Research trajectory of the mechanism of preeclampsia: a scientometric perspective

Abstract

Objective

This study aims to conduct a scientometric analysis on the research history and emerging trends of the pathogenesis of preeclampsia using CiteSpace and VOSviewer software. The goal is to provide guidance for future research and clinical practice. Methods: The core collection database of Web of Science was searched for research literature on the mechanism of preeclampsia from January 1980 to March 2024. CiteSpace6. 1. R6, 5. 7. R5 (64-bit), and VOSviewer1.6.19 software were used for visual analysis, including networks of keywords, countries, authors, institutions, funds, and fields.

Results

A total of 4989 documents were analyzed in this study. The number of published articles has shown a consistent increase from 1990 to 2022, indicating that this topic remains a significant area of research. The countries, institutions, authors, journals, and fields that contributed the most articles include the USA, University of Mississippi, Lamarca, Babbette, Placenta, and the field of OBSTETRICS and GYNECOLOGY. Keyword clustering and emergence analysis identified 7 clusters, while clustering and emergence analysis of cited documents identified 14 clusters. These analyses revealed that current research on the mechanism of preeclampsia primarily focuses on placental ischemia and hypoxia, inflammatory response and immune disorders, angiogenic factor imbalance, abnormal epigenetic modifications, and intestinal flora imbalance.

Conclusions

Research on the mechanisms of preeclampsia is rapidly advancing. Given the presence of multiple mechanisms and pathways, further collaborative research is essential to guide clinical treatment effectively and enhance maternal and child outcomes.

Introduction

Preeclampsia is a hypertensive disorder that occurs during pregnancy and can result in damage to multiple organ functions, leading to various adverse outcomes for both the mother and fetus. These outcomes include HELLP syndrome, placental abruption, fetal growth restriction, premature birth, and stillbirth. While termination of pregnancy is often considered the ultimate solution, numerous studies have indicated that preeclampsia can have long-term negative effects on both the mother and child [1]. For instance, mothers with preeclampsia have been found to have a 3.74-fold increased risk of cardiovascular events [2], while children have an 18% higher likelihood of developing neurodevelopmental disorders [3]. As a result, individuals affected by preeclampsia necessitate extended follow-up care. The pathogenesis of preeclampsia remains unclear, but the widely accepted 'two-stage theory' suggests that the disorder involves inadequate trophoblast cell growth, invasion, and movement in the first stage, leading to abnormal placental positioning and inadequate remodeling of spiral arteries. This results in ongoing placental issues such as ischemia and hypoxia. The second stage involves the release of various substances by the placenta into the bloodstream, which affects blood vessels and triggers an excessive inflammatory response throughout the body. Additionally, maintaining maternal immune tolerance to semi-allogeneic zygotes is crucial for preserving pregnancy homeostasis. Disruption of this immune tolerance by any factor may contribute to adverse pregnancy outcomes [4,5,6]. Finally, an imbalance in the gut microbial community is linked to preeclampsia [7]. This condition stems from the interaction of various mechanisms, and its presence worsens their progression, leading to a detrimental cycle. Currently, preeclampsia can only be anticipated by identifying high-risk factors such as being a first-time mother, advanced age, obesity, history of diabetes, hypertension, immune diseases, family history of preeclampsia, and using risk screening models [8]. Low-dose aspirin is utilized for prevention [9]. Therefore, a thorough understanding of the pathogenesis of preeclampsia is crucial to reducing its incidence at its core.

Bibliometrics, originating in the early twentieth century and becoming an independent discipline in 1969 [10], is a valuable tool in document analysis [11]. It enables the use of quantitative methods to systematically review and explore existing literature in a specific field [12], extracting detailed information such as authors, keywords, journals, countries, institutions, and references. Particularly crucial in the medical field [13], bibliometrics can help predict emerging trends and focuses. Utilizing tools like CiteSpace for visualizing and analyzing trends and VOSviewer for building bibliometric networks, this study analyzes the core collection database of Web of Science. By creating co-occurrence and co-citation networks on the application of whole-exome sequencing in prenatal diagnosis, visual analysis of key indicators is conducted to understand the knowledge structure, hot spots, trends, and frontiers in this research field. The findings aim to provide suggestions and references for clinical work and future research endeavors.

Materials and methods

Search strategy and data sources

This study utilized the Web of Science Core Collection database (WOSCC), recognized as a comprehensive database for scientometric analysis [14], to gather data. The citation index was set to 'all' to ensure data retrieval accuracy. The search formula included terms such as 'Pre-Eclampsia,' 'Pregnancy Toxemia,' 'Gestosis,' and others, combined with ‘mechan*’. The search range spanned from the inception of the database to March 14, 2024. To minimize bias from database updates, complete records of references and citations were captured on the same day and exported to a plain text file.

Inclusion and exclusion criteria

Inclusion criteria: (1) Literature on the application of whole-exome sequencing in prenatal diagnosis from January 1980 to December 2024; (2) The language is English; (3) The article type is 'article' or 'review'.

Exclusion criteria: (1) Conference abstracts, letters, lectures, newspapers, patents, editorial materials, books, chapters, withdrawn publications, etc., unpublished articles, copies, and any articles not related to the topic of this study; (2) Elimination of duplicate data with CiteSpace.

