Gestational tissue transcriptomics in term and preterm human pregnancies: a systematic review and meta-analysis
Eidem et al. BMC Medical Genomics
Gestational tissue transcriptomics in term and preterm human pregnancies: a systematic review and meta-analysis
Haley R. Eidem 1
William E. Ackerman IV 2
Kriston L. McGary 1
Patrick Abbot 1
Antonis Rokas 1
0 35-1634 , Nashville, TN 37235 , USA
1 Department of Biological Sciences, Vanderbilt University, VU Station B
2 Department of Obstetrics and Gynecology, The Ohio State University , Columbus, OH 43210 , USA
Background: Preterm birth (PTB), or birth before 37 weeks of gestation, is the leading cause of newborn death worldwide. PTB is a critical area of scientific study not only due to its worldwide toll on human lives and economies, but also due to our limited understanding of its pathogenesis and, therefore, its prevention. This systematic review and meta-analysis synthesizes the landscape of PTB transcriptomics research to further our understanding of the genes and pathways involved in PTB subtypes. Methods: We evaluated published genome-wide pregnancy studies across gestational tissues and pathologies, including those that focus on PTB, by performing a targeted PubMed MeSH search and systematically reviewing all relevant studies. Results: Our search yielded 2,361 studies on gestational tissues including placenta, decidua, myometrium, maternal blood, cervix, fetal membranes (chorion and amnion), umbilical cord, fetal blood, and basal plate. Selecting only those original research studies that measured transcription on a genome-wide scale and reported lists of expressed genetic elements identified 93 gene expression, 21 microRNA, and 20 methylation studies. Although 30 % of all PTB cases are due to medical indications, 76 % of the preterm studies focused on them. In contrast, only 18 % of the preterm studies focused on spontaneous onset of labor, which is responsible for 45 % of all PTB cases. Furthermore, only 23 of the 10,993 unique genetic elements reported to be transcriptionally active were recovered 10 or more times in these 134 studies. Meta-analysis of the 93 gene expression studies across 9 distinct gestational tissues and 29 clinical phenotypes showed limited overlap of genes identified as differentially expressed across studies. Conclusions: Overall, profiles of differentially expressed genes were highly heterogeneous both between as well as within clinical subtypes and tissues as well as between studies of the same clinical subtype and tissue. These results suggest that large gaps still exist in the transcriptomic study of specific clinical subtypes as well in the generation of the transcriptional profile of well-studied clinical subtypes; understanding the complex landscape of prematurity will require large-scale, systematic genome-wide analyses of human gestational tissues on both understudied and well-studied subtypes alike.
Preterm birth; Gestational tissues; Transcriptomics; Gene expression; microRNA; Methylation; Preeclampsia; Idiopathic preterm birth; Meta-analysis
In humans, gestation typically lasts 40 weeks; preterm
birth (PTB) is defined as birth before 37 completed
weeks of gestation and is the leading cause of newborn
death worldwide. More than 15 million babies are born
too soon every year and rates of PTB had been
increasing until 2006 when changes in obstetrical practices
regarding early cesarean sections led to a recent decrease
in deliveries before term . Nevertheless, 10 % of
pregnancies still end before 37 weeks across the world and
this high incidence of PTB is problematic because
premature babies are at higher risk for lifelong health
and developmental problems [2, 3]. For example, almost
half of all children born premature suffer from vision or
hearing loss and learning disabilities at some point in
their life [4, 5]. The combined medical costs stemming
from care during the labor and delivery process as well
as from care later in life are estimated to be near $26
billion annually .
PTB is a complex, multifactorial syndrome comprised of
multiple clinical subtypes, which often occur at different
gestational ages and can be defined as either ‘spontaneous’
or ‘medically indicated’ . Medically indicated preterm
deliveries account for 30 % of PTB cases and are often
preceded by complications including preeclampsia (PE),
intrauterine growth restriction (IUGR), gestational
diabetes mellitus (GDM), and chorioamnionitis . The
remaining 70 % of PTB cases are idiopathic; 45 % is due
to the spontaneous onset of labor (sPTB) and the
remaining 25 % is due to the preterm premature rupture
of membranes (PPROM) [9–11]. Regardless of PTB
subtype, however, current therapies are not successful in
prolonging time to birth once labor has been initiated and
the most effective therapy, progesterone supplementation,
is only effective in a small number of high-risk cases .
