Abstract
Introduction: Preeclampsia (PE) is a pregnancy-associated, multi-organ, life-threatening disease that appears after the 20th week of gestation. The aim of this study was to perform a systematic review and meta-analysis to determine whether women with PE have disrupted miRNA expression compared to women who do not have PE.
Methods: We conducted a systematic review and meta-analysis of studies that reported miRNAs expression levels in placenta or peripheral blood of pregnant women with vs. without PE. Studies published before October 29, 2021 were identified through PubMed, EMBASE and Web of Science. Two reviewers used predefined forms and protocols to evaluate independently the eligibility of studies based on titles and abstracts and to perform full-text screening, data abstraction and quality assessment. Standardized mean difference (SMD) was used as a measure of effect size.
Results: 229 publications were included in the systematic review and 53 in the meta-analysis. The expression levels in placenta were significantly higher in women with PE compared to women without PE for miRNA-16 (SMD = 1.51,95%CI = 0.55–2.46), miRNA-20b (SMD = 0.89, 95%CI = 0.33–1.45), miRNA-23a (SMD = 2.02, 95%CI = 1.25–2.78), miRNA-29b (SMD = 1.37, 95%CI = 0.36–2.37), miRNA-155 (SMD = 2.99, 95%CI = 0.83–5.14) and miRNA-210 (SMD = 1.63, 95%CI = 0.69–2.58), and significantly lower for miRNA-376c (SMD = –4.86, 95%CI = –9.51 to –0.20). An increased level of miRNK-155 expression was found in peripheral blood of women with PE (SMD = 2.06, 95%CI = 0.35–3.76), while the expression level of miRNA-16 was significantly lower in peripheral blood of PE women (SMD = –0.47, 95%CI = –0.91 to –0.03). The functional roles of the presented miRNAs include control of trophoblast proliferation, migration, invasion, apoptosis, differentiation, cellular metabolism and angiogenesis.
Conclusion: miRNAs play an important role in the pathophysiology of PE. The identification of differentially expressed miRNAs in maternal blood creates an opportunity to define an easily accessible biomarker of PE.
Keywords: epigenetics, miRNA, preeclampsia, pathophysiology, meta-analysis
Introduction
Preeclampsia (PE) has been shown to affect 1–7.5% of all pregnancies, making it one of the leading causes of maternal and fetal morbidity and mortality worldwide (Abalos et al., 2013; Witcher, 2018; Garovic et al., 2020). PE is a multi-factorial, multi-systemic pregnancy specific condition found typically after 20 weeks of gestation or early post-delivery (American College of Obstetricians and Gynecologists, 2019). Although clinical symptoms appear relatively late in pregnancy, PE pathology begins early, making the identification of potential biomarkers during the first trimester a possible strategy for identifying predictors of PE (McElrath et al., 2020). Several potential biomarkers already have been evaluated: C reactive protein (CRP), cytokines (IL-6, IL-8, TNF-α), microparticle proteins (C1RL, GP1BA, VTNC, and ZA2G), oxidative stress markers (malondialdehyde - MDA), and genetic factors (PAI-1 4G/5G polymorphism) (Black and Horowitz, 2018; Giannakou et al., 2018; Taravati and Tohidi, 2018; McElrath et al., 2020). There are few known biomarkers, however, that can accurately predict the risk for PE. The use of combinations of several biomarkers previously has been proposed as a diagnostic or predictive parameter, such as the ratio of soluble fms-like tyrosine kinase-1 to placental growth factor ratio (sFlt-1/PlGF) (Lecarpentier and Tsatsaris, 2016). A study by Garovic et al. reported podocyturia, defined as the presence of podocin-positive cells in urine sampled ≤24 h of delivery, as a 100% sensitive and specific diagnostic marker for PE (Garovic et al., 2007).
Significant progress has been made in the past decade in the assessment of epigenetic mechanisms that might be involved in the pathophysiology of PE, and which aim to identify potential diagnostic and/or predictive epigenetic markers of PE. More specifically, short non-coding microRNAs (miRNAs) are involved in post-transcriptional gene expression and play a role in numerous diseases, modulating regulatory pathways that control development, differentiation, and organ function. MiRNAs are single-stranded RNA molecules consisting of 19–24 nucleotides, and their mode of action is primarily by degrading targeted mRNA transcripts or inhibiting translation of mRNA into a protein product (Hombach and Kretz, 2016). It is also known that miRNA molecules are involved in the physiological regulation of major processes of placentation (Mouillet et al., 2015). It might therefore be anticipated that dysfunction of miRNA expression could be important for the development of PE. Studies recently published explored a possible causal relationship between miRNA expression and PE (Youssef and Marei, 2019; Hemmatzadeh et al., 2020). It has been demonstrated that expression levels of miRNAs in different tissues play a role in physiological pregnancy as regulators of trophoblast proliferation, migration, invasion, apoptosis, differentiation, cellular metabolism and placental angiogenesis (Hayder et al., 2018). The placenta is one of the main sources of miRNAs, but they also can be found in the circulation (Mouillet et al., 2015). Placental miRNA-210 expression has been the most studied in PE and other pregnancy related complications, and increased levels have been demonstrated (Muralimanoharan et al., 2012; Awamleh and Han, 2020). Results from evaluations of other frequently analyzed miRNAs, such as miRNA-155, -223, -126, -183, -182, -281b, -154, -139-5p, -29b, -181a, -15b (Mayor-Lynn et al., 2011; Yang et al., 2011; Zhao et al., 2013; Sheikh et al., 2016; Hemmatzadeh et al., 2020), suggest that miRNA expression differs according to the severity of PE (Jairajpuri et al., 2017), and also differs throughout the course of normal pregnancy (Cai et al., 2017). While some research has been done to investigate the association between miRNA expression levels and PE, there is still a lack of evidence to support the common use of miRNAs as functional biomarkers related to PE. The aim of this study was to perform a systematic review and meta-analysis to determine whether women with PE have disrupted miRNA expressions compared to women without PE.
Materials and Methods
This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and MOOSE guidelines (Stroup et al., 2000; Liberati et al., 2009).
Study Selection
Publications were screened for inclusion in the systematic review in two phases, and all disagreements were resolved by discussion at each stage with inclusion of a third reviewer. We included studies that compared miRNA expression levels between women with and without PE. Studies were eligible for inclusion if the miRNA expression levels were measured in both groups. Studies were excluded if they: 1) investigated other outcomes, 2) did not make comparisons between PE and control groups, 3) examined other populations (animal, cell lines), 4) assessed other epigenetic markers, 5) were abstracts, or 6) were not original articles.
Database Search
Two biostatisticians with expertise in conducting systematic reviews and meta-analyses (NM, AC) developed the search strategy. A systematic review of peer-reviewed publications was performed through searches of PubMed, Web of Science (WoS) and embase electronic databases until October 29, 2021. Search queries differed according to the database. Key words for the PubMed search were: preeclampsia and (epigenetic or epigenetics or miRNA or microRNA or DNA methylation or DNA methylation or long non coding RNA); for Wos: TS = *eclampsia and TS= (epigenetic* or microRNA or DNA methylation or gene imprinting or long non coding RNA), and for embase: preeclampsia and (epigenetics or microRNA or DNA methylation or genome imprinting or long untranslated RNA). Only publications in English were considered. In addition, reference lists of articles identified through electronic retrieval were manually searched, as well as relevant reviews and editorials. Experts in the field were contacted to identify other potentially relevant articles.
Authors of relevant articles were contacted to obtain missing data. Studies with combined data of gestational hypertension and/or chronic hypertension in pregnancy and PE were only eligible if data for the subset of women who developed preeclampsia were available.
Article Screening and Selection
Two reviewers (AC, JML) independently evaluated the eligibility of all titles and abstracts. Studies were included in the full text screening if either reviewer identified the study as being potentially eligible, or if the abstract and title did not include sufficient information. Studies were eligible for full text screening if they included comparisons of miRNA expression levels between women with and without PE. Preeclampsia included more severe, less severe, and not specified forms. The same reviewers independently performed full text screening to select articles for inclusion according to the criteria listed under Inclusion and Exclusion Criteria. Disagreements were resolved by consensus (AC, JML) or arbitration (NM, DS).
Data Abstraction and Quality Assessment
Two reviewers independently abstracted the following data: author(s), country of research, year of publication, study design, sample size, study population, maternal age, preeclampsia definitions, disease severity (more severe, less severe or not-specified PE), inclusion and exclusion criteria used in the original articles, sample type and time of sampling, matching, evaluated miRNAs, method for miRNA expression quantification, miRNA expression value, housekeeping gene for internal control, conclusion in original article. Each reviewer independently evaluated the quality of selected manuscripts using an adapted version of the Newcastle-Ottawa tool for observational studies (Wells et al., 2014). Reviewers used a standardized previously defined miRNA protocol when selecting and abstracting data. All detailed information about quality assessment, data extraction, variables, miRNA expression quantification methods and housekeeping gene for internal normalization are available at https://osf.io/g42ze/.
Statistical Analysis
The primary outcome was expression levels of miRNAs, presented as means with standard deviation. GetData Graph Digitizer version 2.26.0.20 was used to read miRNA values when figures presenting miRNA expression levels were available (Digitize graphs and plots, 2013). Median was used as an approximation of the arithmetic mean, and IQR/1.35 was used as an approximation of standard deviation. If standard error was used in the original article, standard deviation was calculated as sd = se*√n, and if the range was presented, standard deviation was estimated as (max-min)/4.
Methodologies for measuring miRNA expression levels varied; therefore, the standardized mean difference (SMD) was used as a measure of effect size to examine differences between the preeclampsia and non-preeclampsia groups. SMD expresses the difference between group means in units of standard deviation and was estimated by pooling individual trial results using random-effects models via the Der Simonian-Laird method. Heterogeneity was assessed using the Chi-square Q and I2 statistic. I2 presents the inconsistency between the study results and quantifies the proportion of observed dispersion that is real, i.e., due to between-study differences and not due to random error. The categorization of heterogeneity was based on the Cochrane Handbook (Higgins et al., 2019) and states that I2<30%, 30–60% or >60%, correspond to low, moderate and high heterogeneity, respectively. Forest plots were constructed for each analysis showing the SMD (box), 95% confidence interval (lines), and weight (size of box) for each trial. The overall effect size was represented by a diamond. Meta-analysis was performed for all miRNAs with available data from at least three relevant studies.
Sensitivity analyses were conducted to examine the effects of: 1) replacement of studies that measured miRNA expression levels in the chorionic plate with studies exploring the basal plate, 2) inclusion of measurements performed in more severe, less severe or not-specified PE forms only (instead of all PE forms), 3) replacement of miRNA expression levels obtained in term controls with miRNA expression levels in preterm controls, 4) inclusion of studies exploring miRNA expression levels in moderate or mild proteinuria PE groups, instead of severe proteinuria as in the PE group in the first analysis. A p value < 0.05 was statistically significant. Analyses were performed using Review Manager Version 5.4 (Cochrane, 2021).
