Trends in prenatal diagnosis: An analysis of 40 years of Medical Subject Heading (MeSH) terms in publications

Abstract

Objective:

To understand the evolution of the field of prenatal diagnosis over the past four decades.

Method:

We analyzed the publications in the journal Prenatal Diagnosis from its inception in 1980 to 2019 using Medical Subject Headings (MeSH) to examine the major research topics and trends. The results were analyzed by 10-year intervals.

Results:

Publications on prenatal cytogenetics, congenital anomalies and fetal imaging predominated during the first three decades, with a steady increase in molecular genetics over time. Publications on NIPT did not appear until the most recent decade and are likely under-counted because there was no MeSH term for NIPT until 2020.

Conclusion:

The topics covered in Prenatal Diagnosis articles have evolved considerably over the past four decades and reflect a response to advances in technology and widespread incorporation of prenatal screening and diagnosis into standard obstetric care. The strengths of this analysis are its objective nature, its use of the standard MeSH terms used for coding, and application of a novel cluster analysis to visualize trends. The analysis also pointed out the fact that MeSH terms in this sub-specialty area are often inconsistent due to manually coding based on individual subject matter expertise.

1 |. INTRODUCTION

The field of prenatal diagnosis originated in 1966, as it was during that year that amniocytes obtained from amniotic fluid were first successfully cultured.¹ The incorporation of prenatal diagnosis into obstetric care increased over time, to the point where by 1980 2%–3% of all pregnancies in the United States and United Kingdom underwent second trimester amniocentesis.¹ That same year, Professor Malcolm Ferguson-Smith of Cambridge University, UK, founded the journal Prenatal Diagnosis, the official journal of the International Society for Prenatal Diagnosis.¹ In 2020, Prenatal Diagnosis reached a significant milestone: 40 years of publications on prenatal screening and diagnosis. To demonstrate the evolution of the focus of the field of prenatal diagnosis, we conducted an empirical assessment of the major research topics of the Prenatal Diagnosis publications over the 40-year period.

2 |. METHODS

Institutional ethics approval was not required as no human subject data were included in this analysis. Data were derived from PubMed by searching the journal title, Prenatal Diagnosis, on June 15, 2020. There were 7418 articles retrieved from PubMed from the journal’s inception in 1980 to 2019. We then downloaded the related meta-data of the articles for topic analysis. Given that only 53% (or 3958) of the 7418 articles returned with author-given keywords, we focused on major Medical Subject Headings (MeSH). MeSH is a controlled vocabulary thesaurus used by MEDLINE/PubMed for indexing articles. Unlike other vendor databases that assign subject categories at a journal level and then use the same categories for all articles appearing in that journal, MEDLINE/PubMed assigns research topics at an article level. Staff subject specialists are responsible for areas in which they have expertise and they review and manually assign MeSH terms that describe the articles. Each article in MEDLINE/PubMed can be assigned to multiple major MeSH topics, usually obtained from the title and/or statement of purpose. They are the major topics of the article. Although MeSH terms have been criticized for a lack of highly reliable results due to some inaccuracies and inconsistencies in indexing,^2,3 the variety of the MeSH terms allows us to investigate research topics with granularity.

Relatively new MeSH topics such as “noninvasive prenatal testing” or NIPT, which wasn’t introduced to MeSH until 2020, were searched separately as keywords in titles to capture relevant research. In order to map the MeSH terms to the major concepts and terminologies used by this journal, these major MeSH terms were further reviewed, recoded, and relabeled by a medical subject expert (DWB).

3 |. RESULTS

The PubMed search retrieved 7418 publications in Prenatal Diagnosis between 1980 and 2019. As Figure 1 shows, the number of publications grew exponentially over the first two decades and then leveled off. The comparatively lower number of publications in the first 10 years is not surprising given the time a new journal needs to establish and flourish. After that, the journal’s annual publication count remained consistent within the range of 180–260 articles per year.

FIGURE 1.

The total number of publications per year between 1980 and 2019 in the journal Prenatal Diagnosis

Of the 7418 articles, 20 articles from 2018 and 124 articles from 2019 did not yet appear to have MeSH terms because of the time lag in indexing. This left us with 7226 articles (or 97%) that had MeSH terms. A total of 2708 major MeSH terms were found in these 7226 articles. Each of these terms was used 1–2763 times in categorizing the articles, with “prenatal diagnosis” being the most frequently coded term. In the initial review of the MeSH terms we noted ones that were related to each other (e.g., “Chromosomes, Human, Pair 11” and “Chromosomes, Human, Pair 2”). Therefore, to give more meaning to these granular terms, we further reviewed the major MeSH terms that appeared in at least six articles over the past 40 years (n = 598) and then recoded them, reclassifying them to broader categories. In the end, the 598 major MeSH terms were reclassified to 132 broader categories. These are partially listed in Table 1. For example, all terms that had to do with human chromosomes and procedures needed to obtain a prenatal karyotype were reclassified as “Prenatal Cytogenetics.” The complete list of reclassified terms is listed in Table S1. Since each article has multiple MeSH terms, we removed the non-specific term “Prenatal Diagnosis” to allow us to better visualize trends.

