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. 2022 Sep 8;9:973332. doi: 10.3389/fnut.2022.973332

A bibliometric analysis of global research on vitamin D and reproductive health between 2012 and 2021: Learning from the past, planning for the future

Yimeng Lu 1,2,†, Xudong Zhang 1,2,†, Shanshan Wu 1,2, Siwen Zhang 1,2, Jichun Tan 1,2,*
PMCID: PMC9493010  PMID: 36159484

Abstract

Background

Vitamin D plays an invaluable role in reproductive health, but vitamin D insufficiency and deficiency are generally common among couples of childbearing age and pregnant women. This study aimed to evaluate the evolution, development trend, and research hotspot of publications on vitamin D and reproductive health.

Methods

The literature on vitamin D and reproductive health between 2012 and 2021 was retrieved from the Web of Science Core Collection (WoSCC). We used VOSviewer and CiteSpace to analyze publication years, countries, institutions, journals, highly cited authors and publications, and co-occurrence and citation bursts of keywords.

Results

A total of 1,828 articles and reviews on vitamin D and reproductive health published between 2012 and 2021 were identified. The annual publication outputs showed steady growth, with the most publications (272) and citations (7,097) in 2021. The United States contributed the most publications (458) and had the highest h-index (58). In terms of the number of publications and h-index, the journal named Nutrients ranked first. Nutrition dietetics, obstetrics gynecology, and endocrinology metabolism were three well-represented disciplines in research on vitamin D and reproductive health. Hollis BW, Wagner CL, and Litonjua AA were the top three most productive authors in this field during the last decade. Apart from vitamin D, the five keywords with the most frequent occurrence were vitamin D deficiency, pregnancy, risk, vitamin D supplementation, and 25-hydroxyvitamin D. Keyword citation burst analysis revealed that low birth weight, adipose tissue, marker, and embryo had a citation burst lasting until 2021.

Conclusion

In conclusion, vitamin D has received continuous attention in the field of reproductive health, and there appears to have a higher level of research in North America. Multidisciplinary intersection contributed to the in-depth exploration in this field. And the effect of maternal vitamin D levels on fetal lipid metabolism and the prediction of fertility by vitamin D-related markers might be hotspots for the research.

Keywords: vitamin D, vitamin D deficiency, pregnancy, bibliometric analysis, reproductive health, marker

Introduction

Vitamin D is an essential fat-soluble vitamin that serves a vital role in physiological processes such as calcium and phosphorus metabolism, immune regulation, cell growth, differentiation, and apoptosis in the body (1). Vitamin D is a steroid derivative, which can be divided into ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) according to the chemical constitution (2). Vitamin D2 is sourced from the UV irradiation of ergosterol in some plants or fungi, while vitamin D3 is mostly synthesized from 7-dehydrocholesterol in the skin following the UV irradiation (3). It is estimated that about 80% of the body’s vitamin D comes from the endogenous synthesis in the skin (ambient UV exposure), and only 20% comes from exogenous intake, including vitamin D3–exogenous (egg yolks and oily fish), vitamin D2 fortified foods (margarine and breakfast cereals) and vitamin supplements (3, 4). After binding to the multifunctional vitamin D-binding protein (VDBP), vitamin D is transported to the liver, where it is transformed by the action of 25-hydroxylation into 25-hydroxy vitamin D3 [25-(OH)D3], which is its main form of circulation and storage in the human body. Then, 25-(OH)D3 needs to be metabolized to 1,25-(OH)2D3, the main active form of vitamin D, by the action of 1α-hydroxylase, which is expressed by many cell types (i.e., skin, immune cells, bone cells, placenta), but the highest concentration is found in the kidney proximal tubule cells (5, 6).

1,25-(OH)2D3 exerts hormone-like effects by binding to the vitamin D receptor (VDR). VDR belongs to the steroid receptor family, widely present in various tissues of the body, including the intestines, renal tubules, skin, pancreas, skeleton, immune system, and germ tissues (7). The binding of 1,25-(OH)2D3 to the ligand-binding domain of VDR promotes the phosphorylation of VDR and the heterodimerization of retinoid X receptor (RXR) to form a 1,25-(OH)2D3-VDR/RXR complex which interacts with the vitamin D responsive elements (VDRE) in the promotor region of target genes to exert the genomic effects (6, 8). In the non-genomic pathway, the 1,25-(OH)2D3-VDR-caveolin-1 complex induces modifications in cellular signaling pathways, thereby affecting cellular function (9). The VDR gene, located on chromosome 12, has single nucleotide polymorphism, which can have biological functions (8). VDR polymorphisms are closely related to renal diseases, bone biology, cancer, diabetes, and other diseases, which are expected to be a diagnostic tool for the diseases, but further large-scale population studies are needed (10).