It is critical that we gain greater insight into the genes and
pathways that regulate birth timing in humans in order to
develop effective prevention and treatment strategies,
including for cases of sPTB.
A number of environmental risk factors have been
associated with sPTB including infection, nutrition,
socioeconomic status, and stress but the pathways
through which these risk factors act remain unclear .
Recent evidence from family, twin, and case–control
studies suggests that genetics also plays an important
role in birth timing, and the heritability of PTB is
estimated to be approximately 30 % [1, 6, 8]. Thus, PTB
tends to run in families and women who were born
preterm are also more likely to deliver preterm themselves.
Interestingly, however, fathers born prematurely do not
appear to pass on this risk to offspring . Furthermore,
one of the strongest predictors of PTB is previous
preterm birth and, in subsequent pregnancies from the
same woman, birth timing tends to occur around the
same gestational age for each pregnancy [9, 14].
Candidate gene studies have targeted genes with known
biological roles potentially related to processes occurring
during pregnancy but, in general, teasing apart the
complex genetic architecture of pregnancy and PTB has
Further complicating our understanding of PTB
genetic architecture are the numerous maternal and fetal
gestational tissues that must interact to facilitate
parturition [12, 15]. These tissues include decidua,
myometrium, cervix and maternal blood originating from the
mother and villous placenta, fetal membranes (chorion
and amnion), umbilical cord, and fetal blood originating
from the fetus (Fig. 1). Furthermore, the basal plate is a
region at the maternofetal interface that is commonly
biopsied for the study of PTB and includes cells from
both the decidua and villous placenta. The decidua,
myometrium, and cervix act to house the fetus as well
as expel it during labor and delivery, the chorion and
amnion act as membranes separating the fetus from the
mother, and the umbilical cord allows for efficient nutrient
transfer. Together, these tissues share a general
functionality in the efficient maternofetal exchange of nutrients, gas,
Although little is known about the complex etiology of
PTB, many studies have generated pregnancy-related
transcriptomes in various tissue types and pathologies.
Because of the diversity of tissues and clinical subtypes
involved as well as the large number of questions
examined, few studies have attempted to synthesize any
dimension of the admittedly complex transcriptional
landscape of this multifactorial syndrome. To synthesize
Fig. 1 The tissues of pregnancy. Our systematic literature review
surveyed a total of 9 distinct gestational tissue types including 4 of
maternal origin (cervix, myometrium, decidua, and maternal blood;
shown in red), 4 of fetal origin (fetal blood, fetal membranes, umbilical
cord, and placenta; shown in blue), and 1 of mixed maternal and fetal
origin (basal plate; shown in purple)
what is known about PTB transcriptomics, we analyzed
all published genome-wide studies of gestational tissues
(placenta, decidua, myometrium, maternal blood, cervix,
basal plate, fetal membranes, umbilical cord, and fetal
blood) in both healthy and diseased human pregnancies
to identify all statistically supported candidate genetic
elements in PTB subtypes.
Our meta-analysis identified 134 genome-wide studies
of pregnancy and PTB. The majority of PTB research
focused on PE; very few studies were focused on sPTB
(18 %) even though sPTB accounts for 45 % of all PTB
cases. Moreover, there was limited overlap in the identity
of candidate genes across studies. In placenta (n = 53),
for example, 6,444 differentially expressed unique genes
were identified but only 2, LEP and FLT1, were present
in more than 10 gene expression studies. Similarly, in PE
studies (n = 27), 5,329 differentially expressed unique
genes were identified but only 13 were found in 5 or
more gene expression studies. The limited overlap of
differentially expressed genes across studies of the same
tissue or clinical subtype as well as the highly uneven
coverage of studies targeting highly prevalent clinical
subtypes suggest that larger-scale, systematic studies
aimed at understanding the transcriptional profiles of
the diverse clinical PTB subtypes and characterizing
their disease-relevant transcriptional differences will be
necessary to identify genes whose dysregulation
contributes to this complex, multifactorial syndrome.