Statistical analysis

VOSviewer 1.6.19 software was utilized to analyze co-occurring journals, keywords, and co-cited document networks. Additionally, CiteSpace 6.1.R6 and 5.7.R5 (64-bit) were employed for extracting collaboration networks involving countries, institutions, funds, and authors. Citation analysis was conducted to explore co-cited authors, journals, and document clustering, as well as co-occurrence analysis to identify co-occurring author keywords and document field networks. Burst analysis and timeline analysis were also performed. Notably, CiteSpace 5.7.R5 (64-bit) was used to create impact flow diagrams of keywords and co-cited documents to assess the influence of co-cited documents. Various key indicators were analyzed, such as temporal indicators like citation burstness, and structural indicators like centrality, modularity (Q score), and silhouette score (S score). The Q score ranges from 0 to + 1, with a value above 0.3 indicating significant clustering structure. Similarly, the S score ranges from -1 to + 1, with values exceeding 0.3, 0.5, or 0.7 suggesting homogeneity, reasonability, or high credibility within the network. Cluster labels were derived from noun phrases in the keyword lists of articles cited in each cluster through a likelihood ratio test (p < 0.001). According to Price’s law [14], ${\text{P }} = \, 0.{749}\sqrt {N{\text{max}}}$ (where Nmax represents the author's maximum number of publications, and the core author is defined as having several publications greater than P). The time period considered is from January 1900 to December 2024, with a time slice of 2 years.

Results

A total of 5210 articles were retrieved from the WOSCC database initially. After screening, 4989 documents were ultimately included in the analysis. Figure 1 provides a visual representation of the literature screening process. The analysis encompassed 4989 documents, 85,781 citing documents, 81,834 articles post-exclusion of self-citations, 152,668 total citations, 133,663 citations after self-citations were removed. The average number of citations per article was calculated to be 30.59, and the h-index was determined to be 151.

Fig. 1

Flow chart of literature screening process

Publication trends

The annual number of publications can serve as a reflection of the research trends within a specific field [15]. As depicted in Fig. 2, the number of published articles steadily rose from 1990 to 2022, experiencing a slight decline in 2022 and 2023 but consistently remaining above 450 articles. This indicates a sustained level of interest and focus on researching the mechanism of preeclampsia.

Fig. 2

Trends in the number of publications from 1990 to 2024

Author analysis

By examining the author collaboration network, we gain insights into the collaboration patterns among prominent researchers and teams in the field. Identifying the core author is crucial as they serve as the foundation of the research field, offering valuable insights into the dynamics of research. In this research, 133 core authors with over 5 published articles were identified using Price's Law formula, with a total of 1,239 published documents considered. The top 10 authors with the highest number of published articles are listed in Table 1. Utilizing CiteSpace software, a network diagram of core authors was constructed. Additionally, an analysis of authors based on citations resulted in a network diagram showcasing authors with over 150 citations, illustrated in Fig. 3. Table 2 presents the top 10 cited authors, while Table 3 highlights the emergence of cited authors.

Table 1 The top 10 authors with the highest number of publications

Fig. 3

(A) Author collaboration network: Node size indicates publication count, and node color reflects the research timeline (red = recent). Links represent collaboration strength. Prominent authors, such as Granger, Joey P, and Lamarca, Babette, focus on oxidative stress and angiogenic imbalance. Sub-networks highlight collaborations on placental dysfunction and immune dysregulation. (B) Co-citation network: Node size reflects citation frequency, and links represent co-citation relationships. Key authors like Roberts, JM, and Redman, CWG contributed foundational studies on placental ischemia and inflammatory mechanisms. The network shows strong interdisciplinary connections

Table 2 The top 10 authors with the highest number of publications cited

Table 3 Top 25 Cited Authors with the Strongest Citation Bursts

The most prolific author in terms of publications is Lamarca, Babbette, affiliated with the University of Mississippi Medical Center, having published 41 research papers on the mechanisms of preeclampsia. Lamarca's work focuses on in vivo and in vitro research, as well as the pathophysiology and clinical management of preeclampsia mechanisms. One notable research finding [16] highlights the role of CD4 + T cells as crucial mediators of oxidative stress, potentially leading to hypertension due to placental ischemia. Following Lamarca, Joey P. Granger ranks second with 40 publications. Granger's research revealed that enhanced NOS coupling of the metabolite tetrahydrobiopterin (BH4) mitigates the effects of preeclampsia/IUGR [17] and elevates activin A levels during pregnancy, which could contribute to cardiac dysfunction associated with preeclampsia [18]. The most cited author, ROBERTS JM from the University of Pittsburgh, explored the connection between preeclampsia and cardiomyopathy susceptibility, identifying a higher prevalence of protein-changing mutations in genes related to cardiomyopathy, particularly in the TTN gene, among women who develop preeclampsia [19]. RANA S, with a citation strength of 49.99 and affiliated with the University of Chicago, is another highly cited author in the field. RANA S's research delves into the mechanisms of angiogenic factor alterations in preeclampsia, offering insights for potential new preventive and therapeutic strategies for preeclampsia [20].

