Immune Dysregulation and Trophoblastic Dysfunction as a Potential Cause of Idiopathic Recurrent Pregnancy Loss

Biology, vol. 14, pp. 811

Abstract

Recurrent pregnancy loss (RPL) is a multifactorial condition affecting 1-5% of couples, often with unclear etiology. Idiopathic pregnancy losses (iPLs) are particularly challenging due to unknown molecular mechanisms. This study investigates the transcriptomic profiles of first-trimester products of conception (POC) from iPLs to uncover underlying molecular pathways. We performed RNA-sequencing on nine POC samples, identifying two distinct clusters enriched in trophoblast and decidual cells. Deconvolution analysis revealed reduced syncytiotrophoblast (STB) cells, with increased cytotrophoblast (CTB) and extravillous trophoblast (EVT) cells in iPLs. Gene Set Enrichment Analysis highlighted immune pathways enrichment in both villous trophoblasts and decidua. Gene ontology (GO) analysis of downregulated genes implicated hormonal and endocrine processes, consistent with STB reduction, while upregulated genes were associated with MHC protein complex and immune system processes, aligning with EVT increases. Histological analysis showed chronic histiocytic intervillositis (CHI) in iPL samples, supporting maternal immune dysregulation in unexplained RPL. Together, transcriptomic and histological analyses indicate that immune signaling dysregulation and impaired trophoblast differentiation may underlie unexplained iPLs. These findings bridge molecular and histopathological evidence, underscoring the interplay between trophoblast dysfunction and immune imbalance. Our results provide insights into iPL pathogenesis, highlighting potential biomarkers that may contribute to improved diagnosis and future research.

Authors 10

1. Sara Vasconcelos

   Universidade do Porto

   Affiliation as printed

   Genetics Unit, Department of Pathology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal

   RISE-Health, Department of Pathology, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal

2. Ana Costa Braga

   Universidade do Porto · Hospital de São João

   Affiliation as printed

   Department of Pathology, Centro Hospitalar Universitário São João (CHUSJ), ULS São João, 4200-319 Porto, Portugal

   Department of Pathology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal

3. Ioannis Moustakas Aachen Department of Anatomy and Embryology Sequencing Analysis Support Core

   Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands

   Sequencing Analysis Support Core, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands

4. Bruno Cavadas

   Universidade do Porto · i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto

   Affiliation as printed

   i3S—Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal

5. Mariana Santos

   Universidade do Porto

   Affiliation as printed

   Genetics Unit, Department of Pathology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal

6. Carla Caniçais

   Universidade do Porto

   Affiliation as printed

   Genetics Unit, Department of Pathology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal

7. Carla Maria Almeida Ramalho

   Universidade do Porto · Hospital de São João

   Affiliation as printed

   Department of Obstetrics and Gynaecology, Faculty of Medicine, Centro Hospitalar Universitário São João (CHUSJ), ULS São João, 4200-319 Porto, Portugal

   RISE-Health, Department of Pathology, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal

8. Susana M. Chuva de Sousa Lopes Aachen Department of Anatomy and Embryology

   Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands

9. Cristina Joana Marques

   Universidade do Porto

   Affiliation as printed

   Genetics Unit, Department of Pathology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal

   RISE-Health, Department of Pathology, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal

10. Sofia Dória corresponding

    Universidade do Porto

    Affiliation as printed

    Genetics Unit, Department of Pathology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal

    RISE-Health, Department of Pathology, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal