The Top 100 Most Cited Articles on Intrauterine Adhesion: a Bibliometric Analysis

Bibliometric analysis is a statistical method that attempts to assess articles by their citations, analyzing their frequency and citation pattern, which subsequently gleans direction and guidance for future research. Over the past few years, articles focused on intrauterine adhesions have been published with increasing frequency. Nevertheless, little is known about the properties and qualities of this research, and no current analysis exists that has examined the progress in intrauterine adhesion research. Web of Science Core Collection, BIOSIS Citation Index, and MEDLINE database were searched to identify articles on intrauterine adhesion published from 1950 to October 2020. The 100 most cited articles were chosen to analyze citation count, citation density, authorship, theme, geographic distribution, time-related flux, level of evidence, and network analysis. An overwhelming majority of these 100 articles were published in the 2010s (35%). Citations per article ranged from 30 to 253. Chinese authors published the most papers in the top 100, followed by the USA, France, Israel, and Italy. The most salient study themes included operative hysteroscopy and adjunctive treatments for improving reproductive outcomes. The most common level of evidence was level II, and there was no statistical difference in the number of citations between the levels. The network analysis indicated that hysteroscopy, hysteroscopic adhesiolysis, infertility, and the reproductive outcome had a great degree of centrality in the 2000s and 2010s. In comparison, placental implantation had a great degree of centrality in the 2000s, and stem cell and fibrosis had a great degree of centrality in the 2010s. The value of IUA investigation has been gradually appreciated recently. Hysteroscopic adhesiolysis was continuously explored to achieve better reproductive outcome. Over time, the main focus of research has gradually shifted from complications to postoperative adjuvant treatment. Moreover, breakthrough progress is needed in underlying mechanism and early prevention of IUA.


Introduction
Intrauterine adhesion (IUA) was first defined and reported by Asherman in 1950 [1,2]. IUA is caused by mechanical injury or damage from infection to the basal layer of the endometrium, resulting in the formation of fibromuscular or severe connective tissue adhesion of the uterine cavity or cervical canal [3,4]. Hypomenorrhea/amenorrhea [5], infertility [6], recurrent pregnancy loss [7], and obstetric complications [8] are common complications of IUA, and IUA may also lead to low birth weight [9]. At present, IUA remains a relatively intractable disease that seriously affects women's reproductive prognosis and quality of life in childbearing age [6,10].
The current study aimed to identify the 100 most cited essays in the field of IUA, ascertain the research trends and hotspots in this area, and evaluate the research quality and properties of the most cited original papers over the past 70 years. We intend that the findings from this analysis can guide subsequent research in IUA.

Search Strategy
All articles were selected through a search of the Web of Science Core Collection, BIOSIS Citation Index, and MED-LINE to retrieve all articles related to IUA. Two individuals simultaneously conducted the search process to enhance the search sensitivity. The terms used for searching were as follows: Intrauterine adhesion OR Asherman Syndrome.
The search was conducted in October 2020 and yielded a total of 1999 results. Subsequently, search results were filtered. Only original articles were included, meaning reviews, systematic reviews, meta-analyses, and guidelines were all excluded. To limit the number of screened articles, those articles that were cited fewer than 10 times were excluded. As a result, 418 articles were included for analysis. Two independent researchers reviewed the title and the abstract of the selected articles. Articles that met any of the following criteria were included: (1) basic study, animal study, and clinical trials related to any aspect of IUA; (2) the clinical therapeutic, prognostic, diagnostic, epidemiological studies of IUA; or (3) the case report data of IUA. Any disagreements between the 2 reviewers were discussed until a consensus was reached. After the title and abstract review were completed, 241 articles remained. These articles were ranked in descending order of citations, and the top 100 most cited articles were included in this analysis (Fig. 1).

Data Extraction
Two independent, well-trained individuals reviewed all articles. The following information was listed for all articles: the journal name, publication date, first author, year of publication, geographic origin, the total number of citations of the article, overall citation rate (total citations/article age), research theme, and level of evidence (methodology has been described elsewhere [37]).

Statistical Analysis
The Shapiro-Wilk test was used to test the distribution of individual variables for normality. Normally distributed data are presented as mean ± standard deviation. Comparison between means was performed using one-way analysis of variance (ANOVA), and post hoc testing was conducted as necessary. Time-dependent trends were tested using the Mann-Kendall trend test. Correlation between variables was performed using the Spearman rank or Pearson tests. A P value < 0.05 was considered to be statistically significant. Analysis was performed using SPSS Statistics 20.0 (IBM Figure 1 Flowchart illustrating the process of allocation of articles Corp., Armonk, NY, USA). UCINET for Windows, version 6.212, was used to perform the degree of centrality analysis [38].