Literature research scope, fund projects and journal distribution

The scope of literature research, funding for projects, and journal distribution are important aspects to consider. Top publications cover categories such as OBSTETRICS & GYNECOLOGY with 1368 articles, REPRODUCTIVE BIOLOGY with 761 articles, and CARDIOVASCULAR SYSTEM & CARDIOLOGY with 687 articles, which may provide insights into preeclampsia. Mechanism research is closely related to the above categories. See Table 4 and Fig. 4. Funding sources and frequency of support for research findings in the literature include the National Natural Science Foundation of China with 346 grants, the National Institutes of Health with 173 grants, and NIH with 116 grants. The allocation of funds at a national level highlights the significant research activity in this field. See Table 5 and Fig. 5.

Table 4 The top 10 categories with the highest number of publications

Fig. 4

Research domain co-occurrence network: Node size represents publication volume, and links indicate interdisciplinary collaboration. Key domains like “Obstetrics and Gynecology,” “Cardiovascular System and Cardiology,” and “Reproductive Biology” reflect central research areas, with strong connections to "Immunology" and "Molecular Biology."

Table 5 The top 10 funds with the highest number of publications

Fig. 5

Visualization map of grants containing more than 20 articles. Each node represents a grant, with node size proportional to the number of supported documents. Lines between nodes indicate cooperation between grants. Major grants, such as the "National Natural Science Foundation of China" and "National Institutes of Health," dominate the network

Journals with over 100 publications include Prenatal, American Journal of Obstetrics and Gynecology, and American Journal of Hypertension, with Prenatal leading with 241 articles (Table 6). The top journals with the highest citation frequency are AM J OBSTET GYNECOL, PLACENTA, HYPERTENSION, etc (Table 7). Impact factors of journals with significant publications and high-frequency citations were analyzed to study the field's influence. Journals like LANCET and NEW ENGL J MED with high impact factors and high citation frequencies indicate high-quality research. Visualization of journals with over 20 publications by VOSviewer and over 1,000 citations by CiteSpace is depicted in Fig. 6.

Table 6 The top 10 journals with the highest number of publications

Table 7 The top 10 journals with the highest number of publications cited

Fig. 6

A Visualization map of journals containing more than 20 articles created using VOSviewer. Each node represents a journal, with the node size proportional to the number of published articles. Lines between nodes indicate cooperation between journals. Prominent journals, such as American Journal of Obstetrics and Gynecology, Hypertension, and Placenta, are central to the network. B Visualization map of journals cited more than 1000 times created using CiteSpace. Each node represents a journal, with the node size proportional to the number of citations. Lines between nodes reflect co-citation relationships. Key journals, including American Journal of Obstetrics and Gynecology, Hypertension, and Placenta, demonstrate their foundational roles in preeclampsia research

National and institutional cooperation networks

Research cooperation on the mechanism of preeclampsia is closely intertwined at both national and institutional levels, reflecting significant attention to this field across various countries and institutions. This collaboration has led to a notable decrease in the incidence of birth defects. Noteworthy countries with over 300 articles include the USA (1526), People's Republic of China (1190), and England (349), see Table 8. Similarly, institutions with more than 80 publications include University of Mississippi (128), Fudan University (84), and Nanjing Medical University (80), see Table 9. Visual analysis of countries with over 50 publications and institutions with over 40 publications, as obtained by CiteSpace, is depicted in Fig. 7.

Table 8 The top 10 countries with the highest number of publications

Table 9 The top 10 institutions with the highest number of publications

Fig. 7

A Visualization map of countries with more than 50 articles. Each node represents a country, with node size proportional to the number of published documents. Lines between nodes indicate collaboration between countries. Major contributors, such as the USA, China, and England, dominate the network, reflecting their central roles in preeclampsia research. B Visualization map of institutions with more than 40 articles. Each node represents an institution, with node size proportional to the number of documents. Lines between nodes represent institutional collaborations. Key institutions, including the University of Mississippi, Shanghai Jiao Tong University, and Harvard University, highlight the major centers driving research in the field

Keyword co-occurrence, clustering and emergence analysis

Keyword co-occurrence analysis

Keyword co-occurrence analysis is a valuable method for identifying hot topics and trends in a research field. In this study, 1,000 keywords with a frequency greater than 5 were extracted from VOSviewer. The resulting keyword co-occurrence network, depicted in Fig. 8A, illustrates the relationships between keywords, with node size indicating frequency and connections representing co-occurrences. Additionally, Fig. 8B displays a keyword co-occurrence network generated by CiteSpace, focusing on keywords with a frequency exceeding 100. Noteworthy keywords include 'preeclampsia' (3411), 'pregnancy' (1621), and 'expression' (979), as detailed in Table 10.

