Bibliometric analysis and visualization of literature on assisted reproduction technology

Introduction

The World Health Organization (WHO) states that infertility is the failure to conceive after 12 months of having unprotected sexual intercourse. According to WHO, infertility affects about 15 percent of couples worldwide, where the influence of male factors can be found in 30–50% of cases (1). Assisted reproductive technology (ART) involves removing eggs from a woman's ovaries, combining them with sperm in the laboratory, and returning them to the woman's body or donating them to another woman. The techniques used in ART include artificial insemination (AI), in vitro fertilization-embryo transfer (IVF-ET) and related technologies, such as intracytoplasmic sperm injection (ICSI), preimplantation genetic screening (PGS), in vitro oocyte maturation (IVM), assisted hatching (AH) and oocyte vitrification and freezing technology. Recent data from the European Society for Human Reproduction and Embryology (ESHRE) show that ART (including all treatment modalities) pregnancy rates in 39 countries range from 17.1 to 53.1%, and live birth rates range from 7.9 to 37.8% (2), although the increase has been modest.

The term bibliometric was coined by Alan Pritchard in 1969 (3). Bibliometric analysis is a powerful tool for exploring and analyzing large volumes of scientific data (4, 5). CiteSpace and VOSviewer are the most commonly used visual processing tools for bibliometric analysis of co-word, co-citation and literature coupling (6).

Based on the advantages of clustering technology and map presentation, the research trend of a specific field is analyzed and displayed in the form of a multivariate comprehensive visual knowledge map (7, 8). Bibliometric software helps visually present and analyze the literature related to assisted reproduction. This study aims to systematically analyze and visualize ART-related publications through bibliometrics, and to reveal identified topics, hotspots, and knowledge gaps in related fields.

Materials and methods Ethics statement

The study needed no approval from the institutional review board because it involved the analysis of retrieved scientific measurement data from the Web of Science database (WOS), and no human subjects were involved.

Sources and collection

Web of Science (WOS) database is the most commonly used and acceptable database in scientific or bibliometric research because it contains nearly 9,000 of the world's most prestigious high-impact journals and more than 12,000 academic conferences. The published articles in WOS provide a comprehensive overview of the world's research results in science, technology, medicine and other fields (9, 10).

This study searched WOS for information on assisted reproductive technology within 1 day to ensure no data were updated. The search timeframe was set between 2001.01.01 and 2022.08.25, and the retrieval date is 2022.08.26. The search was conducted by selecting “WOS Core Collection” with the topic word “Assisted Reproductive Technology” and the article type “Article” and “Review.” Then the retrieved files were exported in the “Plain Text File” format, and “Full Record and Cited References” was selected for “Record Content.”

The search query string was described as follows: Results for “assisted reproductive technology” (Topic) and Article or Review Article (Document Types) and Book Chapters (Exclude–Document Types).

Bibliometric analysis and software

CiteSpace software (Drexel University, Philadelphia, Pennsylvania, USA) is a freely available Java application widely used to visualize and analyze trends and patterns in the scientific literature (11). CiteSpace software was designed by Dr. Chen Chaomei in 2004 (7). CiteSpace to scientometrics, data and information visualization technology as the foundation, through the analysis of the potential knowledge of literature, regularity and distribution, and present knowledge structure. This study used CiteSpace software for keyword clustering and salient word analysis.

On the other hand, the VOSviewer is a literature measurement analysis software for drawing knowledge. Common words can be used in the literature analysis, total cited and coupling analysis, and visualization display (12). This study used the VOSviewer to visualize countries/regions, authors, institutional collaborations, cited journals, keyword co-occurrence and construct density maps.

This study aims to describe all literature characteristics, including country/institution, journal, highly cited articles, cluster network of co-cited references, and most frequently cited keywords. In addition to noun phrases extracted from article titles and abstracts, burst detection was applied to the keywords of publications in the article collection assigned to the citation extension.

Results Time trends in publications and citations

The number of annual publications is important in the development of scientific research since it reflects the growth of knowledge in this field. As of August 25, 2022, 6,288 articles on ART had been published, as shown in Figure 1, and the number of papers published per year is shown in Figure 2. Although the overall trend of published articles is increasing, the results found that the trend fluctuated in some years. Nonetheless, the study found that the number of publications per year can be divided into three phases: phase one, from 2004 to 2008, when the average annual number of publications was between 139 and 205. Phase two was from 2009 to 2016, with an average number of publications between 204 and 472 per year, and phase three was from 2017 to 2021, with an average annual number of publications between 440 and 763. In addition, the study found that the knowledge of ART showed a linear growth trend (R2 = 0.9379), reflecting the increasing research interest in this field.

Figure 1. Flowchart of the searching stagey in the study.

Figure 2. Annual trends of global publications.

Analysis of top productive countries/regions

In total, 69 countries/regions have published papers on ART. The top 10 countries with outstanding contributions to publications on ART are the USA (1864), China (862), Japan (398), Italy (395), France (394), England (393), Australia (388), Denmark (263), Canada (247) and the Netherlands (223), as shown in Figure 3, Table 1.This study determined that the size of the node is determined by the number of publications (the larger the number, the larger the node) and that the same colors represent the same clusters. On the other hand, the lines between nodes represent the alignment between countries/regions (the stronger the partnership, the wider the boundaries), and the number of total link strengths reflects the combined strength between countries/regions. These results show that the USA has the largest number of publications (1864, 29.61%), the highest number of citations (61,510), and the link strength (961). The results in Table 2 show that the USA has the highest number of citations (61510), followed by Australia (16484), England (15591), the Netherlands (12544) and France (12541). These results indicate that these countries have a great influence on ART research.

Figure 3. Analysis of the research trends based on the origin of publications globally.

Table 1. The top 10 countries contributing to ART research.

Table 2. Number of citations of publications on ART for the top 10 countries.

VOSviewer was used to analyze cooperation across countries, with lines between nodes indicating co-authorship between countries and thicker lines indicating stronger cooperation. The results in Figure 4 show that the USA, China, Australia and England had stronger cooperation and other countries had a weaker cooperation.

Figure 4. Co-occurrence map of Countries/Regions. The size of the nodes represents the number of articles, the thickness of the curve represents the strength of collaboration, and the colors represent different collaboration groups.

Contributions of top organizations

In total, 5,754 institutions published papers on ART, and the top five institutions with outstanding contributions to ART research were Harvard Univ (108), Univ Copenhagen (90), Shanghai Jiao Tong Univ (90), Tel Aviv Univ (88) and Ctr DisControl & Prevent (88), as shown in Table 3. These results indicate that Harvard Univ has the largest number of publications (108, 1.72%), the highest citation (4468), and the link strength of 248. The map has 176 terms, 9 clusters, and 1,627 links for a total link strength of 4,241. Each node represents a different institution. The size of the node is determined by the number of publications (the larger the number, the larger the node), and the same colors represent the same clusters. Boundaries between nodes represent a collaboration between organizations (the stronger the partnership, the wider the boundaries), and the number of link strengths reflect the aggregate strength between institutions. The visual map shows that 176 institutions cooperate both within and between clusters, and the top three institutions with the highest total link strength are Michigan State Univ (n = 375), Harvard Univ (n = 248), Brigham & Women's Hos (n = 232). The results in Table 4 show that the top five institutions with the highest number of citations include Harvard UNIV (4468), Ctr DIS Control & Prevnt (4020), UNIV Adelaide (3843), UNIV New S Wales (3756) and UNIV, Calif SAN Francisco (3674). Harvard UNIV, UNIV Copenhagen and Shanghai Jiao Tong Univ are at the center of the partnership. On the other hand, the results show that most institutions are fragmented and lack cooperation. The overall density of the network is low (density = 0.0139), mainly conducted in institutions in Europe and the United States, as shown in Figure 5.

Table 3. The top 10 institutions contributing to publications on ART.

Table 4. Number of citations by the top 10 institutions contributing to ART research.

Figure 5. Co-occurrence map of Institutions. The size of the nodes represents the number of articles, the thickness of the curve represents the strength of collaboration, and the colors represent different collaboration groups.

Analysis of authors and co-cited authors

Author co-occurrence analysis identifies the core authors and the strength of collaboration between authors. Co-cited analysis means that two authors or papers are cited simultaneously by a third author. This study included 23,752 authors and 78,083 co-cited authors. Among them, Stern, Judy E. (64), Luke, Barbara (62), Kissin, Dmitry M. (60), Jamieson, Denise J. (49) and Pinborg, Anja (47) published the most articles, as shown in Table 5). The collaboration between Stern, Judy E. and Kissin, Dmitry M. More was obtained, forming two solid author cooperative groups shown in Figure 6. The study found no collaboration between other authors and the team, and the research is in a relatively scattered state. The results of the co-cited relationship in Table 6 show that Pinborg, A (913), Luke, B (752), Gardner, DK (728), Schieve, La (727) and Hansen, M (611) are the most frequently cited authors. As a result, these authors significantly contribute to ART research.

Table 5. Number of articles published by the top 10 authors.

Figure 6. CiteSpace visualization map of authors involved in assisted reproduction. Nodes represent authors (the larger the circle, the more publications), the lines between nodes represent the cooperation between two authors of the same article (the wider the line, the more frequent the cooperation), and the color in the node represents the year.

Table 6. Number of co-citations of the top 10 authors.

Distribution of journals

The papers used in this study were published in 1,013 journals. The top five assisted journals were Fertility and Sterility (819), Human Reproduction (445), Reproductive Biomedicine Online (273), Journal of Assisted Reproduction and Genetics (269), and Biology of Reproduction (155), as shown in Table 7, Figure 7.

Table 7. Top 10 most productive journals.

Figure 7. Analysis of cited journals.

The results of the survey on co-cited journals showed that 19,254 journals were co-cited. The top five co-cited journals were Fertil Steril (40105), Hum Reprod (38083), Reprod Biomed Online (8457), Hum Reprod Update (7138) and J Assist Reprod Gen (5325), as shown in Table 8. The top five cited and co-cited journals were divided into Q1 and Q2 subdivisions, reflecting outstanding academic performance in assisted reproductive technology research.

Table 8. Top 10 co-cited journals.

Analysis of highly cited literature and co-cited literature

In total, 6286 references and 139023 co-cited references were obtained. The references that exceeded 500 citations include Jirtle and Skinner (13), Jackson et al. (14), Broekmans et al. (15), Zegers-Hochschild et al. (16), Flenady et al. (17), Broekmans et al. (18), LaMarca et al. (19), Zegers-Hochschild et al. (20), Wadhwa et al. (21), Practice Committee of the American Society for Reproductive Medicine (22), and Davies et al. (23), as shown in Table 9. In addition, 24 references were obtained to highlight the analysis results. The three references with the highest intensity were Zegers-Hochschild F, 2017, HUM REPROD, V32, P1786, DOI 10.1093/humrep/dex234 (42.51), Pinborg A, 2013, HUM REPROD UPDATE, V19, P87, DOI 10.1093/humupd/ DMS044 (40.98), Andersen AN, 2008, HUM REPROD, V23, P756, DOI 10.1093/humrep/ DEN014 (37.63), as shown in Figure 8.

Table 9. Number of citations of the top 10 references.

Figure 8. Top 24 References with the strongest citation bursts.

Keywords analysis

Through keyword co-occurrence and salience analysis, the changing trend of research topics over time was identified to grasp the development of research hotspots better. In total, 15,417 keywords were obtained. The top ten keywords were In the Assisted reproductive technology (3303), and in-vitro were used Fertilization (2139), Ivf (1140), Pregnancy (1140), Women (769), Intracytoplasmic Sperm injection (644), In Fertilization (632), Risk (545), Outcm (423), as shown in Table 10, Figure 9.

Table 10. Top 10 keywords on ART.

Figure 9. Keywords analysis. (A) Keyword co-occurrence analysis map obtained by VOSviewer. The size of the nodes represents the number of occurrences, the thickness of the curve represents the strength of collaboration, and the different colors represent the different clusters. (B) Keyword density visualization analysis. The redder the node, the higher the frequency of the keyword. (C) Keyword clustering map analysis through CiteSpace. A total of 16 categories of keywords were obtained, and different color blocks represent different keyword clusters.

After clustering using the CiteSpace software, 16 keywords were obtained. From 2004 to 2014, research hotspots in ART focused on Intracytoplasmic sperm injection, in vitro fertilization, Early development, Follicle-stimulating Hormone, Gamete biology, Spontaneous abortion, Mice, and Congenital malformation. On the other hand, between 2018 and 2021, the research hotspots in ART changed to Frozen embryo transfer, Fresh, Systematic review, and Recurrent implantation failure, as shown in Figure 10.

Figure 10. Keywords burst analysis by CiteSpace.

Discussion

Scholars can understand the research status of assisted reproduction through a comprehensive and systematic summary of the research topics, research trends and global research status. Assisted reproductive technology (ART) is a common technique to overcome male factor infertility. As a result, recent advances in ART have enabled many infertile couples to have children. Many studies have demonstrated that social factors such as delayed marriage have resulted in more people attending fertility clinics. The studies also state that ART has enabled many older parents to get children. Other studies have stated that the number of people using ART therapy increases yearly (2, 24, 25). ART indications by social change increase the chance of preserving fertility desire and expand, for example, the chances for hope to improve the elderly conception of “social” reasons or for medical reasons (such as saving the oocyte) before the cytotoxic anti-cancer treatment.

With the advent of the era of big data, researchers need to fully understand the developments in their research field. Unlike systematic review or meta-analysis, the bibliometric analysis uses visual software such as VOSviewer and CiteSpace to comprehensively analyze existing literature, to intuitively understand the development trend of research and predict future research hotspots (26). This study is the first to summarize the research status of ART in the past 20 years through bibliometric analysis.

General information about the literature on assisted reproductive technology

In the past 20 years, the number of studies on ART in journals showed a linear upward trend (R2 = 0.9379), especially in the last 4 years, with the annual number of articles published exceeding 500.

From the perspective of countries/regions and institutions, the number of publications and citations of the United States exceeds those of other countries. Although the number of articles published in China ranks second, the number of citations is low, ranking sixth. This finding shows that although the number of papers in China increases yearly, there is still a lack of high-quality articles. This is attributed to the lack of cooperation with international researchers and certain language barriers. Shanghai Jiao Tong Univ is the only institution from Asia among the top 10 organizations with the most published articles, while the rest are from Europe and the United States. Therefore, it is recommended to strengthen communication and cooperation among global cooperative research teams, especially countries and institutions in the Asian region, and look forward to more research results.

This study found that Stern, Judy E. had the highest publication efficiency, and Pinborg, A had the most co-citations, followed by Luke, Barbara, Kissin, Dmitry M., Jamieson, Denise J. Pinborg, and Anja. Stern, Judy E. focuses on intracytoplasmic sperm injection, and Pinborg and A focuses their research on meta-analysis and systematic reviews of ART (27–29).

Related research published in journals is relatively concentrated, with the most published papers followed by other journals. The top five cited and co-cited journals were divided into Q1 and Q2. The study found that most of the papers published are high-quality scientific research achievements.

Hot spots and frontiers

This study found that the most influential authors and references are review articles and clinical guidelines from internationally renowned institutions and journals. Combined with keyword co-occurrence, clustering and salience analysis, the study identified Intracytoplasmic sperm injection and Frozen embryo transfer as the main research topics and hot spots in ART.

Intracytoplasmic sperm injection, the injection of individual sperm cells directly into the ooplasm, is considered one of the most dramatic technological breakthroughs in ART. Intracytoplasmic sperm injection was introduced in 1992 as a modification of traditional IVF. Currently, ICSI is an established laboratory technique used worldwide to treat infertility. Intracytoplasmic sperm injection was originally introduced to overcome the most severe form of male-factor infertility. Studies have found that although the use of ICSI has steadily increased over the years, the proportion of infertile couples diagnosed with male-factor infertility has remained stable (30). In the more than two decades since its introduction to overcome severe male factor infertility, ICSI has been widely used to treat both male and non-male factor infertility. However, the advantage of ICSI over traditional IVF in couples without male factor infertility has not been demonstrated (31).

When performing ART in humans, sperm head morphology, size, and acrosome are important criteria for sperm selection (32), as the size of the sperm head may affect the fertilization rate (33). In contrast, Zahiri and Ghasemian reported that acrosome size and morphology of sperm heads influence sperm chromatin status, fertilization rates, and clinical outcomes (34, 35). Unlike sperm with normal acrosomes, sperm with small or large acrosomes significantly lower fertilization rate. In addition, sperm heads with large acrosomes reduce implantation rates, clinical pregnancy, and live birth rates. Many studies have reported that patients with spherospermia and abnormal acrosomes have significantly higher DNA fragmentation, sex chromosome aneuploidy, and disomy compared than the controls (36). In addition, hidden defects in normal-looking sperm may be responsible for the failed fertilization, suggesting the need for simple routine tests to detect these defects (37).

In a prospective study involving 1,089 randomly selected sibling oocytes during ART cycles in patients with polycystic ovary syndrome (PCOS), fertilization rates and embryo development were compared between C-IVF and ICSI in PCOS patients as a sole indication of infertility. The results showed a higher fertilization rate in the ICSI group (73%) than in the C-IVF group (45%) (38). In one case, after 6 weeks of treatment with 1200 mg of d-chiro-inositol (DCI), ovulation resumed in two non-PCOS anovatory women with elevated progesterone and luteinizing hormone and endometrial thickening (39).

The frequency of frozen embryo transfer (FET) continues to increase worldwide due to improved embryo survival through the introduction of vitrification, the implementation of guidelines to promote single-embryo transfer and therefore increased cryopreservation of excess embryos, efforts to reduce ovarian hyperstimulation rate syndrome (OHSS), the use of preimplantation genetic testing, and increased cryopreservation of embryos for fertility preservation (40–43).

In vitro fertilization laboratories quickly adopted vitrification after its efficiency was revealed in several publications on oocyte cryopreserve. The technique has also been rapidly adopted for embryo cryopreservation and is now the gold standard worldwide (44–46). The three most significant benefits of embryo vitrification are increased embryo survival (maintenance of viability) which increases the efficiency of embryo transfer/IVF treatment, increased cumulative pregnancy rate, and improved safety of assisted reproduction. Vitrification has directly contributed to the widespread acceptance of elective single-embryo transfer resulting in a sharp decline in the incidence of twins and higher rates of multiple pregnancies with IVF treatment.

Vitrification is a breakthrough in ARP since it revolutionized how IVF patients are treated and managed. In addition, vitrification has opened up new options for patients, most notably fertility preservation (via oocyte cryopreservation) and donor egg banking. The fact that vitrification has similar or even better results than fresh embryo transfer on some indicators makes it possible to abandon fresh embryo transfer altogether in favor of freezing all methods; Embryo biopsy (and preimplantation genetic testing) without compromising embryo survival; Elective single embryo transfer (and maintaining a high pregnancy rate); And significantly improved the single transplant cycle and cumulative pregnancy/live birth rate.

In recent years, uterine transplantation (UTX) has enabled women suffering from absolute uterine factor infertility (AUFI) to give birth to biological children and as an alternative to surrogacy. In addition, advances in techniques such as tissue engineering are expected to address UTX-related complications and difficulties in organ supply (47). Besides, in the past few years, a new branch of medicine with distinct multidisciplinary characteristics has developed: tumor fertility, which has attracted more and more attention. Maintaining fertility and family planning are key issues that must be addressed in all cancer patients of reproductive age (48).

According to some studies (49–52), infants born after FET have a lower risk of preterm birth that infants born after fresh embryo transfer. In addition, many studies have reported that infants born after FET have a lower risk of being small for gestational age and a higher birth weight than infants born after fresh embryo transfer (53–56). Of course, given that large-scale implementation of ART is relatively recent, further research is needed to provide more conclusive evidence on outcomes and impacts (57).

ART is a valuable option for couples who are infertile or have fertility problems.At the same time, ART, as an important part of the so-called “reproductive revolution,” has brought about three related results: the rift between reproduction and sexual intercourse, the opportunity to use heterologous fertilization through donor gametes, and the consequent increase in the number of reproductive donors (58). Therefore, some disputes in the legal and ethical aspects of ART need further consensus (59–62). With the outbreak of the COVID-19 pandemic, some experts have pointed out that access to assisted fertilization technology for infertile couples should be a part of the right to health, rather than a right to parenthood or an increase in birth rates (63).

This study found that the development of ART research areas is not balanced as influential authors and institutions are concentrated in Europe and Asia. This is attributed to the fact that ART is needed more in Europe and Asia than in most parts of the world (24, 64, 65). The study also found that the mechanism of ART and the pregnancy and live birth rate need to be further improved.

Limitations and prospects

Although this study is the first bibliometric analysis of research on ART in the last 20 years, it has some limitations. First, most high-quality articles in recent years have not reached the ideal citation time, which is prone to research bias. Second, there may be a time delay in exploring the frontiers of research. Lastly, this study included English literature retrieved from the WOS database. As a result, the likelihood of omitting quality articles published in other languages is high.

Conclusion

The bibliometric analysis of this study provides comprehensive information on the publication of ART research papers in various journals. The results found that ART is booming and has aroused great interest in the research community worldwide. Although ART is still in its infancy, there is great potential to trigger the development of ART. This study concludes that future research on Frozen embryo transfer could be at the forefront of assisted reproduction.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

Author contributions

FM and JW designed the study. LW, YZ, MZ, HL, GG, and DL conducted the literature search. FM, SD, and LW analyzed the data and wrote the paper. JW and XL approved the final manuscript. All authors contributed to the article and approved the submitted version.

Funding

This work was supported by the China Postdoctoral Innovative Talent Support Program (BX20220047), Young Talent Support Project of Beijing Association of Science and Technology (BYESS2022182), and Young Talent Support Project of Chinese Association of Chinese Medicine (CACM-2021-QNRC2-B04).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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