Results
We extracted the top 100 most cited articles in the field of IUA (listed in Table 1). Citations ranged from 30 to 253 in number, with a majority being published in the 2000s (29%) and 2010s (35%), indicating an overall trend of yearby-year increase publication (Fig. 2). The year 2008 saw the highest number of these IUA articles published (n=7). The number of citations was 6462 overall: 47 (0.7%) in the 1960s, 356 (5.5%) in the 1970s, 721 (11.2%) in the 1980s, 1190 (18.4%) in the 1990s, 2097 (32.5%) in the 2000s, and 2051 (31.7%) in the 2010s. The Mann-Kendall trend test showed no time-dependent trend in the publication time of articles (P=0.4654) but did reveal an increasing trend between the citation density and time (P=2.2E-16; Fig. 3). The Spearman rank analysis indicated a positive correlation between time and citation density (r=0.836; P <2.2E-16). The Shapiro-Wilk test and the Kolmogorov-Smirnov test both indicated an abnormal distribution of the citation data. The Shapiro-Wilk test indicated significant departures from normality (P<0.05) for all distributions tested.
These articles were distributed in 22 countries (Fig. 4), led by China (n=19) and followed by the USA (n=18), France (n=8), Israel (n=8), and Italy (n=8). The allocation is presented on the world map (Fig. 5). In terms of regional distribution, most of the articles were published in two continents: North America and Asia. The other articles were scattered in Europe, Africa, and Oceania. Developed countries accounted for 67% of all countries mentioned above. In all, 33 journals accounted for all the articles published, among which 27 were published in Fertility and Sterility, 16 in Human Reproduction, 6 in American Journal of Obstetrics and Gynecology, and 5 in Journal of Minimally Invasive Gynecology (Table 2).
Among the authors of the 100 most cited articles, 10 had more than 2 articles (Table 3). These authors' articles are all clinical studies related to IUA. Among them, March and Yang had 3 first authorships, mainly in the field of IUA. March's focus was on hysteroscopic adhesiolysis, and Yang's research direction was endometrial regeneration. Although Valle had only 2 articles, which were mainly focused on the auxiliary diagnosis of IUA, the number of citations was relatively high, with an overall number of citations of 286.
The 100 most cited articles centered primarily on the following themes: auxiliary treatment of IUA (n = 28), the prognosis of IUA (n=19), incentive factors of IUA (n=16), hysteroscopic adhesiolysis (n=14), evaluation methods for IUA (n=12), complications of IUA (n = 6), relevant mechanism of IUA (n = 4), and new devices for IUA (n=1). The most frequently mentioned theme was the adjuvant treatment of IUA, followed by the reproductive prognosis of patients after hysteroscopic adhesiolysis (Fig. 6). One-way ANOVA revealed no significant difference in the citations per article across the various themes (Fig. 7). Nevertheless, the article's impact factor from different themes was statistically different (P=0.012) (Fig. 8).
In terms of the level of article evidence, the level II (n=39) category had a mean of 69 ± 48 citations per article, representing the largest number among the levels; the level I (n=23) category had a mean 63±30 citations per article, while level IV (n=14) had 48±22 citations. One-way ANOVA indicated that the differences in citations per article between different levels of evidence were not significant ( Fig. 9).
Network analysis of the keywords or subject terms was conducted in 2 periods of publication: in the 2000s (34 articles) and the 2010s (30 articles). The result indicated that "hysteroscopy", "hysteroscopic adhesiolysis", "infertility", and "reproductive outcome" possessed a high degree of centrality in the 2000s and 2010s; "placenta accreta" was considerably centralized in the 2000s; and "stem cell" and "fibrosis" were highly concentrated in the 2010s (Figs. 10,11).

