Abati, MD ^c, Chiara Donati, PhD ^b, Caterina Bernacchioni, PhD ^b, Francesca Castiglione, MD, PhD ^a, Caterina Serena, MD ^c, Federico Mecacci, MD ^c, Enrrico Bloise, PhD ^d,^e, Felice Petraglia, MD ^c,^⁎
^a Pathology, Department of Health Science, University of Florence, Florence, Italy
^b Lipid Cell Signaling and Biology Lab, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
^c Obstetrics and Gynecology, Department of Experimental, Clinical and Biomedical Sciences, Careggi University Hospital, University of Florence, Florence, Italy
^d Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
^e Department of Physiology, University of Toronto, Toronto, ON, Canada

^∗Corresponding author: Felice Petraglia, MD, FRCOG.

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Monday 12 August 2024

Abstract

Background

It is estimated that over 2 million cases of fetal death occur worldwide every year, but, despite the high incidence, several basic and clinical characteristics of this disorder are still unclear. Placenta is suggested to play a central role in fetal death. Placenta produces hormones, cytokines and growth factors that modulate functions of the placental-maternal unit. Fetal death has been correlated with impaired secretion of some of these regulatory factors.

Objective

The aim of the present study was to evaluate, in placentas collected from fetal death, the gene expression of inflammatory, proliferative and protective factors.

Study Design

Cases of fetal death in singleton pregnancy were retrospectively selected, excluding pregnancies complicated by fetal anomalies, gestational diabetes, intrauterine growth restriction and moderate to severe maternal diseases. A group of placentas collected from healthy singleton term pregnancies were used as controls. Groups were compared regarding maternal and gestational age, fetal sex and birthweight. Placental messenger RNA expression of inflammatory (interleukin 6), proliferative (activin A, transforming growth factor β1) and regulatory (vascular endothelial growth factor, vascular endothelial growth factor receptor 2, ATP-binding cassette transporters (ABC) ABCB1 and ABCG2, sphingosine 1-phosphate signaling pathway) markers was conducted using real-time polymerase chain reaction. Statistical analysis and graphical representation of the data were performed using the GraphPad Prism 5 software. For the statistical analysis, Student's t test was used, and P values<.05 were considered significant.

Results

Placental mRNA expression of interleukin 6 and vascular endothelial growth factor receptor 2 resulted significantly higher in the fetal death group compared to controls (P<.01), while activin A, ABCB1, and ABCG2 expression resulted significantly lower (P<.01). A significant alteration in the sphingosine 1-phosphate signaling pathway was found in the fetal death group, with an increased expression of the specific receptor isoforms sphingosine 1-phosphate receptor 1, 3, and 4 (sphingosine 1-phosphate₁, sphingosine 1-phosphate₃, sphingosine 1-phosphate₄) and of sphingosine kinase 2, 1 of the enzyme isoforms responsible for sphingosine 1-phosphate synthesis (P<.01).

Conclusion

The present study confirmed a significantly increased expression of placental interleukin 6 and vascular endothelial growth factor receptor 2 mRNA, and for the first time showed an increased expression of sphingosine 1-phosphate receptors and sphingosine kinase 2 as well as a decreased expression of activin A and of selected ATP-binding cassette transporters, suggesting that multiple inflammatory and protective factors are deranged in placenta of fetal death.

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Key words : activin A, ATP-binding cassette transporters, BCRP, cytokines, fetal death, fibrosis, growth factors, inflammation, IL-6, P-gp, placenta, S1P, sphingosine-1-phosphate pathway, stillbirth, VEGFR2

Plan

Introduction

Material and methods

Study design and selection of samples

Placental pathology

RNA extraction and quantification

Statistical analysis

Results

Placental pathology

Placental mRNA expression

Discussion

Principal findings

Results in the context of what is known

Clinical implications

Research implications

Strengths and limitations

Conclusions

	E.N., I.S., and I.A. contributed equally to this work.
	The authors report no conflict of interest.
	The work was supported by Fondi di Ateneo (ex 60%) to C.B., C.D., and F.P., by Ministry of Education, Universities and Research of Italy (Progetti Dipartimento di Eccellenza to C.D.), by Fondazione Careggi, Project on Woman's Health, by Fondazione Cassa di Risparmio di Firenze to F.P. E.B. is supported by the Higher Education Personnel Improvement Coordination (CAPES-Print fellowship: 88887.370196/2019-00); National Council for Scientific and Technological Development (10578/2020-5; 310489/2023-7), and the Research Support Foundation of the State of Minas Gerais (APQ-00338-18).
	Cite this article as: Nardi E, Seidita I, Abati I, et al. The placenta in fetal death: molecular evidence of dysregulation of inflammatory, proliferative, and fetal protective pathways. Am J Obstet Gynecol 2024;XXX:XX–XX.