A systematic review identified 134 transcriptomic studies
on 9 gestational tissues and 29 different phenotypes
Of the 2,361 studies identified in our PubMed search,
134 genome-wide transcriptomic studies in human
gestational tissue samples were, based on a number of
selection criteria, deemed eligible for systematic review
(Additional file 1) [16–133]. These 134 studies were
identified from a total of 116 distinct publications; this is
so because 14 publications reported multiple
comparisons that were separated into 33 distinct studies for the
purpose of this analysis. Platform-wise, 127/134 (95 %)
were microarray studies, 4/134 (3 %) were
bisulfitesequencing studies, and 3/134 (2 %) were
RNAsequencing studies. All studies were published between
1999 and 2014, primarily in the journals Placenta and
The American Journal of Obstetrics and Gynecology. The
phenotypes examined in these studies were quite diverse;
14/134 (10 %) studies examined preterm pregnancies,
80/134 (60 %) term pregnancies, and 40/134 (30 %) both
preterm and term pregnancies. One non-clinical phenotype
(healthy pregnancies) and 28 distinct clinical phenotypes
were represented. Finally, 21/134 (16 %) were microRNA
studies, 20/134 (15 %) were methylation studies, and the
remaining 93/134 (69 %) were gene expression studies. A
total of 10,993 unique genetic elements were reported
to be transcriptionally active across all 134 studies
(Additional file 2), but only 23/10,993 (0.2 %) were
reported in 10 or more studies.
The 134 studies analyzed 9 distinct gestational tissues,
namely placenta, decidua, myometrium, maternal blood,
cervix, fetal membranes (chorion and amnion), umbilical
cord, fetal blood, and basal plate. The three most
common tissues studied were placenta (82/134; 61 %), fetal
membranes (16/134; 12 %), and myometrium (17/134;
12 %), whereas each of the other six tissues was sampled
in 7 or fewer studies (Fig. 2).
The 134 studies analyzed 29 distinct phenotypes (Fig. 3).
11/134 (8 %) studies focused on healthy pregnancies,
while the remaining 123/134 (92 %) studies focused on
clinical phenotypes. The most common phenotypes studied
were PE (40/134; 30 %), labor (16/134; 12 %), and sPTB
(10/134; 7 %). Definitions for all phenotypes are provided in
Additional file 3.
PTB research focus does not reflect PTB subtype
To evaluate whether the proportion of transcriptomic
studies devoted on different PTB subtypes reflects their
clinical prevalence, we compared the frequencies of the
three major clinical etiologies (sPTB at 45 %, PPROM at
25 %, and medically indicated PTB at 30 %) to the
frequency of transcriptomic studies devoted to these
etiologies (Fig. 4). We found that although only 30 % of all
PTB cases are due to medical indications, such as PE,
IUGR, or GDM, 41/54 (76 %) of the studies categorized
as preterm in our systematic review focused on them;
21/54 (39 %) of the preterm studies focused on PE alone.
In contrast, although sPTB is responsible for 45 % of all
cases, only 10/54 (18 %) of the preterm studies in our
systematic review studied this clinical subtype.
A meta-analysis of 93 gene expression studies across 9
distinct gestational tissues showed limited overlap of
To perform an aggregated meta-analysis, we focused on
the 93/134 gene expression studies. These 93 gene
expression studies analyzed all 9 distinct gestational tissues,
namely placenta, decidua, myometrium, maternal blood,
cervix, fetal membranes (chorion and amnion), umbilical
cord, fetal blood, and basal plate. The three most common
tissues studied for differential gene expression were
placenta (53/93; 57 %), myometrium (17/93; 18 %), and
fetal membranes (11/93; 12 %), whereas each of the
other six tissues was sampled in 4 or fewer studies.
Genome-wide gene expression profiling studies of the
three most commonly studied gestational tissues, i.e.,
placenta, myometrium, and fetal membranes, identified
a total of 8,437 unique differentially expressed genes, of
Fig. 2 The vast majority of genome-wide transcriptomic studies on gestational tissues have focused on the placenta. A targeted PubMed search
for genome-wide transcriptomic studies yielded a total of 134 studies focusing on 9 distinct gestational tissue types. Placental research accounted
for 61 % of all studies in the meta-analysis, followed by fetal membranes (12 %) and myometrium (12 %)
which only 2,123 (25 %) were found in two or more
studies (Fig. 5, Additional file 4). This examination also
showed that only 23 candidate genes were differentially
expressed two or more times in studies of all three
tissues (Additional file 5). Among the genes present in
this overlap were interleukin 1 beta, a proinflammatory
cytokine shown to be involved in infection-related PTB
and PE, and superoxide dismutase 2, an antioxidant
enzyme shown to be involved in oxidative stress
associated with PTB [18, 23, 34, 49, 65, 134–138].