Discussion
This is the first bibliometric analysis of papers in the field of IUA. Several interesting findings can be drawn from this analysis of the top 100 most cited papers published on IUA over the past 70 years, which include insights into those papers which had made important contributions to the progress in the field and the current trends in development. Generally, it is expected that as time passes, the number of citations of papers would increase. However, contrary to this expectation, when we assessed the 100 most cited articles by decade, we found that articles published in the 2010s accounted for the highest proportion, reaching 35%; as time elapsed, both the numbers of articles and the citation density (i.e., number of citations divided by the number of years) grew. For one, this reflects the "obliteration by incorporation" [39] in the field, in which the citations of the original work decrease with time due to its familiarity and long-term, widespread use, coupled with the effect of replacement by novel findings. For another, this indicates that the diagnosis, treatment, and advanced research related to IUA have attracted more of the international community's attention.
In addition, 91% of these articles were clinical studies, and only 9% were basic experimental studies, with these basic studies all being published in the 2010s. Although clinical research has always been the focus of researchers in the field   of IUA, understanding the disease mechanism is also crucial to the treatment of the disease. Recently, the number of studies published concerning the mechanism of IUA has been on the rise, and findings from these and similar studies may suggest novel directions for clinical research.
In contrast to the trend of other bibliometric analysis reports, articles originating from the USA and developed countries did not have the largest number of papers. China and the USA were both important sources of articles, publishing 19 and 18 articles, respectively. Furthermore, 33% of the 100 most cited papers were from developing countries, and 67% were from developed countries. There are several reasons for this: (1) The clinical manifestations of IUA were first reported in the USA in the nineteenth century and later defined and named by American doctors. Therefore, they were able to study it earlier and more systematically [40]. Furthermore, the USA and other developed countries had the requisite funding to support scientific research. The sharing of these research results will help research into IUA [41,42]; (2) The occurrence of IUA is closely related to abortion and curettage, and abortion is illegal in many developing countries due to religious beliefs. In developed countries, the rate of abortion dropped by 19% from 1990 to 2014, while it only fell by 2% in developing countries over the same period [43]. Moreover, least-safe abortions accounted for the largest proportion of abortions in developing countries [44]. Thus, IUA is more likely to be an issue in developing countries, and such concern emerged as the research focus. (3) China and other developing countries have large populations. As the promotion and popularization of contraceptive measures in these populations are typically inadequate, unintended pregnancies and thus election of surgical abortion may be more common. Repeated or informal intrauterine operations can ultimately lead to irreversible damage to the endometrium [45,46]. (4) After China introduced the 2-child policy, the incidence of IUA and the number of cases of recurrent IUA requiring treatment grew [47,48]. IUA is a universal disease; however, nowhere in these 100 most cited papers was a multinational cooperative initiative mentioned.
Our results indicated that the journals that published the identified articles did not have high impact factors. This is likely because these papers were rarely published in comprehensive journals, and the impact factors of professional  Total citation Title  PMCID   99  1999  31  Total corporal synechiae due to tuberculosis carry a very poor prognosis following hysteroscopic synechialysis   10438408   100 1997  30 Simplified therapy for Asherman's syndrome 9418695 obstetrics and gynecology journals are relatively low. This result highlights a growing tendency of researchers perhaps preferring to publish articles in influential professional journals. However, there is no denying that the value of IUA research has not been fully appreciated. Nearly 50% of the 100 papers were issued in 2 journals, Fertility and Sterility and Human Reproduction, followed closely by 2 prominent journals in the field of obstetrics and gynecology, American Journal of Obstetrics and Gynecology and Obstetrics and Gynecology. This demonstrates that IUA was of particular concern in the field of reproductive medicine. Among the 100 most cited articles, the themes of papers published in recent years appeared to be more diverse. They included, for example, a phase I clinical study of autologous stem cell transplantation for the treatment of IUA published in Stem Cell Research & Therapy [49] and a collagen scaffold for endometrial regeneration study published in Biomaterials [50].
Among the authors of the 100 most cited papers, we found that 2 researchers contributed 3 articles. One of these authors was Charles M. March from the USA. His articles were all published before 1990 and emphasized hysteroscopy  [51][52][53]. The other author was Jehn-Hsiahn Yang from Taiwan, China, who is from a younger generation of researchers. The similarity with March was a focus on hysteroscopy. Yang's 3 articles asserted that IUA is a common complication after transcervical resection of multiple apposing submucous myomas [54], the formation of new adhesions after hysteroscopic adhesiolysis affects endometrial repair [55], and the location and area of adhesions are important factors that affect the recurrence of IUA [15].