Fig. 8

A High-frequency keyword co-occurrence network with more than 5 occurrences obtained using VOSviewer. Each node represents a keyword, with node size proportional to its occurrence frequency. Lines indicate co-occurrence relationships. Keywords such as "preeclampsia," "hypertension," and "oxidative stress" dominate the network, highlighting major research focuses. B High-frequency keyword co-occurrence network with more than 100 occurrences obtained using CiteSpace. Each node represents a keyword, with node size proportional to its occurrence frequency. Lines show co-occurrence relationships, with "preeclampsia," "pregnancy," and "endothelial dysfunction" as central themes, reflecting core areas of study in preeclampsia research

Table 10 Top 10 high-frequency keywords

Keyword cluster analysis

Keyword cluster analysis was conducted using the local linear regression method (LLR), resulting in 7 clusters (Q = 0.3108, S = 0.6721), signifying a significant cluster structure and confident results,see Fig. 9. The details of the 7 clusters are presented in Table 11. The analysis revealed that research in this field primarily focuses on the adverse effects of preeclampsia on mothers and fetuses. Researchers have explored its pathogenesis from various perspectives, including inflammation, oxidative stress, placental ischemia, trophoblast invasion disorder, and endothelial damage. They have investigated this at both the level of individual proteins and entire pathways, aiming to facilitate early detection and intervention by understanding the mechanisms of preeclampsia. The close integration of clinical and mechanistic research highlights a comprehensive research system.

Fig. 9

Clustered network of keywords related to preeclampsia research obtained using CiteSpace. Each cluster represents a major research theme, with node size proportional to keyword frequency and lines indicating co-occurrence relationships. Key clusters include #0 “hypertensive disorders of pregnancy,” #1 “invasion,” #2 "blood pressure,” #3 “angiogenic factors,” #4 “oxidative stress,” #5 “antiphospholipid syndrome,” and #6 “systemic hemodynamics.” These clusters highlight the diverse focus areas in preeclampsia research, emphasizing pathophysiological mechanisms and clinical features

Table 11 The clusters of the keywords

Keyword timeline diagram, emergence and impact flow diagram analysis

Keywords are clustered and formed into a timeline diagram, where nodes represent keywords and colors indicate the average publication year. Node size and keyword co-occurrence reflect the explosiveness of the network, weighted by total link strength between keyword nodes and scored based on average publication year. Cluster names are marked on the right side of the timeline plot, see Fig. 10. Table 12 displays relevant information on the two main keywords, Preeclampsia and Mechanism, showing a close relationship between them. The red line segment in the keyword emergence map signifies the duration of explosive keywords, with the strongest emergence degrees belonging to pregnancy induced hypertension (33.6),pre-eclampsia (20.87),endothelial cell (19.4), pathophysiology (18.87), plasma (16.68),see Table 13. The timeline diagram and emergent analysis shed light on hot spots and trend evolution in research on preeclampsia mechanisms, serving as a reference for predicting future research trends. The keyword co-occurrence network (2019–2024) generated by CiteSpace software is input into the impact flow generator program (alluvialgenerator) for screening and color layout, as shown in Fig. 11. The width and length of impact streamlines provide insights into occurrence intensity and impact time of keywords.

Fig. 10

Timeline view of keyword clusters in preeclampsia research generated using CiteSpace. Each node represents a keyword, with size proportional to its frequency. Clusters are labeled with themes, including #0 “hypertensive disorders of pregnancy,” #1 “invasion,” #2 “blood pressure,” #3”angiogenic factors,” #4 “oxidative stress,” and #5 “antiphospholipid syndrome.” The timeline highlights the temporal evolution of research focus, showing how key themes have emerged and developed over time, with sustained attention on major mechanisms like “oxidative stress” and “angiogenic factors”

Table 12 The core keywords in the timeline graph

Table 13 Top 25 Keywords with the Strongest Citation Bursts

Fig. 11

Alluvial diagram of keyword evolution from 2019 to 2024. Each colored block represents a keyword, with the width proportional to its frequency in a specific year. Lines connecting blocks illustrate the continuity and transition of research focus over time. Prominent keywords like “angiogenic factor,” “oxidative stress,” and “preeclampsia” show sustained relevance, while emerging topics like “COVID-19” and “fertility” indicate new research directions in recent years

Document co-citation analysis

Document co-citation network and cluster analysis

Co-citation analysis of academic research focus is demonstrated through a network in Fig. 12, showcasing connections between documents studying the mechanism of preeclampsia. Node connections indicate co-cited documents, with node size reflecting citation frequency. Table 14 presents information on the top 10 co-cited documents, including co-citation frequency, number of citations, and cited documents. Notably, these documents are high-quality publications in significant journals. The top 3 are: Rana S, 2019, CIRC RES, V124, P1094, https://doiorg.publicaciones.saludcastillayleon.es/10.1161/CIRCRESAHA.118.313276, [21], explores the role of anti-angiogenic factors in preeclampsia pathogenesis and the development of angiogenic biomarkers for risk stratification and therapeutic strategies. Burton GJ, 2019, BMJ-BRIT MED J, V366, P0, https://doiorg.publicaciones.saludcastillayleon.es/10.1136/bmj.l2381, [22], focuses on the pathophysiological mechanisms of preeclampsia, distinguishing between early-onset and late-onset preeclampsia. The aim is to translate these insights into new approaches for predicting, preventing, and treating preeclampsia. Phipps EA, 2019, NAT REV NEPHROL, V15, P275, https://doiorg.publicaciones.saludcastillayleon.es/10.1038/s41581-019-0119-6, [23] delves into the pathogenic role of released anti-angiogenic proteins in the development of preeclampsia and proposes novel therapeutic strategies to restore angiogenic imbalance. This study also highlights the long-term maternal and fetal risks associated with preeclampsia.