Results
Systematic Review
A total of 1773 potentially eligible articles were found. 1,517 articles were excluded because they were duplicates, not original articles, were without PE as the outcome, did not compare PE and control groups, examined populations other than women (animals, cell lines), did not explore miRNA expression levels, or were abstracts. Of the 256 reviewed full text articles, 229 were selected for inclusion in the systematic review. A flow diagram illustrating this selection process is presented in Figure 1.
FIGURE 1.
Flow diagram.
Characteristics of all 229 publications included in the systematic review are presented in detail in Table 1. They were published between 2007 and 2021, with a total of 13043 participants; 6,459 women with and 6584 without PE. The minimum sample size of the PE group was four, and a minimum of one for the control group. The maximum sample size was 200 in PE and 321 in the control group. Four publications did not report the number of participants. 139 studies were cross-sectional, 64 were case-control, 11 were nested case-control studies, while only six were prospectively followed cohorts. Five studies included two or three sub-studies with the same or different study designs. In eighteen publications, the study design was not clearly stated. Most studies were from China (138), United States (19), and Czech Republic (8). Study groups were matched in 73 (32%) of all articles, and gestational age at the time of delivery was the most used variable for matching (in 53 of 73 publications). Maternal age at the time of delivery was used for matching in 35 publications. Other matching variables were BMI at the time of delivery, parity, race and/or ethnicity, gravidity, delivery, fetal gender, family history of PE, smoking history, additional comorbidities, systolic blood pressure at the time of inclusion, diastolic blood pressure at the time of inclusion, proteinuria at the time of inclusion, infant weight, pre-pregnancy indices, duration of storage of plasma samples, and maternal body weight at the time of delivery. Regression analysis was used to account for confounders in 14 publications. Ethnicity was reported in eight and race in eleven publications. Fetal gender was reported in 25 publications. The expression levels of miRNA were explored according to fetal gender in just three studies, and a regression model was adjusted for fetal gender in one publication. The most examined source of miRNAs was placenta, reported in 155/229 publications. Ninety-eight studies used maternal peripheral blood: plasma in 46, serum in 28, plasma exosomes in 9, mononuclear cells in 2, serum exosomes in 2, whole blood in 2, and leukocytes and buffy coat in one study each. Twelve studies analyzed miRNA expression levels in umbilical cord cell populations: mesenchymal stem cells in 4, and HUVECs, vein cells, maternal blood, exosomes, endothelial progenitor cells, serum, fetal blood, and umbilical cord tissue in one study each. Other rarely sampled tissues were myometrium, urine, maternal subcutaneous fat tissue endothelium, and placental blood vessel endothelium. Tissue was sampled at the time of delivery in 149 (65%) studies. In 60 studies, sampling was done prior to delivery and, in two studies, after delivery; 1 year after (Murphy et al., 2015), and 3–11 years after delivery (Hromadnikova et al., 2019b). Time of sampling was not reported in 34 (15%) publications. Most articles did not differentiate the type of PE (70%). Inclusion and exclusion criteria were not reported in most studies assessing miRNA in preeclamptic pregnancies. Only primiparous women were included in six studies, only non-smokers in 17, and only women without chronic hypertension in 89 publications. Detailed additional inclusion and exclusion criteria are presented in Supplementary Table S1. The presence of renal disease was the most common (50/229). The presence of diabetes mellitus (49/229) and the presence of cardiovascular disease (32/229) were reported less often. The presence of obesity was reported in six and preeclampsia in the previous gestation in five publications.
TABLE 1.
Systematic review.
Author year* Country |
Study design | Sample size | Maternal age a PE vs. Controls (years) | Sample | Time of sampling | Controls/Unexposed | Matching | Inclusion criteria | |||
---|---|---|---|---|---|---|---|---|---|---|---|
n PE | n Controls | All primiparas | All non-smokers | No chronic hypertension | |||||||
Pineles 2007* (Pineles et al., 2007) United States | Not clear (cross-sectional, case-control study) | 9 | 9 | 28 (19–39) vs. 24 (18–37) | placenta | NR | pregnant women with presence of regular uterine contractions at a frequency of at least 2 contractions every 10 min that were associated with cervical changes and resulted in delivery at 37 completed weeks of gestation who delivered normal infants with birthweights appropriate for gestational age (10th–90th percentile) matched for gestational age at delivery (within 2 weeks) | Gestational age | NR | no | yes |
Hu 2009* (Hu et al., 2009) China | Cross-sectional | 24 | 26 | 28.1 ± 1.3 vs. 28.7 ± 1.1 | placenta (chorion) | at the time of delivery | pregnant women with normal term pregnancy, without chronic hypertension, cardiovascular disease, renal disease, hepatitis, diabetes, any evidence of intrapartum infection or other pregnancy complications, such as fetal anomalies or chromosomal abnormalities | Maternal age and gestational age | no | NR | yes |
Zhu 2009* (Zhu et al., 2009) China | Cross-sectional | 23 Total 8 mPE 15 sPE | 11 | 31.9 ± 3.8 (sPE); 29.5 ± 5.3 (mPE) vs. 31.8 ± 3.7 | placenta (villi) | NR | normal pregnancies | Gestational age | all nulliparous | NR | yes |
Zhang 2010* (Zhang et al., 2010) China | Case-control | 20 | 20 | NR | placenta (chorion) | at the time of delivery | normotensive pregnancies with gestational age matched groups | Gestational age | NR | NR | yes |
Cheng 2011 (Cheng et al., 2011) China | Cross-sectional | 5 | 5 | 33 ± 3 (25–40) vs. 29 ± 1 (27–33) | UC HUVECs | at the time of delivery | Healthy women | NR | NR | NR | NR |
Enquobahrie 2011 (Enquobahrie et al., 2011) United States | Not clear (participants were selected from cohort and case-control studies) | 20 | 20 | 32.8 ± 7.4) vs. 30.4 ± 5.6) | placenta | at the time of delivery | normotensive pregnancies uncomplicated by proteinuria matched for parity, maternal race/ethnicity, and labor status | Parity, maternal race/ethnicity and labor status | no | NR | yes |
Gunel 2011 (Gunel et al., 2011) Turkey | Cross-sectional | 20 | 20 | NR | MPB (plasma) | NR | healthy pregnant women | NR | NR | NR | NR |
Guo 2011 (Guo et al., 2011) China | Cross-sectional | NR | NR | NR | placenta | NR | normal pregnant women | NR | NR | NR | NR |
Mayor-Lynn 2011* (Mayor-Lynn et al., 2011) United States | Cross-sectional | 6 | 10 Total 5 term controls 5 preterm controls | 23.8 (20–26) vs. 28.3 (21–38) | placenta (villi) | at the time of delivery | term controls - pregnancies who delivered normal infants at term without labor via elective Caesarean section preterm controls - presence of preterm regular uterine contractions of at least 3 contractions in 10 min that were associated with cervical changes that resulted in delivery at ≤35 completed weeks of gestation | NR | no | no | NR |
Yang 2011 (Yang et al., 2011) China | Cross-sectional | 4 Total 2 mPE 2 sPE | 1 | Individual data sPE: 28; 34 mPE: 26; 27 Control: 28 years | MPB (serum) | before delivery (during 3rd trimester) | normal pregnant women | NR | all nulliparous | NR | NR |
Bai 2012*(Bai et al., 2012) China | Cross-sectional | 15 | 17 | 27.5 ± 4.3 vs. 29.7 ± 2.6 | placenta | at the time of delivery | normal pregnant women defined as a single gestation in a previously normotensive woman who did not suffer from high blood pressure and proteinuria during pregnancy, and delivered a healthy neonate with a weight adequate for gestational age after 37 weeks of pregnancy | Gestational age | no | NR | yes |
Hromadnikova 2012 (Hromadnikova et al., 2012) Czech Republic | Not clear (retrospective, cohort) | 16 + 7 who later developed PE | 50 | NR | MPB (plasma) | NR | normal progression of pregnancy defined as those without medical, obstetric, or surgical complications at the time of the study and who subsequently delivered full-term, singleton, healthy infants weighing >2,500 g after 37 completed weeks of gestation | Gestational age | NR | NR | NR |
Ishibashi 2012 (Takizawa et al., 2012) China | Cross-sectional | 8 | 10 | Individual data for PE patients: 28, 28, 29, 31, 31, 32, 32, 36; NR for controls | placenta | NR | normal pregnancies | Gestational age | NR | NR | NR |
Lazar 2012 (Lázár et al., 2012) Hungary | Not clear (prospective study) | 31 | 28 | 29 (18–39) vs. 28 (20–41) | placenta | at the time of delivery | normotensive pregnant women | NR | no | NR | NR |
Liu 2012*(Liu et al., 2012) China | Cross-sectional | 11 | 16 | NR | UC-MSCs placenta (decidua) | NR NR | women with normal pregnancy | NR | NR | NR | NR |
Muralimanoharan 2012*(Muralimanoharan et al., 2012) United States | Cross-sectional | 6 | 6 | 32.6 ± 3.6 vs. 28.6 ± 2.6 | placenta (villi) | at the time of delivery | uncomplicated pregnancies | NR | NR | NR | NR |