Among the 100 articles, the level of evidence was between I and V. The overall distribution was average, with level II being relatively high, which is different from other bibliometric studies. This may be attributable to the design of clinical trials. Treatment of IUA is closely related to patients' reproductive prognosis, and for women, age is also a significant factor. Therefore, considering the effect of placebo control on patients, experimental studies are mostly unilateral. In the future, with the increase in the demand for childbirth and the introduction of 2 or even 3-child policies in some countries, it is expected that the rate of research into hysteroscopic adhesiolysis, postoperative adjuvant treatment, and related subjects will rapidly increase.
We also studied the thematic distribution of articles. The adjuvant treatment of IUA ranked first, followed by the prognosis of reproductive outcome after hysteroscopic adhesiolysis, the incentive factors of IUA, hysteroscopic adhesiolysis, and the evaluation method of IUA. Hysteroscopic adhesiolysis is the primary treatment method for IUA. However, how to improve the therapeutic effect through drugs and biological agents after the surgery has been a problem that researchers have sought to overcome in recent years [56]. Network analysis of the authors' keywords or subject terms was conducted in 2 periods of publication: in the 2000s (34 articles) and the 2010s (30 articles). The result indicated that "hysteroscopy", "hysteroscopic adhesiolysis", "infertility", and "reproductive outcome" were highly centralized in both 2000s and 2010s, and "placental implantation" was highly concentrated in the 2000s. This was consistent with the research trend in recent years. However, the topic of IUA prevention presented a blank state in the highly cited papers, indicating that breakthroughs in early prevention are urgently needed in this field. Researchers have gradually realized that even if patients with IUA succeed in conception, there remain many risks of pregnancy complications. The most cited article in this study was also an article about IUA complications, in which the author proposed that patients with IUA were associated with many risks during pregnancy. In analyzing the citation density of papers published in the 2010s, we found that each theme was evenly distributed. In analyzing the impact factor under each theme, it could be seen that articles related to devices and materials were relatively high, while research on mechanisms was relatively low. Stem cell and fibrosis were highly concentrated in the 2010s. In recent years, researchers have paid increasing attention to the effectiveness of adjuvant therapy after hysteroscopic adhesiolysis in suppressing the reformation of adhesion and promoting endometrial regeneration [57]. Previous research focused on the placement of uterine stents, Foley catheters, hyaluronic acid, or hormone replacement therapy [58]. Nevertheless, more importance was attached to biotherapy, especially in the field of stem cell therapy. Bone marrow mesenchymal stem cells (BMSCs) [59], umbilical cord mesenchymal stem cells (UCMSCs) [60], and menstrual blood mesenchymal stem cells (MbMSCs) [61,62] have been used clinically in patients with IUA, resulting in an improvement in reproductive outcome. Furthermore, researchers reported that stem cells could not only promote endometrial cell proliferation, but also inhibit the process of fibrosis [63].
In 2020, a review gathered the controversial views of different researchers on the treatment of IUA [64]. One perspective advocated that the adjuvant treatment after the surgery should be given more attention, and another suggested that IUA be treated with multiple operations. However, hysteroscopic adhesiolysis has always been the center of research over the years, and discussions concerning surgical methods and surgical techniques are still sparse [65]. It is undeniable that combined adjuvant treatment after surgery is the dominant trend of IUA treatment.
This analysis does generate some valuable information, but some limitations should be mentioned. First, the citation analysis was mainly based on the Web of Science, and the number of citations may be misleading. Meanwhile, we might have missed some important papers that were not included in the Science Citation Index database. Second, we might have overlooked the newly published articles that were meaningful in this area but have yet to reach high citation levels due to the criterion that the number of citations sorted papers. Overall, our analysis was by no means exhaustive, but the list of most cited articles still includes many influential papers in the field of IUA.

Conclusion
This article highlights the top 100 most cited articles in IUA research published over the last 70 years, including their publication time and regional centers, first author, level of evidence, and research theme. Furthermore, our findings support the notion that postoperative adjuvant therapy has played a key role in the field of IUA, and more and more basic and clinical studies are now exploring suitable and effective adjuvant treatments for IUA. Meanwhile, the method and techniques of surgical therapy have been controversial. Regardless, the current prognosis of IUA remains extremely poor, and many difficult challenges need to be overcome. Researchers have concentrated their focus on clinical trials rather than on basic laboratory research. Thus, the foremost difficulty lies in addressing the limited understanding of the underlying mechanisms of adhesion formation in the uterus and the other influencing factors.