The high prevalence of vitamin D deficiency is a worldwide problem, especially in pregnant and reproductive-age women (11, 12). Recent studies have shown that vitamin D played an important role in the regulation of female reproductive health and was involved in the oocyte development, and production of anti-mullerian (AMH), ovarian steroidogenesis, and endometrial receptivity (13). Vitamin D deficiency can lead to adverse pregnancy outcomes and cause a variety of reproductive disorders. Some meta-analyses have reported that vitamin D deficiency could increase the risks of preeclampsia, gestational diabetes mellitus (GDM), maternal infections, intrauterine growth restriction, and preterm birth (14–16). Vitamin D deficiency is associated with a high risk of hypertensive disorders in pregnancy (17). Matias et al. found that vitamin D can downregulate the activation of the inflammasome and the TLR4-MyD88-NF-κB pathway in preeclampsia (18). Evidence suggested that vitamin D could improve insulin sensitivity by enhancing insulin responsiveness to glucose transport (19) and thus prevent the occurrence of GDM. A prospective study demonstrated follicular fluid vitamin D level was positively correlated with clinical pregnancy and implantation rates and was an independent predictor of the success of in vitro fertilization treatment (20). Moreover, vitamin D was also involved in the development of reproductive disorders including polycystic ovary syndrome (PCOS) (21), endometriosis (22), and uterine fibroids (23).

Bibliometric analysis is a world-accepted statistical evaluation of published articles and has grown in popularity (24), which was first proposed by American bibliographers in 1969. Through qualitative and quantitative analysis of publications, it could use literature metrology characteristics to provide investigators with crucial messages and discover frontiers and evaluate the distribution of countries/regions, authors, and journals in a certain specific field (25). In line with the growing interest in the role of vitamin D in reproductive health, there is a growing body of literature, including numerous systematic reviews and meta-analyses, but few bibliometric analyses explored the hot spots and frontiers of research in this field. In this study, we aimed to provide a general description of quantitative and visual information in the global literature on the associations between vitamin D and reproductive health, identifying its emerging trends and potential hot spots from various aspects through integrative analysis of relevant information from manuscripts published worldwide from 2012 to 2021. We presented a brief discussion of vitamin D-reproductive research and predicted possible trends in this field over the next few years, laying a foundation for the direction and development of future research.

Materials and methods

Data collection and search strategy

All relevant articles published between 2012 and 2021 were retrieved from the Web of Science (WoS) Core Collection (WoSCC), one of the most widely used literature search databases. The main merits of the WoS database are a wide range of applications, few utilization restrictions, convenience to support horizontal comparison, and robust tools that assist in conducting advanced assessments over gathered information. The search strategies were as follows: Topic = (“reproducti*” OR “*fertil*” OR “steril*” OR “pregnan*”) AND Topic = (“*Vitamin D*”) AND Language = (English). The timespan was set from January 1, 2012, to December 31, 2021. For document types, only original articles and reviews were included in the study, with a total of 4,187 publications. Similarly, we searched for studies with the Topic = (“Vitamin D*”) following the same search strategies. A total of 48,493 relevant literature were retrieved. To avoid possible bias produced by continuous database updating, the retrieval and export of documents were created within 1 day (May 1, 2022). As well, to ensure the accuracy of retrieval, two independent authors (Xudong Zhang and Yimeng Lu) performed the search process and confirmed the search query and results. After excluding those on unrelated search topics (n = 2,359), the remaining 1,828 publications were included in the subsequent analyses.

Data extraction and analysis

The retrieved data were downloaded and exported into different formats for further analysis. The “Analyze Results” and “Citation Report” functions of WoS were utilized for basic information statistics, including annual production, WoS categories, and quality of publications by country, institution, author, and journal. The quality of publications in this study mainly referred to the number of publications, the sum of the times cited, average citations per item (ACI), and h-index. Impact factors and category quartiles of journals for individual publications were collected from the 2021 Journal Citation Reports (JCR) (Clarivate Analytics, Philadelphia, United States). The country distribution maps were created using the online mapchart.1

VOSviewer and CiteSpace, two common software for bibliometric analysis, were employed to further analyze the underlying connections and key themes. We used VOSviewer (1.6.17, Leiden University, the Netherlands) to visualize co-authorship among countries/institutions/authors, co-citation of references, and co-occurrence of keywords. The specific steps included creating a map based on the bibliographic data, reading data from bibliographic database files, selecting the appropriate type and unit of analysis, and setting the counting method to full counting. In the figures obtained, the node represented country/institution/author/keyword, the size of the node indicated the number of publications or frequency of occurrence, the thickness of the curve showed the strength of the link, and the color reflected the cluster. CiteSpace is a Java-based software program and one of its features is citation burst analysis (26). CiteSpace (5.8. R3) was utilized to view citation bursts and a timeline of keywords. The parameters of CiteSpace were set as follows: link retaining factor (LRF = 3), look back years (LBY = 5), time slicing (from 2012 to 2021), years per slice (1), links (strength = cosine; scope = within slices), selection criteria (g-index, k = 25), and minimum duration (MD = 2). In the network graph, nodes represented various keywords, whereas the size of nodes reflected the frequency, and the connections between nodes represented the link.

Results

Temporal distribution map of the literature

A total of 1,828 pieces of literature from 2012 to 2021 related to Vitamin D and reproductive health were retrieved from WoS. There were 1,534 articles (83.92%) and 294 reviews (16.08%), respectively. As shown in Figure 1A, the number of publications on vitamin D and reproductive health generally showed an upward trend. From 2012 to 2016, the number of publications increased steadily, with a slight decline in 2017, and then continued to increase until reaching its peak (272 publications) in 2021. Similarly, the percentage of research on vitamin D and reproductive health in all vitamin D-related publications gradually increased from 2012 to 2016, declined in 2017, and remained volatile at approximately 4.40% from 2018 to 2021 (Figure 1B). Cited times of publications increased year by year, except for a slight drop in 2019, and the most citations (7,097 times) were achieved in 2021 (Figure 1A).

FIGURE 1.

FIGURE 1

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Trends in the growth of publications from 2012 to 2021. (A) The number of publications and citations per year on vitamin D and reproductive health. (B) Trends in the proportion of research on vitamin D and reproductive health in vitamin D-related research.

Distribution of countries and institutions

A total of 96 countries contributed to publications in this field (Figure 2). As shown in Table 1, the United States contributed the greatest number of publications (458, 25.06% of all), followed by China (283, 15.48%), England (187, 10.23%), Australia (147, 8.04%), and Canada (139, 7.60%). The top five countries in terms of ACI values were Canada (29.00), the United States (28.91), England (27.78), Denmark (24.29), and Australia (21.61). Regarding the h-index, the United States (58), England (38), and Canada (35) ranked in the top three. A total of 44 countries with more than five publications in the field were analyzed in the co-authorship analysis (Figure 3A). The five countries with the highest total link strength were the United States (total link strength = 359 times), England (264), Canada (168), Australia (135), and Denmark (124) (Table 1).

FIGURE 2.

FIGURE 2

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World map of countries contributing to vitamin D and reproductive health.

TABLE 1.

Top 10 productive countries regarding the research on vitamin D and reproductive health.

Rank Country Region Quantity Percentage ACI h Total link strength
1 United States North America 458 25.06% 28.91 58 359
2 China Eastern Asia 283 15.48% 13.21 31 65
3 England Western Europe 187 10.23% 27.78 38 264
4 Australia Oceania 147 8.04% 21.61 32 135
5 Canada North America 139 7.60% 29.00 35 168
6 Iran Western Asia 107 5.85% 17.71 28 25
7 Denmark Northern Europe 106 5.80% 24.29 30 124
8 Turkey Western Asia 82 4.49% 8.76 14 20
9 Italy Southern Europe 68 3.72% 19.87 23 109
10 Brazil South America 66 3.61% 9.15 15 53
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ACI, Average Citations per Item; h, h-index.

FIGURE 3.

FIGURE 3

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Co-authorship analysis of countries and institutions. (A) Network map of co-authorship between countries with more than five publications. (B) Network map of co-authorship between institutions with more than 15 publications.

As shown in Table 2, the institution with the highest number of research publications in this field is Harvard University with a quantity of 96, followed by the University of Copenhagen (68) and Harvard Medical School (47). The research institution with the highest ACI value in this field was the Medical University of South Carolina, which had an ACI value of 65.62, followed by the University of London (31.72) and Brigham and Women’s Hospital (31.40). We analyzed the co-authorship of 46 institutions with more than 15 publications. The exclusion of one item that was not connected revealed the collaborations of 45 institutions (Figure 3B). The three institutions with the highest total link strength were the University of Copenhagen (total link strength = 149 times), Harvard Medical School (145), and Brigham and Women’s Hospital (127) (Table 2).

TABLE 2.

Top 10 institutions in the studies of vitamin D and reproductive health.

Rank Institution Country Quantity STC ACI Total link strength
1 Harvard University United States 96 2,884 30.04 95
2 University of Copenhagen Denmark 68 1,601 23.54 149
3 Harvard Medical School United States 47 1,031 21.94 145
4 Harvard T.H. Chan School of Public Health United States 45 1,316 29.24 61
5 University of Southampton England 45 1,351 30.02 126
6 University of Toronto Canada 44 1,066 24.23 82
7 Brigham and Women’s Hospital United States 43 1,350 31.40 127
8 University of London England 43 1,364 31.72 63
9 Medical University of South Carolina United States 42 2,756 65.62 43
10 National Institutes of Health United States 41 792 19.32 55
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STC, sum of the times cited; ACI, average citations per item.

Analysis of journals and distribution of disciplines

A total of 1,828 articles were published in 518 journals. As shown in Table 3, the journal with the highest number of articles in this field was Nutrients (108), followed by PLoS One (68), Journal of Steroid Biochemistry and Molecular Biology (49), Journal of Maternal Fetal Neonatal Medicine (43), and BMC Pregnancy and Childbirth (42). The journal with the highest ACI value was Journal of Clinical Endocrinology Metabolism (41.69), followed by American Journal of Clinical Nutrition (34.78), Fertility and Sterility (34.68), PLoS One (22.46), and European Journal of Clinical Nutrition (21.95). The top five journals in terms of h-index were Nutrients (25), PLoS One (24), Journal of Clinical Endocrinology Metabolism (24), BMC Pregnancy and Childbirth (17), and American Journal of Clinical Nutrition (17).

TABLE 3.

Top 15 journals in the studies of vitamin D and reproductive health.

Rank Journal title Quantity ACI IF Q h
1 Nutrients 108 18.64 6.706 Q1 25
2 PLoS One 68 22.46 3.752 Q2 24
3 Journal of Steroid Biochemistry and Molecular Biology 49 17.76 5.011 Q2 16
4 Journal of Maternal Fetal Neonatal Medicine 43 14.67 2.323 Q3 10
5 BMC Pregnancy and Childbirth 42 17.79 3.105 Q2 17
6 Journal of Clinical Endocrinology Metabolism 35 41.69 6.134 Q1 24
7 British Journal of Nutrition 34 19.59 4.125 Q3 15
8 American Journal of Clinical Nutrition 27 34.78 8.162 Q1 17
9 Gynecological Endocrinology 27 8.33 2.277 Q3 9
10 Clinical Nutrition 23 13.39 7.643 Q1 10
11 Fertility and Sterility 22 34.68 7.49 Q1 14
12 Scientific Reports 22 11.68 4.996 Q2 9
13 European Journal of Clinical Nutrition 21 21.95 4.884 Q2 9
14 Journal of Nutrition 21 13.76 4.687 Q2 8
15 American Journal of Reproductive Immunology 17 10.59 3.777 Q2 9
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ACI, average citations per item; IF, impact factors; Q, quartile in the category; h, h-index.

As shown in Table 4, the top three disciplines according to the number of publications were nutrition dietetics (393, 21.50%), obstetrics gynecology (384, 21.01%), and endocrinology metabolism (337, 18.44%). Additional disciplines represented in the literature were reproductive biology (142, 7.77%), pediatrics (119, 6.51%), biochemistry molecular biology (110, 6.02%), medicine general internal (105, 5.74%), public environmental occupational health (97, 5.31%), immunology (96, 5.25%), multidisciplinary sciences (94, 5.14%), and other disciplines.

TABLE 4.

The top 20 subject categories in the studies of vitamin D and reproductive health.

Rank WOS categories Quantity Percentage
1 Nutrition dietetics 393 21.50%
2 Obstetrics gynecology 384 21.01%
3 Endocrinology metabolism 337 18.44%
4 Reproductive biology 142 7.77%
5 Pediatrics 119 6.51%
6 Biochemistry molecular biology 110 6.02%
7 Medicine general internal 105 5.74%
8 Public environmental occupational health 97 5.31%
9 Immunology 96 5.25%
10 Multidisciplinary sciences 94 5.14%
11 Medicine research experimental 71 3.88%
12 Allergy 46 2.52%
13 Pharmacology pharmacy 39 2.13%
14 Physiology 33 1.81%
15 Cell biology 32 1.75%
16 Agriculture dairy animal science 27 1.48%
17 Psychiatry 25 1.37%
18 Environmental sciences 23 1.26%
19 Food science technology 22 1.20%
20 Andrology 20 1.09%
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Analysis of authors

As shown in Table 5, Hollis BW from the Medical University of South Carolina has the highest number of published articles (33), followed by Wagner CL from the Medical University of South Carolina (30) and Litonjua AA from the University of Rochester (26). The top three authors in terms of ACI values were Hollis BW (71.00), Wagner CL (64.93), and Camargo CA (49.88) from Massachusetts General Hospital. Five of the top 10 authors are from the United States, four are from England, and one is from Canada.

TABLE 5.

Top 10 authors in the studies of vitamin D and reproductive health.

Rank Author Country Institute TP P ACI h
1 Hollis BW United States Medical University of South Carolina 33 1.81% 71.00 23
2 Wagner CL United States Medical University of South Carolina 30 1.64% 64.93 20
3 Litonjua AA United States University of Rochester 26 1.42% 40.58 14
4 Cooper C England University of Southampton 25 1.37% 38.28 16
5 Harvey NC England University of Southampton 24 1.31% 40.29 16
6 Godfrey KM England University of Southampton 23 1.26% 35.48 16
7 Weiss ST United States Brigham and Women’s Hospital 23 1.26% 34.09 11
8 Roth DE Canada University of Toronto 22 1.20% 26.55 12
9 Camargo CA United States Massachusetts General Hospital 16 0.88% 49.88 13
10 Hewison M England University of Birmingham 16 0.88% 42.50 10
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TP, total publications; P, percentage; ACI, average citations per item; h, h-index.

We analyzed a total of 204 authors that were co-authored in more than four publications (Figure 4). The five authors with the highest total link strength were Weiss ST (total link strength = 142 times), Litonjua AA (138), Harvey NC (130), Cooper C (129), and Godfrey KM (119). Three of the five are from the same institution called the University of Southampton.

FIGURE 4.

FIGURE 4

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Network map of co-authorship between authors with more than four publications.

Citation and co-citation analyses

Table 6 lists the top 10 documents with the highest citations. There were 501 citations for “Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality-A review of recent evidence,” (27) followed by “Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies,” (15) with 335 citations. The third-ranked article for the largest number of citations was “Maternal vitamin D status and adverse pregnancy outcomes: a systematic review and meta-analysis,” (14) with 290 citations.

TABLE 6.

Top 10 citation analysis of documents on vitamin D and reproductive health.

Rank Title Journal Type Authors Y C IN CN
1 Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality-a review of recent evidence Autoimmunity Reviews Review Pludowski et al. (27) 2013 501 3 1
2 Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies British Medical Journal Review Aghajafari et al. (15) 2013 335 1 1
3 Maternal vitamin D status and adverse pregnancy outcomes: a systematic review and meta-analysis Journal of Maternal-Fetal & Neonatal Medicine Review Wei et al. (14) 2013 290 2 2
4 Vitamin D supplementation for women during pregnancy Cochrane Database of Systematic Reviews Review De-Regil et al. (104) 2012 238 3 2
5 Effect of prenatal supplementation with vitamin D on asthma or recurrent wheezing in offspring by age 3 years the VDAART randomized clinical trial Journal of the American Medical Association Article Litonjua et al. (73) 2016 237 11 2
6 Micronutrient deficiencies in pregnancy worldwide: health effects and prevention Nature Reviews Endocrinology Review Gernand et al. (105) 2016 205 3 1
7 Vitamin D supplementation for women during pregnancy Cochrane Database of Systematic Reviews Review De-Regil et al. (106) 2016 196 4 3
8 Vitamin D and fertility: a systematic review European Journal of Endocrinology Review Lerchbaum et al. (107) 2012 192 1 1
9 Vitamin D supplementation in pregnancy: a systematic review Health Technology Assessment Review Harvey et al. (108) 2014 189 4 1
10 Vitamin D during pregnancy and maternal, neonatal and infant health outcomes: a systematic review and meta-analysis Pediatric and perinatal epidemiology Review Thorne-Lyman et al. (109) 2012 188 1 1
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Y, publication year; C, citations; IN, institute number; CN, country number.

Table 7 lists the top 10 references with the highest co-citations. The five references with the largest number of citations were by Aghajafari et al. (15), Holick (28), Holick et al. (29), Hollis et al. (30), and Bodnar et al. (31).

TABLE 7.

Top 10 co-citation analysis of cited reference on vitamin D and reproductive health.

Rank Title Journal Type Authors Y C IN CN
1 Vitamin D deficiency The New England Journal of Medicine Review Holick (28) 2007 381 1 1
2 Evaluation, treatment, and prevention of vitamin D Deficiency: an endocrine society clinical practice guideline Journal of Clinical Endocrinology & Metabolism Article Holick et al. (29) 2011 369 8 3
3 Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness Journal of Bone and Mineral Research Article Hollis et al. (30) 2011 280 1 1
4 Maternal vitamin D deficiency increases the risk of preeclampsia Journal of Clinical Endocrinology & Metabolism Article Bodnar et al. (31) 2007 249 3 1
5 Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies British Medical Journal Review Aghajafari et al. (15) 2013 201 1 1
6 Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study Lancet Article Javaid et al. (110) 2006 183 2 1
7 Maternal vitamin D status and adverse pregnancy outcomes: a systematic review and meta-analysis Journal of Maternal-Fetal & Neonatal Medicine Review Wei et al. (14) 2013 180 2 2
8 Maternal vitamin D status during pregnancy and child outcomes European Journal of Clinical Nutrition Article Gale et al. (111) 2008 172 1 1
9 High prevalence of vitamin D insufficiency in black and white pregnant women residing in the northern United States and their neonates Journal of Nutrition Article Bodnar et al. (31) 2007 157 2 1
10 Maternal early pregnancy vitamin D status in relation to fetal and neonatal growth: results of the multi-ethnic Amsterdam born children and their development cohort British Journal of Nutrition Article Leffelaar et al. (112) 2010 139 3 1
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Y, publication year; C, citations; IN, institute number; CN, country number.

Research hotspots and frontier analysis

Keywords are highly summarized and focused on descriptions of the subject of the article, which means that keywords with high frequency can reflect the research hotspots and trends of major issues in related fields. As shown in Table 8, in addition to vitamin D, keywords with a high frequency of occurrence were vitamin D deficiency (890), pregnancy (858), risk (493), vitamin D supplementation (396), 25-hydroxyvitamin D (378), and women (377).

TABLE 8.

The top 20 keywords in the studies of vitamin D and reproductive health.

Rank Keywords Occurrences Total link strength Rank Keywords Occurrences Total link strength
1 Vitamin D 912 5,584 11 Outcomes 204 1,501
2 Vitamin D deficiency 890 5,724 12 Preeclampsia 196 1,369
3 Pregnancy 858 5,369 13 Insulin resistance 172 1,122
4 Risk 493 3,317 14 Expression 166 881
5 Vitamin D supplementation 396 2,805 15 Vitamin D receptor 162 876
6 25-hydroxyvitamin D 378 2,613 16 Children 161 999
7 Women 377 2,436 17 Prevalence 153 1,005
8 Association 288 1,929 18 Supplementation 146 1,012
9 Health 213 1,438 19 Pregnant women 144 986
10 Calcium 205 1,261 20 Meta-analysis 135 991
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We analyzed a total of 120 keywords that were identified as occurring more than 20 times (Figure 5). The size of the node represents the number of times the keyword appears, and the thickness of the curve between the nodes represents the frequency of the two keywords appearing together. The keywords formed five clusters, which represented the five major research directions in the field.

FIGURE 5.

FIGURE 5

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Network visualization of keywords in studies on vitamin D and reproductive health.

The red cluster was dominated by female, infertility, semen quality, PCOS, and VDR. Vitamin D could affect the synthesis of human hormones (32), the development of oocytes in women (13), the quality of sperm in men (33), and the implantation of the embryo (34). PCOS is one of the critical causes of infertility in childbearing women and its incidence was closely linked to vitamin D deficiency. VDR polymorphisms played an important role in the development of PCOS and associated hormonal and metabolic abnormalities (35).

The yellow cluster focused on randomized controlled trial (RCT), meta-analysis, and neonatal outcomes. RCTs and meta-analyses were the more common types of studies investigating the association between vitamin D and reproductive health. Most RCTs evaluated the efficacy of vitamin D supplementation on IVF outcomes (36), infant acute respiratory infections (37), psychological distress (38), maternal postnatal bone indices (39), and so on. The meta-analysis was a secondary analysis primarily based on RCTs. Neonatal outcomes involved in exploring the effects of maternal vitamin D deficiency on offspring, including small-for-gestational-age (40), neonatal bone mass (41), infant glucose metabolism (42), infant atopic dermatitis (43), infant acute respiratory infections (37), infant birth weight (44), offspring sex ratio (45), infant gut microbiota (46), offspring socioemotional development (47), infant neurodevelopment (48, 49).

The blue cluster was mainly composed of diet, nutrition, and pregnancy outcomes. Vitamin D is an exogenous nutrient that can be influenced by dietary patterns (50), making diet and nutrition a significant subject in this field. Pregnancy outcomes are primarily concerned with adverse maternal effects of abnormal vitamin D status (insufficiency or deficiency), including GDM, hypertension, and preeclampsia (14).

The main research topics of the green cluster were allergy, asthma, wheeze, population, and depression. The first three parts were mainly to study the relationship between preconception and pregnancy serum vitamin D concentration and childhood atopic diseases (51–53). Population referred to discussing the relevant social factors affecting vitamin D levels (54). Depression discussed the role of poor vitamin D in perinatal depression (55).

The high-frequency ones in the purple cluster were vitamin D supplementation, season, and determinants. This clustering mainly addressed relevant determinants of vitamin D levels, such as vitamin D supplementation and season.