Wang 2012*(Wang et al., 2012a) United States | Cross-sectional | 10 | 10 | 23 ± 1.2 vs. 23 ± 1.2 | placenta | at the time of delivery | normotensive term pregnancies | NR | NR | yes | NR |
Wang 2012*(Wang et al., 2012b) China | Cross-sectional | 20 | 20 | 30.81 ± 0.74 vs. 30.50 ± 0.76 | placenta (decidua MSCs) | at the time of delivery | maternal age and gestational age at delivery matched normotensive controls | NR | NR | NR | yes |
Wu 2012*(Wu et al., 2012) China | Case-control | 10 | 9 | 29.9 ± 3.1 vs. 30.4 ± 1.3 | MPB (plasma) | NR | term matched normal pregnancies | Yes (no variable) | no | yes | NR |
Zhang 2012 (Zhang et al., 2012) China | Case-control | 30 Total 15 mPE 15 sPE | 15 | 30.9 ± 4.1 (sPE) 31.6 ± 3.6 (mPE) vs. 29.7 ± 3.6 | MPB (plasma) | NR | healthy pregnant controls who had had normal blood pressure with the absence of medical and obstetrical complications matched for age, gestational age, parity, and body mass index (BMI) at the time of blood sampling | Maternal age, gestational age, parity, and BMI at the time of sampling | NR | NR | yes |
Anton* 2013 (Anton et al., 2013) United States | Case-control | 40 (PE + GHTA) | 33 | 25.5 ± 7.5 vs. 26.2 ± 6.7 | MPB (serum) | before delivery (during 3rd trimester) | women without hypertension-related complications who presented for delivery at term (≥37 gestational weeks) | NR | no | NR | NR |
Nested case-control | 41 (PE + GHTA) | 56 | 31.2 ± 7.5 vs. 29.7 ± 6.6 | MPB (serum) | before delivery (15–20 gw) | randomly selected from the cohort | NR | no | no | yes | |
Betoni 2013*(Betoni et al., 2013) United States | Case-control | 16 | 12 | 26.0 ± 5.9 vs. 30.9 ± 5.8 | placenta | NR | patients without PE matched for maternal age and ethnicity, as well as for type of delivery, gestational age, birth weight and sex of the child | Gestational age | no | no | yes |
Choi 2013 (Choi et al., 2013) China | Cross-sectional | 11 | 10 | 31.0 ± 5.3 vs. 30.7 ± 3.9 | placenta | NR | normotensive pregnancies uncomplicated by proteinuria | NR | no | NR | yes |
Fu, 2013*(Fu et al., 2013) China | Cross-sectional | 15 | 22 term controls | 30.8 ± 1.9 (preterm PE) 34.8 ± 2.2 (term PE) Vs. 32.0 ± 1.23 (preterm controls) 33.4 ± 0.7 (term controls) | placenta | at the time of delivery (36–40 gw) | normal pregnancies | Gestational age | NR | NR | NR |
Cross-sectional | 29 Total 13 preterm PE 16 term PE | 44 Total 13 preterm controls 31 term controls | 29.8 ± 0.7 (preterm PE) Vs. 29.5 ± 0.8 (preterm controls) 29.2 ± 1.0 (term PE) Vs. 31.7 ± 0.6 (term controls) | MPB (plasma) | before delivery (15-18 gw and 36-40 gw) | normal pregnancies | NR | NR | NR | NR | |
Cross-sectional | 37 Total 16 preterm PE 11 term PE | 23 preterm controls 25 term controls | NR | placenta | at the time of delivery (25-35 gw and 36–40 gw) | normal pregnancies | NR | NR | NR | NR | |
Guo 2013 (Guo et al., 2013) United States | Cross-sectional | 16 | 29 | NR | placenta | NR | control group | NR | no | NR | yes |
Hromadnikova 2013 (Hromadnikova et al., 2013) Czech Republic | Cohort | 63 Total 24 mPE 39 sPE 24 EOPE 39 LOPE | 55 | NR | MPB (plasma) | NR | pregnant women without complications who delivered full term, singleton, healthy infants weighting >2,500 g after 37 completed gw | Gestational age | NR | NR | no |
Kumar 2013 (Kumar et al., 2013) China | Cross-sectional | 8 | 8 | NR | placenta | at the time of delivery | term gestation-matched normotensive pregnant women | Gestational age | NR | NR | yes |
Li 2013 (Li et al., 2013a) China | Cross-sectional | 4 mPE +4 sPE profiling study 16 mPE +22 sPE validation study |
4 in profiling study 32 in validation study | 34 (28–39) (sPE) 29 (23–36) (mPE) vs. 28 (26–30) in profiling study 33 (24–43) (sPE) 31 (26–39) (mPE) vs. 29 (25–36) in validation study | MPB (plasma) | before delivery | normal pregnancies, age, gestational week and gravidity matched with PE | Maternal age, gestational age, and gravidity | yes | NR | yes |
Li 2013*(Li et al., 2013b) China | Cross-sectional | 24 | 26 | 28.1 ± 1.3 vs. 28.7 ± 1.1 | placenta (chorion) | at the time of delivery | normal term pregnancies without chronic hypertension, cardiovascular disease, renal disease, hepatitis, diabetes, any evidence of intrapartum infection or other pregnancy complications, such as fetal anomalies or chromosomal abnormalities | NR | no | NR | NR |
Yan 2013 (Yan et al., 2013a) China | Case-control | 12 | 12 | 31.4 ± 4.03 vs. 30.3 ± 3.67 | placenta | NR | normotensive and nonproteinuric during pregnancy and delivered healthy infants of appropriate weight | Maternal age, BMI, and gestational age | NR | yes | yes |
Campos 2014 (Campos et al., 2014) Brasil | Cross-sectional | 19 | 14 | 26 ± 6 vs. 27 ± 6 | MPB (plasma) | before delivery (at the time of clinical attendance) | healthy pregnant women | NR | no | yes | yes |
Chen 2014 (Chen et al., 2014) China | Cross-sectional | 20 Total 15 mPE 5 sPE | 40 | 27 (24–34) vs. 25 (25–30) | placenta | NR | normal deliveries | NR | NR | NR | NR |
Doridot 2014 (Doridot et al., 2014) France | Cross-sectional | 5 | 8 | NR | placenta | NR | Women who underwent Caesarean surgery without suffering any disease during pregnancy | NR | NR | NR | NR |
Hong 2014 (Hong et al., 2014) China | Case-control | 115 | 115 | NR | placenta | at the time of delivery | gestational age matched normotensive pregnancies | Gestational age | NR | NR | yes |
Lalevee 2014*(Lalevée et al., 2014) Switzerland | Not clear (prospective case–control study) | 15 | 14 | 36.1 (22.6–44.5) vs. 33.3 (26.5–37.2) | placenta | at the time of delivery | controls | NR | no | NR | NR |
Li 2014 (Li et al., 2014a) China | Case-control | 13 | 26 | 29.58 ± 0.68 vs. 29.56 ± 0.48 | Placenta (basal plate and chorionic plate) | at the time of delivery | gestation-week-matched pregnant healthy controls without renal disease, cardiovascular disease, transient hypertension in pregnancy, gestational diabetes mellitus, hepatitis. Any evidence of spontaneous abortion, intrauterine fetal death, fetal chromosomal or other pregnancy complications were excluded from this study | Gestational age | no | NR | yes |
Li 2014*(Li et al., 2014b) China | Cross-sectional | 19 | 22 | 27.6 ± 4.2 vs. 28.2 ± 4.5 | placenta | at the time of delivery | normal pregnant women defined as previously and currently normotensive female during pregnancy who delivered a healthy neonate following 37 weeks of gestation | NR | NR | NR | yes |
Luo 2014*(Luo et al., 2014) China | Case-control | 15 | 26 | 29.3 ± 1.3 vs. 31.6 ± 0.9 | placenta (chorionic villi) placenta (chorionic plate and basal plate) | after abortion/elective termination (7–8 gw) at the time of delivery | normal pregnant women defined as gestation in a previously normotensive woman who did not suffer from any complications during pregnancy and who delivered a healthy neonate with a weight adequate for a gestational age of more than 37 weeks of pregnancy | Gestational age | NR | NR | yes |
Luque 2014 (Luque et al., 2014) Spain | Nested case-control | 31 | 44 | 32.6 ± 6.6 vs. 32.3 ± 5.6 | MPB (serum) | before delivery (11 + 0, 13 + 6 gw) | normotensive pregnancies without proteinuria | NR | no | no | yes |
Ura 2014 (Ura et al., 2014) Italy | Not clear (retrospective study) | 24 | 24 | 34.4 (33.0–36.8) vs. 33.7 (30.3–36.1) | MPB (serum) | before delivery (12–14 gw) | normal pregnancies | NR | no | no | NR |
Wang 2014 (Wang et al., 2014) China | Not clear | NR | NR | NR | placenta | NR | normal pregnancies | NR | NR | NR | NR |
Weedon-Fekjaer 2014 (Weedon-Fekjær et al., 2014) Norway | Cross-sectional | 49 Total 23 EOPE 26 LOPE | 23 | NR | placenta | at the time of delivery | uncomplicated pregnancies delivered at term (37–41 gw) | NR | NR | NR | yes |
Winger 2014 (Winger et al., 2014) United States | Not clear (retrospective study) | 12 Total 7LOPE 5EOPE | 19 | 43.7 ± 8.7 vs. 37.6 ± 5.1 | MPB | before delivery (1st trimester) | delivery of a singleton normal karyotype baby with the following pregnancy criteria: (i) delivered at 37- to 40-weeks of gestation, (ii) birthweight of ≥6 lbs, (iii) normal maternal blood pressure throughout pregnancy or (iv) twin delivery with gestational age ≥35 weeks with birthweights of ≥5.1 lbs and (v) no other pregnancy or delivery complications | NR | NR | NR | NR |
Xu 2014*(Xu et al., 2014) China | Case-control | 14 | 33 | NR | placenta (chorionic plate and basal plate) | at the time of delivery | gestational week matched normal pregnant women | Gestational age | NR | NR | NR |
Case-control | 20 | 20 | NR | MPB (plasma) | before delivery (15–19 gw) at the time of delivery (35–39 gw) | gestational week matched normal pregnant women | Gestational age | NR | NR | NR | |
Zhao 2014*(Zhao et al., 2014) China | Case-control | 20 | 20 | 28.9 ± 1.2 vs. 29.2 ± 1.4 | Placenta (decidual MSCs) | at the time of delivery | age matched normotensive controls | Maternal age | no | NR | yes |
Zou 2014 (Zou et al., 2014) China | Cross-sectional | 30 | 30 | 30.2 ± 5.7 vs. 30.6 ± 3.5 | placenta | at the time of delivery (immediately after placental delivery) | normal pregnant women defined as not having PE or any other complications (including maternal history of hypertension and/or renal disease, maternal infection, smoking, alcoholism, chemical dependency, and fetal congenital anomalies) | NR | yes | no | NR |