Fig. 12

Co-citation network of references in preeclampsia research. Each node represents a cited reference, with node size proportional to its citation frequency. Clusters of nodes indicate groups of references frequently cited together, reflecting shared research themes. Prominent references, such as Levine et al. (2004), Maynard et al. (2003), and Steegers et al. (2010), highlight foundational studies on key topics like angiogenic factors, oxidative stress, and hypertensive disorders in pregnancy. Lines between nodes show co-citation relationships, illustrating the interconnectedness of research within this field

Table 14 Top 10 co-cited references

Analyzing the cited documents from 1980 to 2024, 14 clusters with high significance and high credibility were formed (Q = 0.807, S = 0.9051) [15]. The top 10 are visualized in Fig. 13. Clustering related information can be found in Table 15. The main research directions of this cluster can be summarized by examining the keywords with the highest frequency in each cluster, and identifying the research focus in different time periods. Research on the mechanism of preeclampsia based on clustering results primarily covers two main aspects: (1) Early research primarily concentrated on investigating the effects of preeclampsia on both mothers and infants. This included examining the correlation between preeclampsia and vascular endothelial function, as well as exploring the mechanisms of vascular endothelial cell damage in preeclampsia through animal studies. (2) Research frontier topics include the placenta-derived nature of preeclampsia, involving placental trophoblast cells, abnormal proliferation and invasion function, epithelial-mesenchymal transition, oxidative stress, and RNA-level research such as non-coding RNA and circular RNA. Additionally, a timeline diagram is presented, with nodes representing co-cited documents colored by average publication year and sized based on the explosiveness of co-cited documents. The total links between co-cited documents are weighted by intensity and scored by average publication year, with cluster names displayed on the right side of the timeline plot. Refer to Fig. 14 for a visual representation.

Fig. 13

Clustered co-occurrence network of research topics in preeclampsia generated using CiteSpace. Each cluster represents a major research theme, with node size proportional to frequency and links indicating co-occurrence relationships. Key clusters include #0 “hypertensive disorder,” #1 “angiotensin II type,” #3 “trophoblast cell,” #4 “hypoxia-inducible transcription factor,” and #8 “endothelial function.” These clusters highlight critical areas of focus, such as molecular mechanisms, cellular studies, and transcriptional regulation, reflecting the multidimensional approach to understanding preeclampsia

Table 15 The clusters of the co-cited references

Fig. 14

Timeline view of research clusters in preeclampsia generated using CiteSpace. Each cluster represents a key research theme, with nodes indicating studies and their publication year. Major clusters include #0 “hypertensive disorder,” #1 “angiotensin II type,” #3 “trophoblast cell,” and #4 “hypoxia-inducible transcription factor.” The timeline demonstrates the evolution of research focus, with early studies on endothelial function and hypertensive disorders transitioning to recent themes such as transcriptional regulation and trophoblast biology, reflecting advancements in understanding preeclampsia mechanisms

Analysis of research hot spots based on emergent literature

Emergent literature, which are highly cited documents at a certain stage, can reveal research hot spots in a field [24] (Table 16). The earliest literature in this area suggests that preeclampsia may occur when pregnant women experience a generalized intravascular inflammatory response to pregnancy under specific conditions. This disease is considered more of a syndrome rather than having a specific cause, with placental dysplasia being a significant predisposing factor. It is unlikely that a single gene, specific test, or preventive measure will be able to fully address preeclampsia [25]. Recent documents with longer emergence durations include studies by Rana S, 2019 [20], Burton GJ, 2019 [22], Phipps EA, 2019 [23], Brown MA, 2018 [26], which provide valuable insights for managing pregnancy. Clinicians specializing in hypertension during pregnancy offer practical guidance on classification, diagnosis, and treatment. Staff AC, 2019 [27], proposed a two-stage placental model for preeclampsia, suggesting that both early-onset and late-onset preeclampsia are linked to placental syncytiotrophoblast stress. Ives CW, 2020 [28] This review offers a detailed discussion on the pathogenesis of preeclampsia, focusing on the mechanisms behind its clinical features. The onset of the clinical syndrome is linked to placental abnormalities and the subsequent release of anti-angiogenic markers, primarily sFlt-1 and sEng. Elevated levels of sFlt-1 and sEng result in endothelial dysfunction, vasoconstriction, and immune dysfunction, potentially impacting every maternal organ system and the fetus.