Burst patterns of keywords can reveal the frontiers and priorities of research between vitamin D and reproductive health. As shown in Figure 6, the timeline is depicted as a year-sliced blue line, where the red section is the detected burst, indicating the start and end years and duration of the burst. Vitamin D insufficiency ranked first with the highest burst strength (10.55), followed by high prevalence (6.63), male (5.18), lactation (5.16), 25 hydroxyvitamin D concentration (4.78), and parathyroid hormone (4.78). The burst times of the terms bone mineral content, adverse pregnancy outcome, and low birth weight lasted for 4 years. Low birth weight, adipose tissue, marker, and embryo are currently within the burst period and might become new research foci in this field.

FIGURE 6.

FIGURE 6

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Top 20 keywords with the strongest citation bursts based on CiteSpace.

Discussion

In this paper, we conducted a bibliometric analysis of the literature on vitamin D and reproductive health published from 2012 to 2021 based on the visualization software CiteSpace and VOSviewer. The spatial and temporal distribution, author and journal contribution, core literature, research hotspots, and research frontier analysis were assessed. The timeline of keywords revealed the evolution of the research theme and the burst analysis suggested current research hotspots.

The research on vitamin D in reproductive health showed a steady upward trend. Research on vitamin D in the field of reproductive health can still arouse great interest so far. On one hand, it is inextricably linked to the benefits of vitamin D. Vitamin D has a physiological role in ovarian follicular development and luteinization, including alteration of AMH signaling, FSH sensitivity, and progesterone production and release (56). Vitamin D also performed vital functions in male reproduction. Serum 25-(OH)D3 level was positively associated with sperm motility and VDR in human spermatozoa could be regarded as a positive predictor of sperm quality (57). On the other hand, some of the effects of vitamin D on reproductive health are controversial and have not yet been elucidated. For example, there were differing views on whether vitamin D was associated with IVF outcomes or whether vitamin D supplementation could improve IVF pregnancy outcomes. A retrospective study that analyzed the association between serum 25-(OH)D3 level 7 days prior to embryo transfer and pregnancy revealed that vitamin D deficiency impaired clinical pregnancy rate in a single blastocyst transfer cycle (58). Conversely, a RCT by Somigliana et al. showed that a single oral dose of 600,000 IU of vitamin D3 did not improve IVF clinical pregnancy rates in women with normal weight (36).

The study of vitamin D in the reproductive health field showed a pattern of extensive coverage, but uneven development. As shown in Figure 1, approximately more than half of the countries in the world, covering 5 continents, have been involved in this area of research in the last decade. This was probably due to the high prevalence of vitamin D abnormalities (vitamin D insufficiency and deficiency) among the reproductive-aged and pregnant women, which was a worldwide phenomenon. Even in abundant sunshine’s tropical countries like India, the prevalence of vitamin D deficiency among reproductive-aged women is as high as 80%. Numerous studies indicated that vitamin D insufficiency or deficiency varied with geography, economic situation, social status, national policy (food fortification), and individual awareness (59–62). From raising population self-awareness, national intervention to the actual improvement of vitamin D levels, each country needs to further explore its own solutions.

Overall, the America, Europe, Asia, and Oceania were relatively active in this field, while Africa might be in a low active state due to limited economic development. Of these, North America, especially the United States and Canada, probably hold a stronger basis and more mature research system in the field, as 7 and 6 of the top 10 productive institutions and authors come from these two countries, respectively. The Medical University of South Carolina in the United States had the highest ACI, and the top two productive authors are from this institution (Tables 1, 2). The research team mainly focused on prenatal vitamin D screening (63), and the effects of vitamin D supplementation on early life (pregnancy, lactation, and childhood), including glycemic, lipidemic, oxidative stress biomarkers (64), inflammatory biomarkers (65), growth factors, immune-mediators (66), bone mineral density (67), the vaginal microbiome (68), preeclampsia (69) during pregnancy, preterm birth (70), offspring epigenetic clock (71), asthma, allergies and recurrent wheeze (72–75). The conclusions of most original studies were derived from RCTs, with high-level evidence and instructive significance. Furthermore, they also dabbled in basic research, using model animals to explore the effects of a low vitamin D diet on maternal hypertension as well as placental and fetal development (76). Researchers of the University of Southampton focused more on the association between vitamin D and bone-related outcomes such as maternal osteoporosis (39, 77), offspring bone structure (78), bone formation (79), bone mass (80), bone health (81–83) and fractures in late childhood (84). Concurrently, genetic variation in gene expression also received greater interest, with studies showing that detection of genetic susceptibility-related variant genes for vitamin D deficiency may guide vitamin D supplementation (85–87). Europe and Asia are also undergoing rapid development and are represented by the University of Southampton and Tehran University of Medical Sciences, respectively. Tehran University of Medical Sciences paid more attention to the role of vitamin D in male reproduction (88–90) and the mechanism by which vitamin D improved female reproductive disorders including endometriosis (91, 92), PCOS (93, 94), repeated implantation failure (51, 95), and endometritis (96).