Akehurst 2015*(Akehurst et al., 2015) Scotland | Not clear (prospective study) | 18 | 18 | 31 ± 5.3 vs. 31 ± 5.4 | MPB (plasma) | before delivery (16–18 gw) | matched for age, BMI, and parity | Maternal age, BMI, and parity | no | no | NR |
Case-control | 19 | 19 | 29 ± 5.4 vs. 30 ± 4.6 | placenta | at the time of delivery | normotensive individuals matched for age, BMI, and parity | Maternal age, BMI, and parity | no | no | NR | |
Not clear | 2 | 9 term | NR | myometrium | at the time of delivery | normotensive women | Maternal age, BMI, and parity | NR | NR | NR | |
Anton 2015 (Anton et al., 2015) United States | Case-control | 31 Total 18 term PE 13 preterm PE | 14 | 28.1 ± 7.7 (total) 28.3 ± 8.2 (term PE) 27.8 ± 7.3 (preterm PE) vs. 27.0 ± 7.2 | placenta | at the time of delivery | women without hypertension-related complications that presented for delivery at term (37 gestational weeks) | NR | NR | NR | NR |
Chen 2015 (Chen et al., 2015) China | Cross-sectional | 5 | 10 | NR | placenta (decidua MSCs) | at the time of delivery | healthy pregnancies | NR | NR | NR | NR |
Ding 2015 (Ding et al., 2015) China | Case-control | 18 | 21 | 28.44 ± 0.95 vs. 30.05 ± 0.72 | placenta | at the time of delivery | normal pregnancy defined as patients with no history of hypertension or proteinuria during weeks 35–40 of pregnancy who delivered healthy neonates via Caesarean section | Maternal age, gestational age | yes | NR | yes |
Hromadnikova 2015a (Hromadnikova et al., 2015a) Czech Republic | Cohort | 80 | 20 | 33 (30–36) vs. 30 (26.5–33) | placenta | NR | without medical, obstetrical, or surgical complications at the time of the study and who subsequently delivered full term, singleton healthy infants weighing >2,500 g after 37 completed weeks of gestation | NR | NR | NR | yes |
Hromadnikova 2015b (Hromadnikova et al., 2015b) Czech Republic | Cohort | 63 | 42 | 31.7 ± 5.0 vs. 30.6 ± 4.4 | placenta | NR | those without medical, obstetrical, or surgical complications at the time of the study and who subsequently delivered full-term, singleton healthy infants weighing >2,500 g after 37 completed weeks of gestation | NR | NR | NR | yes |
Hu 2015 (Hu et al., 2015) China | Cross-sectional | 24 Total 17 7 | 24 Total 17 7 | 27.42 ± 3.89 vs. 27.11 ± 3.18 | umbilical cord vein UC-MSC | NR | normal pregnancies delivered after 34 weeks | NR | NR | NR | NR |
Jiang 2015 (Jiang et al., 2015) China | Cross-sectional | 20 | 20 | 28.1 ± 4.8 vs. 26.3 ± 5.2 | placenta | NR | previously and currently normotensive pregnant female, who delivered a healthy neonate following 37 weeks of gestation | NR | NR | NR | yes |
Lasabova 2015*(Lasabová et al., 2015) Slovak Republic | Case-control | 11 | 7 | 27.6 ± 4.9 vs. 26.6 ± 2.8 | placenta | at the time of delivery | normotensive healthy singleton pregnancies with no history of cigarette smoking, diabetes autoimmune disease, or thrombophilia | NR | NR | NR | yes |
Li 2015*(LI et al., 2015) China | Case-control | 60 Total 12 - 1st trimester 20 - 2nd trimester 28 - 3rd trimester | 60 Total 12 - 1st trimester 20 - 2nd trimester 28 - 3rd trimester | 28.7 ± 3.6 vs. 28.1 ± 3.8 | MPB (serum) | before delivery (after ≥8 h fasting) | healthy pregnant women without complications | Maternal age at delivery within 1-year-old gap and gestational age of blood sampling | NR | NR | NR |
Miura 2015 (Miura et al., 2015) Japan | Case-control | 20 Total 6 sEOPE 14 sLOPE | 20 | 31.9 ± 2.9 sEOPE 30.2 ± 4.4 sLOPE vs. 32.8 ± 4.0 | MPB (plasma) | before delivery (27–34 gw) | Uncomplicated gestational age matched pregnant women | Gestational | NR | NR | NR |
Murphy 2015 (Murphy et al., 2015) Canada | Cohort | 13 Total 7 mPE 6 sPE | 17 | 30.4 ± 7.3 (total) 32.4 ± 6.9 (mPE) 28.0 ± 7.6 (sPE) vs. 28.2 ± 4.1 | MPB (plasma) | at the time of delivery (peripartum) after delivery (1 year postpartum) | Uncomplicated pregnancies | Time | NR | NR | NR |
Sun 2015 (Sun et al., 2015) China | Cross-sectional | 20 | 20 | 29 ± 3.7 vs. 28.9 ± 2.5 | placenta | at the time of delivery | Healthy pregnancies | NR | NR | NR | NR |
Winger 2015 (Winger et al., 2015) United States | Cross-sectional | 12 Total 7 LOPE 5 EOPE 5 preconceptional PEs 5 1st trimester | 20 Total 11 pre-conception controls 9 Controls for 1st trimester | 36.7 ± 3.5 (total) 37.7 ± 3.8 (LOPE) 35.2 ± 2.8 (EOPE) vs. 36.3 ± 4.7 | MPB | before delivery (pre-conception and 1st trimester) | Healthy pregnant women in healthy pregnancies | NR | NR | NR | NR |
Yang 2015 (Yang et al., 2015) China | Cross-sectional | 4 | 1 | PE patients’ individual data mPE: 27, 26 sPE: 34, 28 vs. Controls NR | MPB (plasma) placenta | before delivery at the time of delivery | Pregnant women without complications | NR | NR | NR | NR |
Zhang 2015*(Zhang et al., 2015) China | Cross-sectional | 3 | 3 | 29.58 ± 0.68 vs. 29.56 ± 0.48 | placenta (basal plate and chorionic plate) | at the time of delivery | Normal pregnant controls without any complications | Yes (no variable) | NR | NR | NR |
Hromadnikova 2016*(Hromadnikova et al., 2016) Czech Republic | Not clear (retrospective study from prospective cohort) | 68 Total 32 mPE 36 sPE 24 EOPE 44 LOPE | 20 | 33 (30–36) vs. 30 (26.5–33) | MPB (whole peripheral blood) | NR | Normal pregnancies defined as those without medical, obstetrical, or surgical complications at the time of the study and who subsequently delivered full term, singleton healthy infants weighing >2,500 g after 37 completed weeks of gestation | NR | NR | NR | no |
Hu 2016 (Hu et al., 2016) China | Cross-sectional | 19 | 23 | 27.42 ± 3.89 vs. 27.11 ± 3.18 | placenta | NR | healthy pregnant women at term | NR | no | NR | yes |
Munaut 2016*(Munaut et al., 2016) Belgium | Not clear (retrospective study from prospective cohort) | 23 | 44 | 29 (19–44) vs. 30 (19–38) | MPB (serum) | before delivery | pregnant women presenting, at 24 to <37 weeks’ gestation, clinical suspicion of, but not manifesting preeclampsia/eclampsia/HELLP syndrome | NR | no | no | no |
Ospina-Prieto (Ospina-Prieto et al., 2016) 2016 Germany | Cross-sectional | 11 | 13 | 27.0 ± 2.8 (total) 28.0 mean EOPE 26.4 mean LOPE vs. 29.5 ± 5.8 | placenta (villi) | at the time of delivery (immediately after delivery) | NR | Maternal age | yes | ||
Sandrim 2016a (Sandrim et al., 2016a) Brasil | Case-control | 7 | 10 | 24 ± 6 vs. 28 ± 6 | MPB (plasma) | at the time of delivery | healthy pregnancies matched for gestational age at sampling, maternal age, and BMI | Gestational age, maternal age, and BMI | NR | NR | NR |
Sandrim 2016b (Sandrim et al., 2016b) Brasil | Case-control | 19 | 14 | 26 ± 5 vs. 27 ± 6 |
MPB (plasma) | before delivery | healthy pregnant women | NR | no | yes | yes |
Nested case-control | 8 | 8 | NR | MPB (plasma) | before delivery (35 + 1 and 35 + 5 gw) | healthy pregnant women | NR | no | yes | NR | |
Vashukova 2016 (Vashukova et al., 2016) Russia | Cross-sectional | 5 | 6 | 35.0 ± 2.4 vs. 29.3 ± 0.6 | placenta | at the time of delivery | normal pregnancies | NR | NR | NR | yes |
Wang 2016 (Wang et al., 2016a) United States | Cross-sectional | 5 | 5 | 26 ± 5 (20–33) vs. 29 ± 7 (20–37) | Maternal subcutaneous fat tissue endothelial cells | at the time of delivery | normal pregnancies defined as pregnancy with blood pressure (<140/90 mm Hg), absence of proteinuria, and obstetrical and medical complications | NR | NR | yes | NR |
Wang 2016 (Wang et al., 2016b) China | Case-control | 34 Total 13 PE age 21–29 years 13 PE age >30 years 8 PE with complications (chronic HTA and GDM) | 13 | 25.69 ± 1.31 vs. 29.08 ± 2.60 | MPB | NR | normal pregnant women | NR | no | NR | NR |
Yang 2016 (Yang et al., 2016) China | Cross-sectional | 17 | 40 | 28.85 ± 2.02 vs. 28.96 ± 4.11 | placenta (chorionic plate, basal plate) MPB (plasma) | at the time of delivery NR | normal pregnant women | NR | no | NR | NR |
Zhou 2016*(Zhou et al., 2016) China | Cross-sectional | 31 Total 9 discovery set 22 validation set | 29 Total 9 discovery set 20 validation set | Discovery set 32.1 ± 6.9 vs. 28.3 ± 1.4 Validation set 30.4 ± 4.7 vs. 30.5 ± 4.4 | placenta (chorionic plate) | at the time of delivery | normal pregnant women | NR | NR | NR | NR |
Adel 2017*(Adel et al., 2017) Egypt | Cross-sectional | 35 Total 25 mPE 10 sPE | 35 | 24 (18–40) vs. 25 (19–35) | placenta (villi) | at the time of delivery | primigravid normotensive throughout gestation with no excess albumin in urine | NR | NR | NR | NR |
Azizi 2017*(Azizi et al., 2017) Iran | Case-control | 59 | 40 | 27.42 ± 6.7 vs. 23.78 ± 4.15 | placenta (chorion) | at the time of delivery | gestational age-matched normotensive pregnancies | Gestational age | all nulliparous | NR | yes |
Fang 2017 (Fang et al., 2017) China | Cross-sectional | 12 | 12 | NR | placenta (trophoblast cells) | at the time of delivery | normal pregnancies | NR | NR | NR | NR |