Table 16 Top 25 References with the Strongest Citation Bursts

Analysis of the influence of co-cited documents on the mechanism of preeclampsia based on impulse flow diagram

Analysis of the influence of co-cited documents on the mechanism of preeclampsia was conducted using an impulse flow diagram. The document co-citation network was generated by CiteSpace software, and network information from 2019 to 2024 was inputted into the impulse flow generator program. After screening and color layout, a flow diagram of representative literature on the application of whole exome sequencing in prenatal diagnosis was obtained. Alsnes IV_2017 [29] emerged as the document with the largest pagerank (31%) among the cited documents in 2019. The Norwegian HUNT (Nord-Trøndelag Health Study) study of 15,778 participants revealed that all mothers experienced hypertension during pregnancy, which could increase the lifetime risk of cardiovascular disease in children. Abd Rahman R_2020 [30], the document with the largest pagerank in 2024 (40%), demonstrated that hydroxychloroquine reduced TNF-α-induced 8-isoprostane production in human umbilical vein endothelial cells (HUVEC) through in vitro and in vivo studies (Fig. 15). This intervention also decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression, alleviated TNF-α and preeclampsia serum-induced HUVEC monolayer permeability, and restored zona pellucida occludin 1 (ZO-1). These findings suggest that hydroxychloroquine may serve as a valuable endothelial protectant for women with preeclampsia.

Fig. 15

Alluvial diagram of highly cited references from 2019 to 2024. Each colored block represents a highly cited reference, with the width proportional to its citation frequency in a specific year. The connections between blocks illustrate the continuity and influence of key studies over time. Prominent references, such as those focusing on angiogenic factors, oxidative stress, and hypertensive disorders, demonstrate their sustained relevance in shaping preeclampsia research trends

Discussion

This study is based on 4989 articles on research on the mechanism of preeclampsia retrieved from the WOSCC database. VOSviewer and CiteSpace software were used for bibliometric and visual analysis. The documents analyzed span from 1980 to 2024 (as of 2024–03-14). The aim of this study is to provide an overview of the current research landscape in this field globally, identify research trends, and anticipate future directions. The number of publications remained relatively stable from 1994 to 2012, with a gradual increase observed from 1990 to 2022. Although there was a slight decrease in publications in 2022 and 2023, the number remained consistently above 450 articles, indicating the significant attention given to research on the mechanism of preeclampsia. The number of publications by a country serves as a valuable indicator of its academic prowess. Analysis reveals that the United States and China are the top two countries in terms of publication volume in this field, each having published over 1,000 articles, see Table 8. The United States leads in total citations, while the United Kingdom boasts the highest average citations per article, underscoring the substantial contributions of these countries to preeclampsia research. International collaboration is evident in Fig. 7, showcasing extensive partnerships among countries and institutions in this research area, indicating its global significance.

Tables 1 and 2 present the top 10 authors in the field of preeclampsia mechanism research, with Lamarca and Babbette leading the list with 41 publications. Notably, Romero, Roberto holds the third position with 37 articles but boasts the highest average citations per article (58.86), underscoring their significant impact. Lamarca and Babbette have focused on both in vivo and in vitro research on preeclampsia mechanisms, publishing in journals like HYPERTENSION and PLoS One. Recent research [31] has shown that B2 cells activated by placental ischemia can induce hypertension in normal pregnant rats, involving cellular activation of circulating natural killer cells and production of angiotensin II type 1 receptors. Romero and Roberto concentrate on the mechanisms and clinical relevance of preeclampsia, utilizing maternal characteristics and various markers to predict the condition throughout pregnancy. Key studies have revealed that preeclampsia involves multiple overlapping pathological processes, activating a common pathway of endothelial cell activation, intravascular inflammation, and syncytiotrophoblast stress. This highlights the importance of understanding preeclampsia's etiology for improved treatment and prevention [32].

An analysis of international peer-reviewed journals focusing on research into the mechanisms of preeclampsia can enhance understanding of current trends in this field and assist scholars in identifying key journals. Placenta has the highest number of publications, while AM J OBSTET GYNECOL has the most co-citations, underscoring their importance in the field. Researchers should stay updated on the latest developments in these journals. In Fig. 10, keywords expected to last until 2024 include 'preeclampsia', 'mechanism', 'oxidative stress', 'gene expression', 'fetal growth restriction', 'trophoblast', 'endothelial dysfunction',and 'angiogenic growth factors'. The top five single keywords with the highest outbreak intensity are 'pregnancy induced hypertension', 'pre-eclampsia', 'endothelial cell', 'pathophysiology', and 'plasma'. These findings indicate that current research hotspots on the mechanism of preeclampsia focus on key aspects such as placental ischemia and hypoxia, inflammatory responses and immune disorders, imbalance in angiogenic factors, abnormal epigenetic modifications, and imbalance in intestinal flora. Overall, this provides an insightful overview of the research landscape.

Through scientometric analysis, this study reveals the trends and hotspots in research on the mechanisms of preeclampsia (PE) and compares these findings with existing literature. Previous systematic reviews, such as those by Burton et al. (2019) and Phipps et al. (2019), have summarized the importance of mechanisms such as placental ischemia and hypoxia, anti-angiogenic factor imbalance, and inflammatory dysregulation in PE [33] [34]. By utilizing keyword co-occurrence and clustering analysis, this study validates the sustained focus on these hotspots and further uncovers the emerging prominence of RNA regulation (e.g., non-coding RNAs and circular RNAs) as a frontier in this field—a trend not yet fully discussed in prior reviews. Moreover, this study highlights the significant contributions of U.S. and Chinese researchers in international collaborations on "placental ischemia and hypoxia" research, as well as the high-frequency occurrence of crucial factors like IL-6 and TNF-α in the "inflammatory response" domain, suggesting that future efforts may focus on novel immunomodulatory interventions. Through these findings, this study broadens and deepens the scope of existing literature from a scientometric perspective, providing a more comprehensive view of PE mechanism research and offering valuable references for exploring personalized diagnostic and therapeutic strategies.