It formed a development landscape of multidisciplinary intersection with nutrition, obstetrics and gynecology, and endocrinology metabolism as the core in this field. From Tables 3, 4, we can note that nutrition, gynecology and obstetrics, and endocrinology metabolism are the most dominant WoS categories and the scope of the top 15 journals. These were reflected in the literature on topics such as diet and vitamin D supplementation, the effects of vitamin D on the maternal and offspring, and the expression, role, and variation of vitamin D-related receptors and enzymes. Meanwhile, we should also take note of public environmental, environmental sciences, immunology, multidisciplinary sciences, biochemistry molecular biology, medicine research experimental, pharmacology, cell biology, and so on (Table 4). Multidisciplinary intersection contributed to a more comprehensive understanding of the role of vitamin D in reproductive health to guide the prevention, treatment, and even reversal of the consequences of vitamin D deficiency. The participation of basic disciplines is to split the whole into the tissue, cellular, and molecular levels, to gain an in-depth understanding of the mechanism.

Risk factors and adverse impacts of vitamin D deficiency were the focus of current research. The effect of maternal vitamin D levels on fetal lipid metabolism and the prediction of fertility by vitamin D-related markers might be hot spots and frontier areas in the field. Adipose tissue serves as a reservoir for vitamin D and affects its activity (97). Maternal vitamin D deficiency may affect fetal weight by influencing lipid metabolism, but the current findings are controversial. A birth cohort-based study in China suggested that maternal serum 25-(OH)D3 was positively associated with fetal birth weight and that vitamin D deficiency during pregnancy increased the risk of low birth weight infants (98). A study performed by Morales et al. indicated that maternal deficit of 25(OH)D3 was associated with an increased risk of fetal overweight and overweight in offspring at age 1 year (99). This might be due to maternal vitamin D deficiency resulting in polarization in the adipose depots (100). Moreover, vitamin D-related indexes are expected to be new markers for fertility assessment. Li et al. reported urine VDBP levels were significantly positively correlated with ovarian reserve and were expected to be a biomarker for predicting ovarian reserve (101). In assisted reproductive technology, vitamin D level in the follicular fluid could be used as a marker of oocyte quality, and vitamin D level in serum could be used as a marker of in vitro fertilization outcome (102). For men of childbearing age, the vitamin D metabolizing enzyme CYP24A1 was positively correlated with total sperm count, concentration, motility, and morphology, and the expression of CYP24A1 at the annulus of human spermatozoa might serve as a novel marker of semen quality (103). Therefore, further research is needed to clarify the above-mentioned effects of vitamin D, and RCT with a higher level of evidence might be a more meaningful research approach.

To our knowledge, this study is the first bibliometric analysis to explore the research on vitamin D in reproductive health. However, it had a few limitations. First, we only selected the WoS database and were limited by visual analysis software to include only the WoSCC. Second, we only analyzed the literature over the last decade, but this field has developed for such a considerable period of time that some previous views might be ignored by us. Finally, some of the more recently published articles may have been overlooked by the hotspot analysis because they did not have sufficient citations.

Conclusion

Vitamin D holds great research significance and the clinical application potential in the field of reproductive health. Based on visual analysis software, we evaluated the evolution process, contribution distribution, development trend, research hotspots, and frontiers of vitamin D research in reproductive health over the past decade. The field has received great attention globally, and the multidisciplinary intersection is the development trend. Furthermore, the effect of maternal vitamin D levels on fetal lipid metabolism and the prediction of fertility by vitamin D-related markers might be the focus of the research, and the exploration of population heterogeneity in the diagnostic criteria of vitamin D deficiency and the specific mechanisms of vitamin D effects on reproductive health should also be paid attention to.

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author contributions

XZ and YL were responsible for experiment conception and design, collection and assembly of data, data analysis and interpretation, and manuscript writing. SW and SZ contributed acquisition data and revised the manuscript. JT designed the work, provided technical guidance, and finally approved the manuscript. All authors read and approved the final manuscript.

Footnotes

Funding

This work was supported by the National Key Research and Development Program (2018YFC1002105), the National Natural Science Foundation of China (82071601), the Major Special Construction Plan for Discipline Construction Project of China Medical University (3110118033), and the Shengjing Freelance Researcher Plan of Shengjing Hospital of China Medical University.

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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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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