Gan 2017 (Gan et al., 2017) China | Case-control | 20 | 20 | 28.95 ± 4.16 vs. 30.05 ± 4.22 | MPB (serum) urine | before delivery before delivery | healthy pregnant women without complications were selected as the control based on similar maternal age at delivery and the similar weight at delivery | Maternal age and maternal weight at delivery | NR | NR | NR |
Gao 2017 (Gao et al., 2017) China | Cross-sectional | 26 | 18 | 30.8 ± 5.2 vs. 29.6 ± 4.6 | MPB (plasma)placenta | before delivery (16, 20, 24, 30 gw) NR | normal pregnancies were defined as those without medical, obstetric or surgical complications at the time of the study and who subsequently delivered full term, singleton healthy infants weighing >2,500 g after 37 completed weeks of gestation | NR | NR | NR | NR |
Gunel 2017 (Gunel et al., 2017) Turkey | Case-control | 18 | 18 | NR | MPB (plasma) | at the time of delivery | matched for age, gestational week, and gravidity healthy pregnancies 37-40 gw | Maternal age, gestational age, and gravidity | yes | NR | NR |
Guo 2017 (Guo et al., 2017) China | Cross-sectional | 29 | 26 | 32.14 ± 1.17 vs. 29.64 ± 1.00 | placenta | at the time of delivery | healthy pregnant women | NR | NR | no | yes |
Han 2017 (Han et al., 2017) China | Cross-sectional | 40 | 20 | 30.25 ± 5.16 vs. 29.74 ± 4.16 | placenta | at the time of delivery | women in normal late pregnancy | NR | NR | yes | NR |
Hromadnikova 2017 (Hromadnikova et al., 2017) Czech Republic | Not clear (retrospective study) | 56 Total 15 mPE 41 sPE 19 EOPE 37 LOPE | 44 | 33 (22–43) vs. 32 (20–39) | UC blood | NR | Normal pregnancies defined as those without medical, obstetrical, or surgical complications at the time of the study and who subsequently delivered full term, singleton healthy infants weighing >2,500 g after 37 completed weeks of gestation | NR | no | NR | no |
Hu 2017 (Hu et al., 2017) China | Cross-sectional | 19 | 23 | NR | placenta | at the time of delivery | healthy pregnant women at term | NR | NR | NR | NR |
Huang 2017 (Zhang et al., 2017) China | Nested case-control | 26 | 52 | 28.3 ± 3.8 vs. 28.1 ± 4.4 | MPB (plasma) | before delivery (12–20 gw) | healthy pregnant women who had no relevant disease over the same period | gestational age and maternal age | no | no | yes |
Jairajpuri 2017 (Jairajpuri et al., 2017) Kingdom of Bahrain | Cross-sectional | 15 | 7 | 30 (25–38) (mPE) 34 (28–39) (sPE) vs. 29 (23–36) | MPB (plasma) | NR | no previous history of hypertension, cardiovascular disease, hepatitis, kidney disease, diabetes, and any evidence of intrapartum infection or other complications of pregnancy such as fetal anomalies or chromosomal abnormalities | Maternal age and BMI | yes | NR | no |
Jiang 2017 (Jiang et al., 2017) China | Case-control | 19 | 19 | 31.3 ± 5.8 vs. 30.9 ± 5.6 | MPB (serum) | 1st trimester 10-14 gw 2nd trimester 20-24 gw 3rd trimester 30-34 gw | healthy pregnant women without complications | maternal age (±1 year) at delivery and gestational age | NR | NR | yes |
Jin 2017*(Jin et al., 2017) China | Cross-sectional | 15 | 15 | NR | Placenta MPB | NR NR | normal pregnancies | NR | NR | NR | NR |
Korkes 2017*(Korkes et al., 2017) United States | Cross-sectional | 11 | 11 | 31.6 ± 1.63 vs. 34.36 ± 1.5 | placenta | NR | normal pregnancies | NR | NR | NR | yes |
Li 2017a*(Li et al., 2017a) China | Cross-sectional | NR | NR | NR | placenta | at the time of delivery | Normal pregnancy without preeclampsia or any other complications | NR | NR | NR | NR |
Li 2017b (Li et al., 2017b) China | Case-control | 32 Total 24 (UC tissue) 8 (UC-MSCs) | 30 Total 24 (UC tissue) 6 (UC-MSCs) | 29.5 ± 0.9 vs. 28.9 ± 0.5 (UC tissue) 29.6 ± 0.2 vs. 28.7 ± 0.9 (UC-MCSs) | UC tissue UC-MSCs | at the time of delivery | healthy pregnancies who underwent Caesarean section | NR | no | NR | yes |
Lu 2017 (Lu et al., 2017) China | Cross-sectional | 84 Total 38 mPE 46 sPE | 50 | 28.5 ± 1.6 (mPE) 29.2 ± 2.1 (sPE) vs. 28.6 ± 1.3 | placenta | at the time of delivery | normal pregnancy | NR | NR | no | NR |
Luo 2017 (Luo et al., 2017a) NR | Cross-sectional | 16 | 16 | NR | placenta | NR | NR | NR | NR | NR | NR |
Luo 2017 (Luo et al., 2017b) China | Case-control | 23 | 15 | 30.6 ± 1.0 vs. 28.1 ± 0.9 | placenta | at the time of delivery | healthy women not having preeclampsia or any other complications, such as maternal history of hypertension and/or renal or cardiac disease, maternal infection, multiple pregnancies, premature rupture of membranes or fetal anomalies | NR | NR | NR | NR |
Meng 2017 (Meng et al., 2017) Inner Mongolia (China) | Cross-sectional | 20 | 10 | 28.9 ± 0.15 vs. 28.3 ± 0.21 | placenta | at the time of delivery | normal pregnancy | NR | all nulliparous | NR | NR |
Nizyaeva 2017*(Nizyaeva et al., 2017) NR | Cross-sectional | 10 Total 5 EOPE 5 LOPE | 8 Total 4 preterm 4 full-term | 23–40 for all respondents | Placenta (syncytiotrophoblast and syncytial knots) | NR | preterm controls - women without clinical manifestations of hypertensive disorders and without inflammatory diseases (no inflammatory infiltration was confirmed by results of histological analysis) term controls - uterine scar after the previously surgery, severe myopia, and anatomically narrow pelvis | NR | NR | NR | NR |
Salomon 2017 (Salomon et al., 2017) Chile | Not clear (retrospectively stratified case-control experimental design) | 45 Total 15 11–14 gw 15 22–24 gw 15 32–36 gw | 96 Total 32 11–14 gw 32 22–24 gw 32 32–36 gw | 29 ± 1.6 (18–40) vs. 25 ± 1.2 (18–36) | MPB (plasma exosomes) | 11–14 gw 22–24 gw 32–36 gw | healthy subjects without pregnancy complications or chronic medical problems, and did not differ in racial origin from PE patients | Gestational age | NR | yes | yes |
Shao 2017 (Shao et al., 2017) China | Case-control | 24 Total sEOPE 10 sLOPE 14 | 43 10 Preterm controls 33 Term controls | 29.8 ± 6.5 (total) 30.3 ± 6.2 (sEOPE) 28.8 ± 5.3 (sLOPE) vs. 29.2 ± 5.6 (preterm controls) 28.6 ± 4.7 (normal pregnancy) | placenta | at the time of delivery | Term controls - gestation in a previously healthy woman who did not experience any complications during pregnancy and who delivered a healthy neonate with a weight adequate for a gestational age of longer than 37 weeks Preterm controls - unexplained preterm labor defined as labor of unknown causes earlier than 34 weeks, but without any other diagnosable pregnancy problems | Gestational age | NR | NR | yes |
Singh 2017 (Singh et al., 2017) United States | Cross-sectional | 4 | 4 | NR | placenta (chorionic villi) | before delivery (11–12 gw) | healthy pregnancies who delivered at term matched for gestational age at CVS (+/- 6 days), fetal sex, parity with PE women | Gestational age (+/- 6 days), fetal sex and parity | NR | yes | yes |
Truong 2017 (Truong et al., 2017) United States | Case-control | 6 | 6 | 32 ± 4.3 (28 ± 33) vs. 31 ± 2.9 (29 ± 35) | MPB (plasma exosomes) | before delivery (before 20 gw) | women without chronic medical conditions or obstetric complications | NR | NR | NR | yes |
Tsai 2017 (Tsai et al., 2017) Taiwan | Case-control | 31 | 60 | 33.83 ± 5.77 vs. 31.33 ± 4.31 | MPB (plasma) fetal cord blood (plasma) placenta | before delivery - within hours to 2 days before delivery at the time of delivery | healthy controls | Gestational age | NR | NR | yes |
Wang 2017 (Wang et al., 2017) China | Cross-sectional | 25 | 25 | 20–35 for all respondents | placenta | at the time of delivery | healthy controls | NR | NR | NR | yes |
Wei 2017 (Wei et al., 2017) New Zealand | Cross-sectional | 7 | 4 | 28.0 ± 5.78 vs. 32 ± 4.99 | placenta (trophoblast debris) | at the time of delivery | normotensive term pregnancies | NR | NR | NR | yes |
Xiao 2017 (Xiao et al., 2017) China | Cross-sectional | 30 | 30 | 28.34 ± 4.12 vs. 28.81 ± 4.94 | placenta | at the time of delivery | healthy pregnancies who underwent Caesarean section | NR | NR | NR | NR |
Xu 2017 (Xu and Zhang, 2017) China | Cross-sectional | 25 | 25 | NR | placenta | NR | normal pregnancies | NR | NR | NR | NR |
Yang 2017*(Yang et al., 2017) China | Cross-sectional | 60 | 20 | NR | MPB (serum) placenta | at the time of delivery | subjects who were normotensive during pregnancy and who, both previously and presently, had delivered a healthy neonate after 37 weeks of gestation | NR | NR | NR | yes |
Brkic 2018 (Brkić et al., 2018) China | Cross-sectional | 15 | 15 | 36.67 ± 0.27 vs. 37.56 ± 0.2 | Placenta (chorionic plate and basal plate) | at the time of delivery | previously normotensive women who did not suffer from complications during pregnancy and who delivered a healthy neonate with a weight adequate for a gestational age | Gestational age | NR | NR | yes |
Case-control | 9 Term PE | 69 Total 13 1st trimester 9 2nd trimester 23 preterm control 24 term control | 32 ± 1.17 (term PE) vs. (preterm control) 33 ± 0.76 (term control) | placenta (trophoblast cells) | at the time of delivery | 1st and 2nd trimester - healthy patients undergoing elective termination of pregnancy Preterm controls – spontaneous preterm labor delivered either by Caesarean section for fetal distress or vaginal delivery Term controls - vaginal delivery or elective Caesarean sections with Appropriate for Gestation Age babies | NR | NR | NR | NR | |
Chi 2018 (Chi and Zhang, 2018) China | Cross-sectional | 30 | 30 | 25–35 for all respondents | placenta (placental villi) | NR | age matched healthy controls | Maternal age | NR | NR | NR |