Although gene expression profiles are available for 29
distinct phenotypes, PTB research is dominated by
studies focused on select phenotypes of PTB
The 93 gene expression studies analyzed 29 distinct
phenotypes. From these studies, 5/93 (5 %) focused on a
Fig. 3 Gestational tissue transcriptomic studies in term and preterm human pregnancies organized by phenotype. A targeted PubMed search for
genome-wide transcriptomic studies yielded a total of 134 studies focusing on 29 distinct phenotypes. PE research accounted for 30 % of all studies in
the meta-analysis, followed by labor (12 %) and sPTB (7 %). Phenotype definitions are provided in Supplementary Table S2
Fig. 4 Proportion of transcriptomic research does not correspond to PTB subtype prevalence. Although only 30 % of all PTB cases are due to
medical indications, such as PE, IUGR, or GDM, 76 % of the preterm studies in our systematic review focused on them. In contrast, only 18 % of
the studies focused on sPTB, even though this clinical subtype accounts for the majority (45 %) of PTB cases
non-clinical phenotype (healthy pregnancies), with the
remaining 88/93 (95 %) focused on clinical phenotypes.
Among studies focused on clinical phenotypes, the three
most common phenotypes investigated were PE (27/93;
29 %), labor (15/93; 16 %), and IUGR (8/93; 9 %); each of
the other 26 clinical phenotypes was studied in 5 or fewer
studies. Genome-wide gene expression studies of the three
most commonly studied clinical phenotypes identified a
total of 7,730 unique genes, of which only 1,336 (15 %)
were present in two or more studies (Fig. 6, Additional
file 6). No candidate genes were found two or more times
in studies of all three phenotypes. Generally, overlap of
Fig. 5 Overlap of differentially expressed genes across tissues.
Differentially expressed genes present in two or more gene
expression studies categorized by tissue were compared across the
three most commonly studied (placenta, myometrium, and fetal
membranes). Out of 2,123 genes identified to be differentially expressed
in at least two studies, 23 genes were shared across all three tissues
Fig. 6 Overlap of differentially expressed genes across phenotypes.
Differentially expressed genes identified in two or more gene
expression studies categorized by phenotype were compared across
the most commonly studied (PE, labor, and IUGR). Out of 1,336
genes identified to be differentially expressed in at least two studies,
none were shared across all three phenotypes
differentially expressed genes was more limited across
clinical phenotypes than across gestational tissues.
Overlap of differentially expressed genes identified across
PTB studies is limited
Studies of placenta, myometrium, and fetal membranes,
the three most commonly studied tissues, focused on a
total of 25 distinct phenotypes (Fig. 7a, Additional file 7).
The clinical phenotype studied, however, differed between
tissues, with PE dominating placental research (23/53
placental studies or 43 %), labor dominating myometrial
research (9/17 myometrial studies or 53 %), and PPROM
dominating fetal membrane research (4/13 fetal membrane
studies or 31 %). Likewise, the range of tissues studied
differed between phenotypes. PE was studied across 4 distinct
gestational tissues (placenta, decidua, basal plate, and
maternal blood), labor was studied across 4 distinct gestational
tissues (myometrium, fetal membranes, placenta, and
cervix), and PPROM was studied across only 1 distinct
gestational tissue (fetal membranes) (Fig. 7b, Additional file 8).
To identify common differential gene expression
signatures, we looked for overlap between differentially
Labor in myometrium
PPROM in fetal membranes
Fig. 7 Representation of overlap in differentially expressed genes across the most commonly studied tissues, phenotypes, and tissues &
phenotypes. Studies are represented as distinct wedges in the outermost track, colored by phenotype and sized by number of genes reported.
