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Licensed Unlicensed Requires Authentication Published by De Gruyter October 18, 2022

Molecular subclasses of preeclampsia characterized by a longitudinal maternal proteomics study: distinct biomarkers, disease pathways and options for prevention

  • Nándor Gábor Than EMAIL logo , Roberto Romero , Dániel Györffy , Máté Posta , Gaurav Bhatti , Bogdan Done , Piya Chaemsaithong , Eunjung Jung , Manaphat Suksai , Francesca Gotsch , Dahiana M. Gallo , Mariachiara Bosco , Bomi Kim , Yeon Mee Kim , Tinnakorn Chaiworapongsa , Simona W. Rossi , András Szilágyi , Offer Erez , Adi L. Tarca and Zoltán Papp EMAIL logo



The heterogeneous nature of preeclampsia is a major obstacle to early screening and prevention, and a molecular taxonomy of disease is needed. We have previously identified four subclasses of preeclampsia based on first-trimester plasma proteomic profiles. Herein, we expanded this approach by using a more comprehensive panel of proteins profiled in longitudinal samples.


Proteomic data collected longitudinally from plasma samples of women who developed preeclampsia (n=109) and of controls (n=90) were available from our previous report on 1,125 proteins. Consensus clustering was performed to identify subgroups of patients with preeclampsia based on data from five gestational-age intervals by using select interval-specific features. Demographic, clinical, and proteomic differences among clusters were determined. Differentially abundant proteins were used to identify cluster-specific perturbed KEGG pathways.


Four molecular clusters with different clinical phenotypes were discovered by longitudinal proteomic profiling. Cluster 1 involves metabolic and prothrombotic changes with high rates of early-onset preeclampsia and small-for-gestational-age neonates; Cluster 2 includes maternal anti-fetal rejection mechanisms and recurrent preeclampsia cases; Cluster 3 is associated with extracellular matrix regulation and comprises cases of mostly mild, late-onset preeclampsia; and Cluster 4 is characterized by angiogenic imbalance and a high prevalence of early-onset disease.


This study is an independent validation and further refining of molecular subclasses of preeclampsia identified by a different proteomic platform and study population. The results lay the groundwork for novel diagnostic and personalized tools of prevention.

Corresponding authors: Nándor Gábor Than, MD, PhD, Systems Biology of Reproduction Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary; Maternity Private Clinic of Obstetrics and Gynecology, Budapest, Hungary; Genesis Theranostix Group, Budapest, Hungary; First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary; Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA; and Genesis Theranostix Group, Budapest, Hungary; E-mail: ; and Prof. Zoltán Papp, MD, DSci, Maternity Private Clinic of Obstetrics and Gynecology, Budapest, Hungary; Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary, E-mail:

Award Identifier / Grant number: Contract No. HHSN275201300006C

Award Identifier / Grant number: Momentum Grant LP2014-7/2014


We thank Maureen McGerty (Wayne State University) for her critical reading of the manuscript.

  1. Research funding: The study was funded, in part, by the Perinatology Research Branch, Division of Obstetrics and Maternal Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services (NICHD/NIH/DHHS), and partly with Federal funds from NICHD/NIH/DHHS under contract No. HHSN275201300006C. ALT was supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health. Data analysis and manuscript writing was also funded by the Hungarian Academy of Sciences Momentum Grant LP2014-7/2014 and the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the FIEK_16-1-2016-0005, K124862, K128262, 2020-1.1.2-PIACI-KFI-2021-00273 and 2020-1.1.5-GYORSÍTÓSÁV-2021-00012 funding schemes.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: No potential conflict of interest was reported by the authors. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results. RR has contributed to this work as part of his official duties as an employee of the United States Federal Government.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: Research involving human subjects complied with all relevant national regulations and institutional policies; is in accordance with the tenets of the Helsinki Declaration (as revised in 2013); data and specimens were collected under the protocol “Biological Markers of Disease in the Prediction of Preterm Delivery, Preeclampsia and Intra-Uterine Growth Restriction: A Longitudinal Study.” The study was approved by the Institutional Review Boards of NICHD (OH97-CH-N067) and Wayne State University (WSU IRB#110605MP2F). All patients provided written informed consent prior to sample collection.


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Supplementary Material

The online version of this article offers supplementary material (

Received: 2022-09-05
Accepted: 2022-09-09
Published Online: 2022-10-18
Published in Print: 2023-01-27

© 2022 Walter de Gruyter GmbH, Berlin/Boston

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