Dai 2018 (Dai and Cai, 2018) China | Cross-sectional | 63 Total 55 sEOPE 8 sLOPE | 65 | 29.7 ± 4.2 vs. 30.8 ± 3.9 | placenta (trophoblast cells) | NR | pregnancies free of any pregnancy complications that terminated between 34 and 40 gestational weeks | Maternal age, BMI and gestational age | no | NR | NR |
Fang 2018 (Fang et al., 2018) China | Cross-sectional | 50 | 50 | 29.8 ± 4.2 vs. 30.5 ± 3.2 | Placenta | NR | normal pregnant women | NR | NR | NR | NR |
Gao 2018 (Gao et al., 2018a) China | Cross-sectional | 42 | 42 | 30.12 ± 3.98 vs. 32.36 ± 4.87 | Placenta | at the time of delivery | normal pregnancy | NR | NR | NR | NR |
Gao 2018 (Gao et al., 2018b) China | Cross-sectional | 29 | 35 | 28.3 ± 4.2 vs. 27.2 ± 3.1 | Placenta | at the time of delivery | pregnant women without PE or any other complications, such as premature rupture of membranes, fetal anomalies, maternal history of hypertension and/or renal or cardiac disease, maternal infection, or smoking | NR | NR | NR | NR |
Gunel 2018 (Gunel et al., 2020) Turkey | Cross-sectional | 10 | 10 | 30.7 ± 2.3 vs. 31.75 ± 3.92 | MPB (plasma) placenta | just before delivery at the time of delivery | healthy women | NR | NR | NR | NR |
Guo 2018 (Guo et al., 2018) China | Cross-sectional | 20 | 20 | 28.6 ± 3.1 vs. 27.1 ± 2.6 | MPB (plasma and serum) | at the time of delivery | healthy pregnant women | NR | NR | NR | NR |
Khaliq 2018*(Khaliq et al., 2018) South Africa | Cross-sectional | 28 | 32 | Not clear | MPB (serum) placenta | NR at the time of delivery | normotensives with no obstetrical or medical complications | NR | NR | NR | yes |
Kim 2018 (Kim et al., 2018) Republic of Korea | Cross-sectional | 17 | 17 | NR | MPB (serum) | NR | normal pregnant women | NR | NR | NR | NR |
Li 2018*(Li et al., 2018) China | Cross-sectional | 91 Total 40 mPE 51 sPE | 67 | 29.4 ± 2.8 vs. 28.4 ± 3.5 | MPB (plasma) placenta | during the treatment at the time of delivery | normal pregnant women | NR | NR | NR | yes |
Liu 2018 (Liu et al., 2018) China | Cross-sectional | 18 | 20 | 30.3 ± 4.6 vs. 29.5 ± 4.3 | Placenta | at the time of delivery | normal pregnant women | NR | NR | NR | NR |
Lou 2018 (Lou et al., 2018) China | Case-control | 28 | 34 | NR | Placenta | at the time of delivery | age matched healthy controls | Maternal age | NR | NR | NR |
Lykoudi 2018 (Lykoudi et al., 2018) Greece | Cross-sectional | 16 Total 11 EOPE 5 LOPE | 8 | 35.1 (28–45) EOPE 28.4 (20–35) LOPE vs. 35.7 (35–39) | Placenta | at the time of delivery | uncomplicated term pregnancies | NR | NR | NR | NR |
Martinez-Fierro 2018 (Martinez-Fierro et al., 2018) Mexico | Nested case–control study | 45 in total 6 at 12 gw 10 at 16 gw 14 at 20 gw 15 at the time of diagnosis | 18 | 23.5 ± 5.1 vs. 23.4 ± 5.8 | MPB (serum) | before delivery (12th, 16th and/or 20th gw) at enrolment and PE patients at the time of diagnosis | matched healthy pregnancies without complications (normotensive controls) | NR | no | yes | yes |
Motawi 2018 (Motawi et al., 2018) Egypt | Case-control | 100 Total 23 EOPE 77 LOPE | 100 Total 20 early pregnancy controls 80 late pregnancy controls | 28.77 ± 5.72 vs. 28.06 ± 5.65 | MPB (plasma exosomes) | NR | uncomplicated pregnancy: (1) gestational age at venipuncture between 20 – 42 weeks; (2) no medical, obstetrical, or surgical complications; (3) absence of labor at the time of venipuncture; and (4) delivery of a normal term (≥37 weeks) neonate whose birth weight was between the 10th and 90th percentile for gestational age. Divided into early (<20 gw) and late (>20 gw) pregnancy control groups | Maternal age | NR | NR | yes |
Niu 2018* (Niu et al., 2018) China | Cross-sectional | 25 | 20 | 27.9 ± 2.9 vs. 28.1 ± 3.2 | Placenta | at the time of delivery | healthy pregnant women | NR | NR | yes | yes |
Nizyaeva 2018*(Nizyaeva et al., 2018) Russia | Cross-sectional | 22 Total 12 EOPE 10 LOPE | 15 Total 10 late normal 5 early normal | NR | placenta (syncytiotrophoblast) endothelium | at the time of delivery | Late normal pregnancies defined as women with physiological course of pregnancy and full-term gestational age. Early normal pregnancies defined as women with preterm operative delivery at 26–31 gw | NR | NR | NR | NR |
Shen 2018 (Shen et al., 2018) China | Case-control | 10 | 10 | 29.11 ± 5.01 vs. 27.56 ± 3.21 | MPB (serum exosomes) | before delivery (prior to treatment) | gestational age-matched normal pregnant women | Gestational age | NR | NR | yes |
Timofeeva 2018 (Timofeeva et al., 2018) Russia | Cohort | 28 Total 16 EOPE 2 moderate EOPE 14 severe EOPE 12 LOPE 11 moderate LOPE 1 severe LOPE | 26 Total 16 full term 10 indicated for Caesarean | NR | Placenta MPB (plasma) | at the time of delivery | women with full term physiological pregnancy (37–40 gw) and pregnant women with an indication for an emergency Caesarean section due to the lack of prolonging the pregnancy because of cervical insufficiency, placental abruption, or premature rupture of the fetal membrane without clinical manifestations of PE | NR | NR | NR | NR |
Cohort | 6 sEOPE | 10 | NR | MPB (plasma exosomes) | before delivery (11-13 gw, 24–26 gw and 30–32 gw) | women with physiological pregnancy | NR | NR | NR | NR | |
Wang 2018 (Wang and Yan, 2018) China | Cross-sectional | 20 | 20 | 29.7 ± 2.4 vs. 28.6 ± 3.2 | Placenta | at the time of delivery | pregnant women with normal term pregnancy (without PE or other complications) | NR | NR | NR | NR |
Wang 2018 (Wang et al., 2018a) China | Cross-sectional | 9 | 8 | 34.8 ± 1.4 vs. 34.3 ± 2.2 | MPB (plasma) | at the time of delivery | preterm labor control defined an uniparous gestation in a previously normotensive woman who did not exhibit any gestational complication and delivered a healthy newborn of gestational age before 37 weeks of pregnancy | Gestational age | no | NR | yes |
Wang 2018*(Wang et al., 2018b) China | Case-control | 10 | 10 | 31.3 ± 4.84 vs. 30.5 ± 4.37 | Placenta | NR | normal pregnancies | NR | NR | NR | NR |
Wang 2018 (Wang et al., 2018c) Australia | Case-control | 16 Total 8 EOPE 8 LOPE | 48 Total 8 term controls 7 at 10–11 gw 8 at 14.3–17.8 gw 8 preterm controls | NR | Placenta | at the time of delivery | Term controls defined as uncomplicated singleton pregnancies delivering at term (38.2–40.4 weeks gestation) by elective Caesarean section in the absence of labor. Women treated with non-steroidal anti-inflammatory drugs or who had a history of infection, chorioamnionitis, PE, or who were undergoing induction of labor, were excluded from this group. Women undergoing elective terminations of pregnancy at 10–11 gw or 14.3–17.8 gw. Preterm controls defined as equivalent gestational age women who delivered preterm (at 31.6–35.1 gestational weeks) after spontaneous labor/rupture of membranes and vaginal delivery with no evidence of hypertension | Gestational age | NR | NR | NR |
Winger 2018 (Winger et al., 2018) United States | Not clear (retrospective study) | 4 | 20 | 30.9 ± 8.8 vs. 33.3 ± 6.5 | MPB (buffy coat) | before delivery (11–13 gw) | Normal delivery defined as the delivery of a singleton, normal karyotype baby with the following pregnancy criteria: delivery at 38 ± 42 weeks gestation, baby weight within the normal range for gestational age and maternal BMI <30 | NR | NR | NR | NR |
Zou 2018 (Zou et al., 2018) China | Cross-sectional | 15 | 18 | NR | placenta (basal plate) placenta (chorionic plate) | NR | normal pregnant women | NR | NR | NR | NR |
Awamleh 2019 (Awamleh et al., 2019) Canada | Case-control | 19 | 20 | 28.6 ± 7.0 vs. 28.2 ± 5.0 | placenta (villi) | at the time of delivery | gestational age- matched patients with preterm labor and no other complications before 34 weeks of gestation | Gestational age | NR | NR | yes |
Biro 2019*(Biró et al., 2019) Hungary | Cross-sectional | 21 Total 8 13 | 15 Total 8 7 | 33.43 ± 6.48 vs. 31.25 ± 5.80 | MPB (plasma) placenta | before delivery (3rd trimester) at the time of delivery | normotensive group with the exclusion of women with history of pregnancy-related or other forms of hypertension, spontaneous abortion, preterm birth, and intrauterine growth restriction | NR | NR | NR | NR |
Chen 2019*(Chen et al., 2019) China | Cross-sectional | 29 | 27 | 31 ± 7 vs. 26 ± 6 | Placenta | at the time of delivery | pregnant women with normal uncomplicated pregnancies (≥36 weeks of gestation) | NR | no | NR | yes |
Devor 2019 (Devor et al., 2020) United States | Case-control | 4 | 5 | 35.8 ± 2.8 vs. 29.2 ± 2.1 | MPB (plasma exosomes) | before delivery (in each trimester) | matched healthy controls who underwent a normal spontaneous vaginal delivery | Yes (no variable) | NR | NR | NR |
Dong 2019*(Dong et al., 2019) China | Case-control | 40 Total 20 EOPE 20 LOPE | 40 Total 20 early control 20 late control | 29.10 ± 6.03 (EOPE) 29.15 ± 5.13 (LOPE) vs. 29.6 ± 4.88 (early controls) 30.05 ± 4.91 (late controls) | MPB (plasma) | before delivery (prior to any surgery) at the time of delivery (for PE patients) | Early controls defined as 20–34 gestational week normal pregnant women who underwent routine outpatient antenatal examinations and did not develop preeclampsia. Late controls defined as 34–41 gestational week normal pregnant women who underwent routine outpatient antenatal examinations and did not develop preeclampsia | Gestational age | no | yes | yes |