Genes that show a high degree of overlap across studies (4 or more placenta, PE, or PE in placenta studies; 4 or more myometrium, labor, or
labor in myometrium studies; 4 or more fetal membranes studies; or 2 or more PPROM or PPROM in fetal membranes studies) appear as black
links connecting each study reporting the gene. In general, the scarcity of links illustrates the considerable lack of overlap in the genes identified
as differentially expressed across PTB studies. a Representation of overlap in differentially expressed genes across the most commonly studied
tissues. Studies of placenta, myometrium, and fetal membranes, the three most commonly studied tissues, focused on a total of 25 distinct
phenotypes with PE dominating placental research, labor dominating myometrial research, and PPROM dominating fetal membranes research.
b Representation of overlap in differentially expressed genes across the most commonly studied phenotypes. PE was studied across 4 distinct
gestational tissues (placenta, decidua, basal plate, and maternal blood), labor was studied across 4 distinct gestational tissues (myometrium, fetal
membranes, placenta, and cervix), and PPROM was studied across only 1 distinct gestational tissue (fetal membranes). c Representation of overlap
in differentially expressed genes across the most commonly studied tissue and phenotype combinations. The most studied combinations were
PE in placenta (n = 23), labor in myometrium (n = 9), and PPROM in fetal membranes (n = 3). Examination of PE in placenta studies identified 16
genes that were present in 4 or more studies, examination of labor in myometrium studies identified 15 genes that were present in 4 or more
studies, and examination of PPROM in fetal membranes studies identified 6 genes that were present in 2 or more studies
Table 1 The most often recovered differentially expressed
genes in PE in placenta, labor in myometrium, and PPROM in
Official gene symbol
expressed genes reported in studies of the same
phenotype and tissue. The most studied phenotype-tissue
combinations were PE in placenta (n = 23), labor in
myometrium (n = 9), and PPROM in fetal membranes (n = 4)
(Fig. 7c, Table 1). Examination of PE in placenta studies
identified 16 genes that were present in 4 or more
studies including LEP, a fat-regulating hormone commonly
shown to be differentially expressed in gestational tissues
of women with PE and HELLP Syndrome, and FLT1, a
growth factor known to be highly expressed in
preeclamptic placental trophoblast cells [21, 32, 44, 48, 53,
75, 80, 88, 94]. Examination of labor in myometrium
studies identified 15 genes that were present in 4 or more
studies including PTGS2, a cyclooxygenase involved in
inflammation and commonly upregulated in myometrium
during labor [18, 26, 40, 64, 66, 136, 139]. Finally, 6 genes
were present in 2 or more PPROM in fetal membranes
studies including IL8, a proinflammatory chemokine often
associated with PTB [36, 37, 55, 87, 92, 140].
To examine whether the sets of genes that were most
prevalent in each of the three tissue and phenotype pairs
(PE in placenta, labor in myometrium, and PPROM
in fetal membranes) disproportionally represented
particular functions, we examined whether any Gene
Ontology functional category was statistically
significantly enriched (p < 0.0001) in each of the three gene
sets (Additional file 9). Candidate genes identified in PE
in placenta studies were enriched for regulation of cell
death (GO:0010941) and apoptosis (GO:0042981),
candidate genes identified in labor in myometrium were
enriched for wounding (GO:0009611) and inflammatory
response (GO:0006954), and candidate genes identified
in PPROM in fetal membranes were enriched for
immune system process (GO:0002376) and immune
PTB is a complex, multifactorial syndrome with high
prevalence worldwide, whose pathogenesis remains poorly
understood, especially for cases of early spontaneous labor.
To provide an overview as well as a synthesis of the current
landscape of PTB transcriptomics, we conducted an
indepth systematic review of the literature as well as a
metaanalysis of 93 gene expression studies on a wide diversity of
gestational tissues and clinical phenotypes. Examination of
our results identifies two key findings. First, the
correspondence between PTB subtype prevalence and proportion
of transcriptomic research devoted to these subtypes is
weak. Second, the overlap between differentially expressed
genes identified in different studies is quite small, even on
studies aimed on the same phenotypes and tissues. Below,
we discuss the possible factors that underlie these two key
findings and their implications for research on PTB.