Placental ischemia and hypoxia

Placental ischemia and hypoxia play a crucial role in the development of preeclampsia. Studies have shown that extrachorionic trophoblast cells (EVT) in women with preeclampsia have reduced invasive capacity. Inadequate remodeling of spiral arteries and increased vascular resistance led to decreased blood flow and oxygen delivery to the placenta, resulting in placental dysfunction [35]. In preeclamptic placentas, trophoblast cells experiencing oxygen deprivation undergo autophagy, further compromising blood supply and promoting cell death.

Farrell et al. [36] discovered that hypoxia can reduce angiomotin (AMOT) levels, impair extravillous trophoblast (EVT) invasiveness, and consequently weaken EVT's ability to invade the myometrium and degrade maternal spiral arteries. This association highlights the role of hypoxia in the pathogenesis of preeclampsia. Further studies [37]have shown that hypoxia triggers the induction of hypoxia-inducible factor 1α, leading to the upregulation of E1A-binding protein P300. This, in turn, forms a protein–protein complex of hypoxia-inducible factor 1α/E1A-binding protein P300, which binds to the promoter of the gene G protein signaling regulator 2. Subsequent inhibition of G protein signaling regulator 2 transcription may play a role in the pathogenesis of preeclampsia. Additionally, Li GL [37] and other researchers have highlighted that prolonged hypoxic stress can disrupt the regulation of trophoblast invasion mediated by HGF/Met signaling, providing novel insights into the mechanism of this disorder.

Inflammatory response and immune dysregulation

Maternal immune responses to the allogeneic fetal placenta are a normal part of pregnancy adaptation. However, an overactive or dysregulated immune response, often characterized by inflammation, is believed to be a key contributor to the development of preeclampsia. The infiltration and activation of macrophages, natural killer cells, and T lymphocytes are commonly observed in the decidua and placenta of individuals with preeclampsia. Moreover, systemic inflammatory changes, such as elevated levels of TNF-α and interleukin (IL), have been identified in the maternal circulation [38]. TNF-α, a proinflammatory cytokine produced by monocytes and macrophages, is implicated in the initiation of inflammation in preeclampsia.

The innate immune system at the maternal–fetal interface is crucial in the development of preeclampsia, characterized by an overactive immune-inflammatory response [39]. Chronic activation of various immune cells and systems, such as CD4 + T cells, B cells, macrophages, NK cells, and the complement system, is linked to placental ischemia, a key factor in preeclampsia [40]. Cytokines and the microenvironment influence CD4 + T cells to exhibit either pro-inflammatory (Th1 or Th17) or anti-inflammatory (Th2 or Treg) properties [41]. Pro-inflammatory cells like Th1 and Th17 are activated by cytokines like TNF-α, INF-γ, IL-6, and IL-17, promoting inflammation, while anti-inflammatory Th2 cells are supported by IL-4 and IL-10, leading to anti-inflammatory effects. Preeclampsia is characterized by an imbalance between pro- and anti-inflammatory factors. Decidual cell single-cell sequencing reveals abnormal gene expression affecting the function of decidual macrophages, disrupting their interaction with other immune cells and ultimately contributing to the development of preeclampsia [42]. NK cells, crucial in anti-tumor and anti-infection immunity, play a central role in the etiology of preeclampsia at both the peripheral blood and maternal–fetal interface. Targeted therapeutic measures for NK cells are essential to maintain immune balance locally and systemically [43].

The pathogenesis of preeclampsia involves systemic inflammatory responses and ongoing immune activation, marked by elevated pro-inflammatory cytokines and immune effector cells, as well as reduced anti-inflammatory cytokines and regulatory cells. Additional research is necessary to fully understand the intricate mechanisms underlying inflammatory immune responses.

Vascular dysfunction

The imbalance between pro-angiogenic factors and anti-angiogenic factors in the maternal circulation leads to endothelial dysfunction and triggers the occurrence of preeclampsia. Key angiogenesis regulatory factors involved in the pathogenesis of preeclampsia include VEGF and sFlt-1. VEGF, a growth factor, stimulates vascular endothelial production, promoting placental angiogenesis and increasing vascular permeability. On the other hand, sFlt-1, an anti-vascular endothelial protein, is generated by the cleavage of vascular endothelial growth factor receptor-1 (VEGFR-1), and acts to counter the effects of VEGF and placental growth factor (PlGF). In a normal pregnancy, VEGF, sFlt-1, and PlGF are balanced. However, in pregnant women with preeclampsia, increased sFlt-1 production due to placental vascular hypoperfusion [44] disrupts this balance by competing with VEGF and PlGF for antagonistic receptors, leading to vascular endothelial dysfunction. Research by Lopes Perdigao J et al. [45]. has shown a significant link between abnormal angiogenesis characteristics prior to delivery and severe preeclampsia as well as perinatal complications.