Eghbal-Fard 2019 (Eghbal-Fard et al., 2019) Iran | Case-control | 50 | 50 | 33.2 ± 5.1 vs. 31.8 ± 3.4 | MPB (mononuclear cells) | before delivery | healthy gestational matched pregnant women | Gestational age | NR | NR | NR |
Hocaoglu 2019*(Hocaoglu et al., 2019) Turkey | Case-control | 23 Total 6 mEOPE 6 sEOPE 5 mLOPE 6 sLOPE | 28 | 29.8 ± 5.9 (Total) vs. 28.1 ± 5.8 | MPB (leukocytes) | before delivery | no obstetrical or medical complications whose gestational weeks were matched | Gestational age | no | no | yes |
Hromadnikova 2019a*(Hromadnikova et al., 2019b) Czech Republic | Not clear (cohort case-control study) | 101 Total 24 mPE 77 sPE | 89 | 32 (21–44) at delivery 38 (28–52) at follow-up vs. 32 (25–43) at delivery 38 (29–50) at follow-up | MPB | after delivery (3–11 years postpartum) | normal gestation | NR | no | no | NR |
Hromadnikova 2019b (Hromadnikova et al., 2019a) Czech Republic | Nested case-control | 43 Total 13 mPE 30 sPE 10 EOPE 33 LOPE | 102 Total 50 control 1 52 control 2 | 32.34 ± 0.73 Total vs. 31.88 ± 0.56 (control 1) 31.21 ± 0.56 (control 2) | MPB (plasma exosomes) | before delivery (10–13 gw) | normal pregnancies without complications delivering full term, healthy infants after 37 weeks of gestation weighting >2,500 g, were selected for equal gestational age, equal age of women at the time of sampling and equal plasma sample storage times | NR | no | NR | NR |
Hu 2019 (Hu et al., 2019) China | Cross-sectional | 25 | 25 | 29.24 ± 4.05 vs. 28.04 ± 3.09 | Placenta | NR | normal pregnancy | NR | NR | NR | NR |
Huang 2019 (Huang et al., 2019) China | Cross-sectional | 20 | 20 | 29.6 (5.8) vs. 31.3 (4.6) | Placenta | at the time of delivery | normotensive pregnant women | NR | yes | NR | NR |
Li 2019 (Li et al., 2019) China | Cross-sectional | 10 | 10 | 27.92 ± 3.94 (23–34) vs. 28.00 ± 3.54 (22–34) | Placenta | at the time of delivery | healthy controls | NR | NR | NR | NR |
Liu 2019 (Liu et al., 2019a) China | Cross-sectional | 20 | 20 | NR | Placenta | at the time of delivery | normal pregnant women | NR | NR | NR | NR |
Liu 2019 (Liu et al., 2019b) China | Cross-sectional | 39 | 42 | NR | Placenta | NR | normal pregnant women | NR | NR | NR | NR |
Liu 2019 (Liu et al., 2019c) China | Cross-sectional | 30 | 30 | 27.07 ± 2.53 vs. 28.67 ± 2.78 | Placenta | at the time of delivery | normal pregnant women | NR | NR | NR | yes |
Ma 2019 (Ma et al., 2019) China | Not clear (prospective study) | 89 | 70 | 27.25 vs. 26.81 | MPB (serum) | before delivery (20 gw) | pregnant women with no evident anomalies detected during physical examinations | NR | NR | no | yes |
Martinez-Fierro 2019 (Martinez-Fierro et al., 2019) Mexico | Nested case-control | 30 Total 6 12 gw 10 16 gw 14 20 gw | 18 | 23.5 ± 5.1 vs. 23.4 ± 5.8 | MPB (serum) | before delivery (at the time of PE diagnosis, and at the 12th, 16th and/or 20th gw) | healthy pregnancies without complications matched by age, nulliparity, body mass index (BMI), and a personal and family history of PE | Maternal age, nulliparity, BMI and personal and family history of PE | no | yes | NR |
Mei 2019 (Mei et al., 2019) China | Cross-sectional | 20 | 20 | NR | Placenta | at the time of delivery | normal pregnant women | NR | NR | NR | NR |
Nejad 2019 (Nejad et al., 2019) Iran | Case-control | 20 | 20 | 29 ± 1.1 vs. 28 ± 0.92 | MPB (plasma) | NR | healthy controls matched for BMI (body mass index, 29–39 kg/m2), ethnicity (Iranian), smoking (non-smoker) | BMI (29–39 kg/m2), ethnicity (Iranian), smoking (non-smoker) | NR | yes | yes |
Pillay 2019 (Pillay et al., 2019) South Africa | Case-control | 30 Total 15 EOPE 15 LOPE | 15 Preterm controls (≤33 gw) 15 Term controls (≥34 gw) | 25.25 ± 5.13 (EOPE) 27.11 ± 5.23 (LOPE) vs. 28.43 ± 2.23 (≤33 gw) 26.12 ± 3.62 (>34 gw) | MPB (plasma exosomes) | before delivery (at the time of clinical diagnosis of PE) | Gestationally matched normotensive pregnant woman (blood pressure of 120 ± 10/80 ± 5 (systolic/diastolic mm Hg) with absent proteinuria as detected by a rapid urine dipstick test) | Gestational age | NR | NR | NR |
Sekar 2019 (Sekar et al., 2019) India | Cross-sectional | NR | NR | NR | MPB | NR | Normotensives | NR | NR | NR | NR |
Shi 2019 (Shi et al., 2019) China | Cross-sectional | 15 | 15 | 29.5 ± 2.8 vs. 28.3 ± 3.7 | placenta | at the time of delivery | Normal-term pregnancies without PE or any other complications | NR | NR | NR | NR |
Tang 2019 (Tang et al., 2019) China | Case-control | 30 | 30 | 27.8 (24.5–31.0) vs. 27.3 (25.0–28.0) | placenta | at the time of delivery | healthy pregnant women with uncomplicated pregnancies | Gestational age | no | yes | yes |
Wang 2019 (Wang et al., 2019a) Taiwan | Case-control | 33 | 55 | 34.02 ± 5.57 vs. 31.33 ± 4.31 | MPB (plasma) | before delivery (prepartum after hospital admittance for delivery) | healthy controls | NR | no | NR | NR |
Wang 2019 (Wang et al., 2019b) China | Cross-sectional | 20 | 20 | Individual data 29.00 ± 3.82 vs. 27.50 ± 3.35 | Placenta MPB (serum) | at the time of delivery | normal controls | NR | NR | NR | NR |
Wang 2019 (Wang et al., 2019e) China | Cross-sectional | 42 | 39 | 28.9 ± 2.1 vs. 29.1 ± 1.9 | Placenta MPB (serum exosomes) | NR | normal pregnancies | NR | NR | NR | NR |
Wang 2019*(Wang et al., 2019c) China | Case-control | 17 | 17 | 28.1 ± 0.8 vs. 29.7 ± 1.2 | placenta | at the time of delivery | normotensive healthy nulliparous and nonproteinuric during pregnancy matched for age and BMI | Maternal age and BMI | NR | yes | NR |
Wang 2019 (Wang et al., 2019d) China | Cross-sectional | 30 | 30 | 28.2 ± 3.2 vs. 28.9 ± 3.0 | placenta | at the time of delivery | healthy pregnant women | NR | NR | NR | yes |
Xiaobo 2019 (Xiaobo et al., 2019) China | Cross-sectional | 15 Total 10 EOPE 5 LOPE | 15 | 30.2 ± 5.4 vs. 29.3 ± 4.7 | placenta | at the time of delivery | healthy pregnant women | NR | NR | NR | yes |
Xie 2019 (Xie et al., 2019) Chin | Cross-sectional | 57 | 57 | 27.12 ± 4.11 vs. 26.37 ± 3.29 | placenta | NR | healthy patients | NR | NR | NR | NR |
Xue 2019 (Xue et al., 2019) China | Case-control | 20 | 20 | 28.55 ± 0.83 vs. 27.00 ± 0.68 | Placenta MPB (serum) | at the time of delivery NR | women without renal disease, cardiovascular disease, transient hypertension in pregnancy, gestational diabetes mellitus, hepatitis, any evidence of spontaneous abortion, intrauterine fetal death, fetal chromosomal or other pregnancy complications | Maternal age and gestational age | no | NR | NR |
Yang 2019*(Yang et al., 2019a) China | Cross-sectional | 57 Total preterm PE 12 term PE 14 31 plasma | 32 Total preterm age matched control 11 term age matched control 12 9 plasma | 31.57 ± 2.98 vs. 32.83 ± 3.19 | Placenta MPB (plasma) | at the time of delivery | Early trimester controls – patients undergoing terminated pregnancies through dilation and curettage procedure | Maternal age | no | NR | NR |
Yang 2019a (Yang and Guo, 2019) China | Cross-sectional | 30 | 30 | 28.63 ± 2.24 vs. 28.83 ± 2.42 | placenta | at the time of delivery | control group | NR | NR | NR | yes (essential HTA) |
Yang 2019b (Yang and Meng, 2019) China | Cross-sectional | 30 | 30 | 27.80 ± 2.10 vs. 28.20 ± 1.50 | placenta | at the time of delivery | normal group | NR | NR | yes | yes |
Yang 2019a (Yang et al., 2019b) China | Cross-sectional | 40 | 40 | 30.5 ± 5.3 vs. 30.9 ± 4.6 | placenta | at the time of delivery | healthy controls | NR | NR | NR | NR |
Yang 2019b (Yang et al., 2019c) China | Cross-sectional | 57 | 70 | 73.8 ± 3.3 vs. 67.2 ± 2.6 | placenta | at the time of delivery | normal controls | NR | yes | NR | yes |
Youssef 2019*(Youssef and Marei, 2019) Egypt | Cross-sectional | 30 Total mPE 12 sPE 18 | 20 | 31.77 ± 3.16 vs. 29.75 ± 4.24 | MPB (serum) | before delivery | healthy pregnant women without any pregnancy complications who came for delivery between 38 and 40 weeks of gestation | NR | no | NR | yes |
Zhong 2019 (Zhong et al., 2019) China | Cross-sectional | 3 | 3 | NR | MPB (plasma) | before delivery | normal pregnancies | NR | NR | NR | NR |
Ayoub 2019* (Ayoub et al., 2019) Egypt | Cross-sectional | 80 | 80 | 30.5 (21–41) vs. 32 (19.42) | MPB (serum) | At the time of diagnosis of PE | Normal pregnancies | No | NR | Yes | Yes |
Cao 2019 (Cao et al., 2019) China | Cross-sectional | 25 | 28 | 29.78 ± 5.25 vs. 30.45 ± 4.62 | Placenta MPB (plasma) | NR | Normal pregnancies | No | NR | NR | NR |
Demirer 2019 (Demirer et al., 2020) Turkey | Not clear (prospective study) | 96 total 48 EOPE 48 LOPE | 23 + 3 early stage 3 late stage | 30.12 ± 5.7 Total 31.0 ± 5.5 EOPE 29.4 ± 5.8 LOPE | MPB | Before delivery | Healthy pregnant women with no obstetrical or medical complications | No | No | No | Yes |
Lip 2019 (Lip et al., 2020) Netherlands | Cross-sectional | 10 EOPE | 10 | 31.5 ± 5.7 vs. 28.0 ± 4.4 | MPB (plasma) | At the time of PE diagnosis | Healthy pregnant women | Gestational age at sampling | NR | No | Yes |