TABLE 1.

Trends in MeSH terms over time

Topic	1980–1984	1985–1989	1990–1994	1995–1999	2000–2004	2005–2009	2010–2014	2015–2019
Prenatal Cytogenetics	94%	87%	91%	71%	60%	55%	39%	31%
Congenital Anomalies	45%	38%	47%	37%	46%	49%	39%	41%
Fetal Imaging	22%	22%	24%	29%	33%	35%	30%	18%
Single gene disorders	29%	30%	28%	19%	16%	14%	9%	8%
Serum Screening	11%	12%	22%	20%	15%	14%	14%	14%
Molecular Genetics	2%	8%	11%	15%	14%	16%	15%	19%
Blood	15%	10%	6%	10%	7%	7%	4%	2%
Maternal Health	1%	4%	3%	4%	4%	8%	12%	4%
Multiple Gestation	8%	3%	7%	4%	4%	9%	7%	4%
Placenta	3%	5%	6%	5%	4%	5%	8%	5%
Sex Chromosomes	6%	6%	6%	6%	6%	7%	3%	3%
NIPT	0%	0%	0%	0%	0%	2%	7%	18%
Fetal Therapy	9%	1%	0%	2%	1%	3%	7%	7%
Health Attitudes	1%	1%	2%	2%	3%	5%	6%	4%
Abortion	5%	5%	5%	2%	3%	5%	4%	3%
Genetic Counseling	2%	2%	2%	1%	5%	4%	4%	4%
Preimplantation Genetic Testing	0%	1%	1%	2%	8%	5%	2%	2%
Growth Restriction	1%	2%	2%	2%	3%	3%	5%	3%
Neoplasms	5%	3%	5%	2%	3%	2%	2%	1%
Infection	0%	1%	3%	3%	2%	2%	2%	1%
Enzyme	15%	9%	4%	2%	2%	0%	0%	0%

The deepest shade of green is the highest value.

The lightest shade of green is the lowest value.

The midpoint is at the 70%.

Following the reclassification, the top six categories are listed below: (1) Prenatal Cytogenetics (3089 articles), which includes MeSH terms such as Down syndrome, trisomy, chromosome aberrations, amniocentesis, chorionic villi sampling, etc. (2) Congenital Anomalies (2275 articles), which includes MeSH terms such as multiple abnormalities, congenital heart defects, neural tube defects, etc. (3) Fetal Imaging (1497 articles), which includes MeSH terms such as prenatal ultrasonography, nuchal translucency measurement, magnetic resonance imaging, three-dimensional imaging, etc. (4) Single Gene Disorders (851 articles), which includes MeSH terms such as cystic fibrosis, genetic carrier screening, thalassemia, inborn genetic diseases, fragile X syndrome, etc. (5) Serum Screening (834 articles), which includes MeSH terms such as alpha-fetoprotein, chorionic gonadotropin, mass screening, etc. (6) Molecular Genetics (777 articles), which includes MeSH terms such as DNA, polymerase chain reaction, mutation, gene deletion, etc.

Since “noninvasive prenatal testing” (NIPT) was only introduced to MeSH in 2020, we used a different strategy to retrieve relevant articles. We first looked at 10 articles published between 2010 and 2019 that were known to include NIPT as a major topic to see how they were indexed in Medline/PubMed.^4–13 They were variously indexed as “prenatal diagnosis,” “maternal screening tests,” or “genetic testing.” Since there did not seem to be a consistent indexing for NIPT, we used natural language to find article titles that had any of the following terms as an indicator of relevance: “NIPS,” “noninvasive prenatal screening,” “cell-free fetal DNA,” “cffDNA,” “circulating fetal DNA,” “NIPD,” “noninvasive prenatal diagnosis,” “noninvasive prenatal testing” or “NIPT.” We found 236 articles between 2003 and 2019 in this dataset that met this criterion and subsequently created a category for this topic.

The classification results are displayed in Table 1. Within each cell is a percentage, defined as the number of articles that included that MeSH term divided by the total number of articles published during the 5-year interval. For visual clarity, only categories that appeared at least in 100 articles are displayed.