Abnormal epigenetic modifications

Epigenetics refers to long-lasting and heritable changes in gene expression or cell characteristics [46], such as DNA methylation, histone adjustments, and microRNA [47], play a critical role in placental development and are key factors in the development of preeclampsia. The occurrence of preeclampsia is often linked to abnormal epigenetic regulation [48].

DNA methylation plays a crucial role in regulating various cellular processes such as genomic imprinting, chromosome stability, chromatin structure, embryonic development, cell differentiation, and transcription [49]. There is a growing body of evidence linking epigenetics to preeclampsia, with studies revealing significant differential methylation in genes associated with early-onset preeclampsia, including those encoding insulin-like growth factor 2 binding protein, insulin-like growth factor 2 receptor, and cadherin 13 [50]. Research by Knihtilä, HM and others has demonstrated distinct cord blood DNA methylation patterns in cardiovascular pathways, such as the apelin signaling pathway [51], in relation to preeclampsia. Furthermore, abnormal histone modifications have been implicated in the development of preeclampsia, with epigenetic changes in the placenta attributed to increased histone H3K4 methylation due to the upregulation of histone methyltransferases SETD1A and SMYD3, contributing to the pathophysiology of hypoxia-related [52] preeclampsia. Meister S et al. [53] also observed reduced expression of histone modification proteins H3K9ac and H3K4me3 in preeclampsia. Yao ZZ et al. [54] investigated the role of tissue transglutaminase (TG2) and highlighted its involvement in gene expression, protein homeostasis, cell signaling, autoimmunity, inflammation, and hypoxia, as well as its association with the development of preeclampsia (PE). Non-coding RNA has been shown to regulate various cellular processes such as gene expression, transcription, chromatin structure, epigenetic memory, alternative RNA splicing, and protein translation [55]. Several studies have reported dysregulated expression of miRNA in the placenta or peripheral blood of preeclampsia patients [56,57,58]. Further research is needed to fully understand the epigenetic modifications in normal and preeclamptic pregnancies.

Intestinal flora imbalance

Intestinal microbiota is a complex and rich microbial community in the digestive tract, which is crucial for host metabolism, immunity and nutrient absorption. Changes in maternal intestinal flora have been closely linked to the onset and progression of preeclampsia [59]. A study using Mendelian randomization found a causal relationship between Bifidobacteria and preeclampsia-eclampsia [60]. Zong YC et al. [61] explained that intestinal flora influences the release of various metabolites, vascular factors, and active peptides, ultimately impacting systemic immune responses and potentially leading to early eclampsia. In a study investigating the effects of sodium butyrate (NaB) on preeclampsia in a rat model, it was observed that exogenous NaB could enhance intestinal barrier function and mitigate adverse outcomes. This improvement may be associated with the modulation of intestinal microbiota and its metabolites, particularly short-chain fatty acids (SCFAs) [62]. It is important to note that while intestinal microbiota imbalance is a significant factor in the development of preeclampsia, it is not the sole explanation for the condition.

In summary, Preeclampsia is a multifaceted disease with various causes, mechanisms, and pathways that exhibit significant variability. Further research is necessary to elucidate the underlying factors and severity determinants of preeclampsia. Understanding the sources of this variability can establish a solid theoretical basis for the prevention and precise treatment of preeclampsia.

This study employs scientometrics for visual analysis to guide researchers on the historical development and emerging trends in the use of whole-exome sequencing for prenatal diagnosis. It identifies key authors, institutions, countries, journals, and pivotal documents in this area, offering valuable insights for clinical diagnosis and treatment, ultimately enhancing outcomes for mothers and infants. Nonetheless, this study is subject to limitations as scientometric research relies on citation-related indicators, potentially introducing bias. Additionally, the data collection is limited to WOSCC, which may result in incomplete retrieval of publications. Moreover, the focus on the first author in the co-citation network may not fully capture the author's influence.

All authors declare no conflicts of interest.

Bridging research trends and clinical applications in preeclampsia

This study reveals the research hotspots in preeclampsia (PE) mechanisms, providing important insights for clinical practice. First, the sustained high-frequency focus on the imbalance of angiogenic factors, such as VEGF and sFlt-1, underscores their potential clinical application as serum biomarkers for early risk prediction, paving the way for personalized diagnosis and intervention. Second, the extensive investigation of inflammatory responses and immune dysregulation, particularly the roles of IL-6 and TNF-α, offers new perspectives for immunomodulatory therapies that may improve maternal and fetal outcomes by regulating the maternal–fetal immune microenvironment. Furthermore, the recent focus on non-coding RNAs, such as microRNAs and circular RNAs, suggests that molecular-level interventions may become a key direction for the future management of PE. For instance, alterations in non-coding RNA expression could serve as novel diagnostic and therapeutic targets, further advancing the role of precision medicine in managing pregnancy complications. These research trends, closely aligned with clinical advancements, highlight the practical value of scientometric analysis in guiding future clinical research designs and optimizing intervention strategies.