Official gene symbol
Official gene symbol
In general, transcriptomic studies on placental tissue
samples from women with preeclampsia dominate PTB
research. Furthermore, there are very few studies
focusing on sPTB, a subtype responsible for 45 % of all PTB
cases. Although genes commonly associated with PTB
clinical subtypes (i.e., LEP and FLT1) are identified in
many of the gene expression studies to be differentially
expressed, the overlap between the differentially
expressed genes identified across studies is generally very
limited. This is not surprising in comparisons between
tissues (Fig. 5) because these often involve examinations
of different clinical subtypes, although it does suggest
that there is little overlap in tissue-specific
transcriptional profiles of different clinical subtypes. Similarly, it
is not surprising that comparisons between clinical
subtypes do not show a high degree of overlap (Fig. 6)
because these often involve examinations of different
tissues. Nevertheless, it should be noted that
differentially expressed genes with substantial overlap across
studies appear to be biologically meaningful. For
example, genes involved in hormone regulation (i.e., CGB,
CRH, INHA, and GH2), which have been previously
shown to be key in the maintenance of pregnancy, show
substantial overlap in preeclampsia studies. Genes
involved in inflammation (i.e., IL8), which have been
previously shown to be dysregulated in PPROM and other
clinical PTB subtypes, are also identified to be
differentially expressed in multiple studies.
The observed minimal overlap between the
differentially expressed genes identified across studies focused
on the same tissue and clinical phenotype (Fig. 7) is
possibly more serious. One potential explanation may be
the difficulty in obtaining appropriate controls important
in pregnancy research; comparing studies that differ with
respect to the presence of labor, gestational age, and fetal
sex is challenging, since all of these factors are thought
to influence the gene expression landscape in gestational
tissues. Even though matching of samples with respect
to all these factors is very challenging, the reporting of a
standard list of such factors as required metadata in
transcriptomic studies would facilitate further
examination of their importance and likely influence on
In addition to transcriptomics, several other systematic
reviews and meta-analyses have focused on identifying
biomarkers, usually proteins, that are associated with
PTB [141–143]. Overlapping 19 previously identified
common PTB biomarkers with the studies in our
metaanalysis indicates that most (12/19; 63 %) are replicated
in 4 or more studies (Table 2). Therefore, our
comparison shows evidence of considerable overlap between
transcriptomic and proteomic studies in PTB. Further
research from both approaches is necessary, however,
because our comparison also indicates that transcriptomics
and proteomics can target unique candidate genes and
proteins as well.
Furthermore, the recent publication of comprehensive
phenotyping tools necessitates the connection of
evidencebased phenotype knowledge with genomic data collection
in order to make more targeted conclusions . It’s
challenging to compare and contrast gene expression signatures
between distinct subtypes without knowing whether the
transcriptomes came from cases of sPTB due to maternal
stress, uterine distention, or another subtype. Therefore, a
greater focus needs to be placed on collecting the most
detailed meta-data available regarding sPTB diagnosis as
well as performing genome-wide studies of these newly
described sPTB subtypes.
Finally, it is important to note that different studies
follow different guidelines with respect to data
availability. For example, some studies do not report the
full list of differentially expressed genes identified or
do not make them easily available for subsequent
analysis (e.g., reporting tables that contain differential
expression data on hundreds or thousands of genes in
PDF format), therefore limiting and biasing the data
available for subsequent analyses. The publishing of the data
for all genes with differential expression above an explicit
significance threshold in an easily accessible format is
crucial in order to carefully analyze aggregated results and
draw meaningful conclusions.
This study synthesizes all high-quality transcriptomic
studies on gestational tissues to examine the landscape of
PTB as well as to identify genes and genomic elements
associated with it. We found that highly prevalent PTB
subtypes, such as sPTB, are not well studied and that
differentially expressed genes identified in different studies
are often non-overlapping. Thus, the identification of the
genes whose dysregulation contributes to this complex
and multifactorial syndrome will require many more
large-scale, systematic studies aimed at understanding the
transcriptional profiles of these diverse clinical PTB
subtypes across gestational tissues and characterizing their
disease-relevant transcriptional differences.
Note Added in Proof
While this manuscript was in review, by studying the
variation in the placental transcriptome of healthy humans,
Hughes and coworkers estimated that more than 90 % of
the observed transcriptomic variation is explained by
variation within and between individuals . These results
provide an alternative, yet complementary, explanation for
our finding that profiles of differentially expressed genes
were highly heterogeneous both between and within
clinical subtypes and tissues as well as between studies of the
same clinical subtype and tissue.