Over time, the research focus of prenatal diagnosis changed considerably, as captured in Figure 2, which displays the top six categories by per cents of publications in all years: prenatal cytogenetics; congenital anomalies, fetal imaging, single gene disorders, serum screening, and molecular genetics. A seventh category, NIPT, was also included to track the impact of this new prenatal screening technique. Publications on prenatal cytogenetics, congenital anomalies, and fetal imaging predominated during the first three decades. Preimplantation genetic diagnosis was a major focus of the journal at the beginning of the millennium.¹ This is shown in Table 1, which documents the peak of papers on this topic between 2000 and 2005, with a slow decline. Molecular genetics increased steadily throughout the past 40 years. From 2003 to 2019, new work on NIPT produced 236 publications.

FIGURE 2.

Trends over time in the six top topics plus noninvasive prenatal testing (NIPT) in published articles in Prenatal Diagnosis

In order to see how the major MeSH terms interacted with and connected to each other over the 40 years, we then used the Louvain Method of community detection¹⁴ to see, decade by decade, which major MeSH terms are more densely connected with each other than to the rest of the network. This method placed densely connected MeSH terms into clusters of major research themes.

Figure 3 displays the scope and major research themes over the 40 years based on the community detection analysis. Figure 3A shows that over the first decade, amniocentesis was the predominant diagnostic procedure, with many articles focused on prenatal cytogenetics, including the sex chromosomes and sex-linked disorders. Figure 3B demonstrates the second decade’s impact and changes in practice and research brought about by the implementation of maternal serum screening for Down syndrome and chorionic villus sampling as an alternate diagnostic procedure. Figure 3C demonstrates an increase in diversity of topics grouped together as “Miscellaneous” during the third decade. Figure 3D shows the impact of molecular genetics, the impact of the introduction of chromosome microarrays, and a decreased emphasis on diagnostic procedures during the fourth decade. As a category, fetal imaging and anomalies remained as a major research theme during all four decades.

FIGURE 3.

(A)–(D) The four figures show the scope of research topics reflected by major MeSH terms in the publications of Prenatal Diagnosis from 1980 to 2019. Each figure represents one decade, beginning with 1980–1989 in (A) to 2010–2019 in (D). Each circle is a major MeSH term as indexed in Medline/PubMed. The size of the circle is proportional to the frequency with which the associated MeSH term appear in total publications. Colors represent the clusters identified by the Louvain method and remain consistent throughout the 4 decades. Research themes are italicized next to the cluster

4 |. DISCUSSION

In summary, the topics in Prenatal Diagnosis have evolved considerably over four decades. Its publications reflect a response to advances in technology and widespread incorporation of prenatal screening and diagnosis into standard obstetric care. The strengths of this analysis are its objective nature, its use of the standard MeSH terms used for coding, and application of a novel cluster analysis to visualize trends over time. A weakness lies in the fact that the MeSH terms are manually coded based on subject matter expertise in an individual, which may result in indexing inconsistency. Although an indexing automation tool such as Medical Text Indexer has already been providing indexing recommendations based on the MeSH vocabulary since 2002,¹⁵ artificial intelligence-based approaches are needed in the future in order to provide more consistency in coding. Furthermore, one author (DWB) grouped MeSH terms together to allow ease of analysis. No standards exist for this, but to provide transparency, the groupings are provided in Table S1. Despite these limitations, this objective analysis demonstrated the constancy of fetal imaging over 40 years, an initial focus on prenatal diagnostic procedures and cytogenetics that declined over time, and an increase in molecular genetics and noninvasive screening in the more recent decades. This analysis also highlighted the importance of authors supplying key words with their manuscripts, as it is the authors who presumably have the most expertise regarding the topics covered in their paper.

What’s already known about this topic?

• Prenatal diagnosis, as a medical and laboratory specialty, has only existed since 1966.

• The main indication for prenatal diagnosis has been to determine the risk of a fetal chromosome abnormality.

What does this study add?

• Using Medical Subject Heading (MeSH) terms, 40 years of papers published in the official journal of the International Society for Prenatal Diagnosis were analyzed to understand the evolution of the field.

• Prenatal cytogenetics, congenital anomalies, and fetal imaging predominated over the first three decades.

• Molecular genetics studies increased over time as technology evolved.

• The advent of noninvasive prenatal testing (NIPT) after 2010 was relatively undercounted due to the lack of a specific MeSH term until 2020.

DATA AVAILABILITY STATEMENT

Data used for the analyses in this study are publicly shared in Table S1.