This systematic review and meta-analysis followed
guidelines set by the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) (Additional files
10, 11 and 12) . The electronic search was performed
on August 16, 2014 in PubMed with no restrictions to
identify all articles relating to differentially expressed or
methylated genes and microRNAs in human gestational
tissues. The search strategy was constructed based on
related MeSH terms:
“Pregnancy”[mh] AND “Humans”[mh] AND (“Gene
Expression Profiling”[mh] OR “Gene Expression
Regulation”[mh]) AND (“Placenta”[mh] OR
“Decidua”[mh] OR “Myometrium”[mh] OR “Cervix
Uteri”[mh] OR “Extraembryonic Membranes”[mh] OR
“Blood”[mh] OR “Plasma”[mh] OR “Umbilical
We collected abstracts for all 2,361 studies identified
from this search and annotated eligibility based on 6
1. Published in English
2. Full text available
3. Original research
4. Human gestational tissue samples
5. Genome-wide analysis
6. Candidate gene list assembled
134 studies met all 6 criteria and were included in the
systematic review. Furthermore, studies were excluded
when the study data was not accessible (the number of
gene candidates was reported but the list of candidate
genes was not), the study data was not reported (the
number of candidate genes was not reported and a list
of candidate genes was not provided), the data was
unclear, there were no significant gene candidates, the
study was not genome-wide, the study was not
humanspecific, the study was not relevant, the study was not
single-gene based (i.e., was focused on pathways or gene
sets), the study used data from proteomics, the study
was performed on cell line rather than in an in-vivo
tissue, the study’s supplement was not available, or when
the study’s tissue was collected before the third trimester
(Additional file 12).
1. Studied differential gene expression
2. Provided candidate gene list
3. DAVID ID conversion successful
116 references met all inclusion criteria and, due to
multiple comparisons or analyses in 14 of these
references, a total of 134 distinct studies were summarized
(Additional file 1). Of the 134 studies included in our
systematic literature review, 93 gene expression studies
met these criteria and were further analyzed. All
differentially expressed genes reported in these studies were
first extracted and then converted to Entrez ID format
using the DAVID online tool, selecting the smallest
Entrez ID number if multiple IDs mapped to single
genes. We extracted all reported significantly
differentially expressed genes based on each study’s significance
threshold for differential expression. Overlap was
determined simply by the presence of the same gene in the
gene lists from different studies. DAVID was used to
assay functional enrichment according to Gene Ontology
categories. All analyses were performed using Python
and visualizations were performed using ggplot2 and
Circos [147, 148].
Additional file 1: Summary of studies in systematic review.
Additional file 2: All reported candidate genomic elements.
Additional file 3: Phenotype definitions.
Additional file 4: Duplicated genes in well-studied gestational
tissues. Genes in 2 or more placenta studies or 2 or more myometrium
studies or 2 or more fetal membranes studies.
Additional file 5: Well-replicated genes in well-studied gestational
tissues. 22 genes in 2 or more placenta studies and 2 or more
myometrium studies and 2 or more fetal membranes studies.
Additional file 6: Duplicated genes in well-studied clinical phenotypes.
Genes in 2 or more PE studies or 2 or more labor studies or 2 or more
Additional file 7: Well-replicated genes in placenta, myometrium,
and fetal membranes. Genes in 5 or more placenta studies or 5 or
more myometrium studies or 5 or more fetal membranes studies.
Additional file 8: Well-replicated genes in PE, labor, and PPROM.
Genes in 5 or more PE studies or 5 or more labor studies or 2 or more
Additional file 9: GO enrichment. Enriched GO functional categories
for replicated genes in PE in placenta, labor in myometrium, and PPROM
in fetal membranes.
Additional file 10: PRISMA checklist.
Additional file 11: PRISMA flow chart.
PTB: Preterm birth; sPTB: Spontaneous idiopathic preterm birth;
PE: Preeclampsia; IUGR: Intrauterine growth restriction; GDM: Gestational
diabetes mellitus; PPROM: Preterm premature rupture of membranes;
MeSH: medical subject headings.
The authors declare that they have no competing interests.
HRE and AR designed the study with input from WEA, KLM, and PA. HRE
carried out the study and drafted the manuscript with subsequent
contributions and revisions from AR. All authors read and approved the final
We thank Louis J. Muglia for offering invaluable advice on experimental
design at an early stage of this experiment. This work was conducted in part
using the resources of the Advanced Computing Center for Research and
Education at Vanderbilt University. HRE was supported by the Graduate
Program in Biological Sciences at Vanderbilt University. Research on this
project was supported by the March of Dimes through the March of Dimes
Prematurity Research Center Ohio Collaborative.
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