Lv 2019 (Lv et al., 2019) China | Cross-sectional | 18 | 18 | 32.94 ± 4.64 vs. 31.06 ± 4.02 | Placenta | At the time of delivery | Normal singleton pregnant women by Caesarean | No | NR | NR | Yes |
Qian 2019 (Qian and Liu, 2019) China | Cross-sectional | 16 | 16 | 29.3 ± 2.5 vs. 28.4 ± 3.1 | Placenta (villi) | At the time of delivery | Normal pregnant women | No | NR | NR | NR |
Xu 2019 (Xu et al., 2019) United States | Cross-sectional | 6 | 6 | 29 ± 6 vs. 29 ± 7 | Maternal subcutaneous adipose tissue | At the time of delivery | Normal pregnant women | No | NR | Yes | NR |
Yang 2019 (Yang and Meng, 2020) China | Case-control | 30 | 30 | 28.30 ± 2.07 vs. 29.00 ± 1.55 | Placenta | At the time of delivery | Normal full term pregnancy | No | Yes | Yes | Yes |
Yuan 2019* (Yuan et al., 2020) China | Cross-sectional | 30 | 30 | 27.8 ± 2.8 vs. 26.52 ± 4.9 | Placenta | At the time of delivery | Normal pregnancies | No | NR | NR | NR |
Zhang 2019 (Zhang et al., 2019b) China | Cross-sectional | 30 | 30 | 28.36 ± 4.78 vs. 24.34 ± 2.87 | MPB (serum) | At the time of delivery | Healthy pregnancies | No | NR | NR | NR |
Akgor 2020* (Akgör et al., 2021) Turkey | Cross-sectional | 31 | 32 | 29.9 ± 6.66 vs. 29.47 ± 6.33 | MPB (plasma) | Before delivery | Term-matched healthy pregnancies | Gestational age, BMI, additional comorbities, parities, age | No | NR | NR |
Devor 2020 (Devor et al., 2020) United States | Case-control | 4 LOPE | 5 | 35.8 ± 2.8 vs. 29.2 ± 2.1 | MPB (plasma) | Before delivery (1st trimester -before 13 GW 2nd trimester -13-26 GW 3rd trimester -26-40 GW) | Matched healthy controls | Mmaternal age, BMI | NR | NR | Yes |
Dong 2020*(Dong et al., 2020) China | Cross-sectional | 20 | 20 | 31.7 ± 3.2 vs. 29.7 ± 2.3 | MPB Placenta | Before delivery At the time of delivery | Women without PE | No | NR | NR | Yes |
Fan 2020* (Fan et al., 2020) China | Cross-sectional | 25 | 25 | 27.92 ± 2.81 vs. 26.84 ± 2.30 | Placenta | At the time of delivery | Normal pregnant women without any other complications, such as premature rupture of membranes, fetal anomalies, maternal history of hypertension and/or renal or cardiac disease, maternal infection, or smoking | No | NR | Yes | Yes |
Gong 2020 (Gong et al., 2020) China | Cross-sectional | 8 | 8 | 31 ± 4.3 vs. 30 ± 4.5 | Placenta | At the time of delivery | Healthy pregnancies | No | NR | NR | Yes |
Han 2020 (Han et al., 2021) China | Cross-sectional | 60 Total 30 severe EOPE 30 mild EOPE 20 PE | 30 20 | 31.56 ± 4.76 Severe EOPE vs. 30.34 ± 4.28 Mild EOPE 31.18 ± 4.16 vs. 30.86 ± 4.72 | MPB (serum) UCB Placenta | At the time of delivery | Normal pregnancies | Gestational age, maternal age | NR | Yes | Yes |
Huang 2020 (Huang et al., 2020) China | Cross-sectional | 46 sPE | 57 | 29.6 ± 3.9 vs. 28.5 ± 4.1 | Placenta | At the time of delivery | pregnant women without any pregnancy complications (34–40 gestational weeks) | Gestational age, BMI, maternal age | NR | NR | Yes |
Jelena 2020 (Jelena et al., 2020) Serbia | Case-control | 19 | 17 | 34 (20–51) vs. 32 (22–40) | MPB (plasma) | At the time of delivery | Healthy pregnant women | No | NR | No | Yes |
Kim 2020 (Kim et al., 2020) South Korea | Case-control | 92 | 92 | 32.73 ± 0.54 vs. 31.49 ± 0.50 | MPB (serum) | Before delivery | Normotensive pregnant women selected at random | No | NR | NR | Yes |
Li W 2020 (Li et al., 2020d) China | Cross-sectional | 30 | 30 | NR | Placenta | At the time of delivery | Healthy | No | NR | NR | NR |
Li T 2020* (Li et al., 2020c) China | Case-control | 30 sPE | 20 | 25.45 ± 3.03 vs. 25.27 ± 3.19 | Placenta | At the time of delivery | Healthy pregnant women | No | yes | NR | Yes |
Li Q 2020 (Li et al., 2020b) China | Nested case-control | 15 | 29 | 31.13 ± 1.24 vs. 30.62 ± 0.72 | MPB (plasma) Placenta | Before delivery (between 12 + 0 and 13 + 6 GW) At the time of delivery | Gestational age matched healthy pregnancies without any other complications during pregnancy | Gestational age | NR | NR | Yes |
Li H 2020 (Li et al., 2020a) China | Cross-sectional | 24 | 24 | NR | Placenta | At the time of delivery | Healthy Pregnancies | No | NR | NR | Yes |
Licini 2020 (Licini et al., 2021)li Russia | Nested case-control | 13 10 | 18 20 | 33 (31; 34) 36.9 ± 5.25 vs. 30.2 ± 7.59 1st trimester 32.6 ± 4.05 3rd trimester |
MPB (plasma) Placenta | Before delivery (12th GW) At the time of delivery | Healthy pregnant women (normal uterine and umbilical Doppler flow velocimetry during gestation and where the foetus was appropriate for the gestational age (newborns _10th _ 90th percentile for gender and gestational age according to Italian charts) Voluntary terminations in the 1st trimester, and healthy term prgnancies | Gestational age | NR | No | Yes |
Ma 2020 (Ma et al., 2020) China | Cross-sectional | 36 | 30 | NR | Placental monocytes MPB (serum exosomes) |
NR | Normal pregnant volunteers | No | NR | NR | NR |
Mavreli 2020 (Mavreli et al., 2020) Greece | Case-control | 17 LOPE 5 for NGS 12 for qRT-PCR | 17 5 for NGS 12 for qRT-PCR | 31.81 (21.2–39.50) vs. 33.19 (26.75–41.27) | MPB (plasma) | Before delivery (1st trimester) | Uncomplicated pregnancies delivered at 38–42 GW, chromosomally normal baby weighing within the normal range for gestational age, matched for maternal age, gestational age and duration of storage of plasma samples | Maternal age, gestational age, duration of storage plasma samples | NR | No | Yes |
Sheng 2020 (Sheng et al., 2020) China | Case-control | 200 | 200 | 31.19 ± 4.84 vs. 31.02 ± 4.26 | MPB (plasma) | NR | Healthy pregnant women | No | NR | Yes | Yes |
Song 2020 (Song et al., 2020) China | Cross-sectional | 24 | 24 | NR | Placenta | At the time of delivery | Healthy pregnant women | No | NR | NR | NR |
Tao 2020 (Tao et al., 2020) China | Cross-sectional | 35 | 35 | 28.31 ± 2.86 vs. 28.66 ± 3.0 | Placenta | At the time of delivery | Normal pregnancies | No | NR | NR | NR |
Wang 2020 (Wang et al., 2020) China | Cross-sectional | 24 | 24 | NR | Placenta | At the time of delivery | Healthy pregnancies | No | NR | NR | NR |
Whigham 2020 (Whigham et al., 2020) Australia | Case-control | 34 PE 36 GW 43 PE 28 GW 32 sEOPE 34 LOPE | 196 Controls 36 GW 91 Controls 28 GW 22 gestation matched preterm 12 gestation matched term | 28 GW 31 (36–34) vs. 32 (29–34.8) 36 GW 31 (28–33) vs. 31 (26.5–36.3) | MPB (whole blood) Placenta | Before delivery (28 GW) At the time of delivery | Pre-term controls - pre-term rupture of membranes, placenta praevia or antepartum haemorrhage without any evidence of infection (histopathological examination of the placentas), hypertensive disease or maternal comorbidities. Term controls – healthy pregnancies matched fo gestational age | Gestational age | NR | NR | Yes |
Wu 2020 (Wu et al., 2020a) China | Cross-sectional | 30 | 30 | 31.2 ± 4.8 vs. 28.6 ± 5.7 | Placenta | At the time of delivery | Healthy pregnant women | No | NR | NR | Yes |
Wu 2020 (Wu et al., 2020b) China | Cross-sectional | 64 Total 26 mPE 28 sPE | 35 | NR | Placenta | At the time of delivery | Healthy pregnant women | No | NR | NR | NR |
Xueya 2020 (Xueya et al., 2020) China | Cross-sectional | 18 | 20 | 32.5 ± 1.25 vs. 32.1 ± 0.75 | UCB (exosomes) MPB (plasma exosomes) Placenta | After childbirth After PE diagnosis At the time of delivery | Healthy donors | No | NR | NR | NR |
Yang 2020 (Yang et al., 2021) China | Cross-sectional | 20 | 20 | NR | Placenta UCMSC | At the time of delivery | Normotensive pregnant women | No | NR | NR | Yes |
Zhao 2020 (Zhao et al., 2020) China | Case-control | 30 | 30 | NR | Placenta | At the time of delivery | Normal pregnancies | No | NR | NR | NR |
Zheng W 2020 (Zheng et al., 2020) China | Cross-sectional | 30 sPE | 20 | 28.2 ± 2.1 vs. 27.3 ± 1.9 | Placenta MPB (serum) | At the time of delivery | Healthy pregnant women | No | NR | NR | Yes |
Zhou 2020 (Zhou et al., 2020) China | Cross-sectional | 32 | 28 | 32 ± 4.6 vs. 33 ± 3.9 | MPB (serum) Placenta | At the time of delivery | Normal pregnant women | Maternal age, gestational age, pre-pregnancy indices | NR | NR | NR |
Zhu 2020 (Zhu et al., 2020) China | Cross-sectional | 30 | 30 | NR | Placenta | At the time of delivery | Normal full term pregnancies | No | Yes | NR | NR |
Ali 2021 (Ali et al., 2021) Pakistan | Cross-sectional | 27 | 27 | 26 (23–30) vs. 25 (22–28) | MPB (serum) | At the time of delivery | Healthy pregnant women with normal blood pressure (BP) and comparable age in the final trimester (28–40 weeks) | Maternal age, gestational age | NR | Yes | Yes |
Brodowski 2021 (Brodowski et al., 2021) Germany | Cross-sectional | 12 (6 UCB +6 MPB samples) | 9 (6 UCB +6 MPB samples) | UCB ECFC 31.5 ± 3.7 vs. 32.8 ± 5.2 MPB ECFC30.8 ± 5.5 vs. 31.7 ± 7.4 | UCB (endothelial colony forming cells) MPB (endothelial colony forming cells) | Before delivery | Healthy uncomplicated pregnancies | Gestational age at delivery, BMI, and maternal age | No | NR | Yes |
Cai 2021 (Cai et al., 2021) China | Cross-sectional | 40 | 40 | 29.95 ± 2.67 vs. 28.00 ± 3.20 | Placenta | At the time of delivery | Normal pregnancies defined as blood pressure or urine protein in the normal range within 35–40 weeks of pregnancy, followed by Caesarean delivery of healthy infants | No | NR | NR | Yes |
Chu 2021 (Chu et al., 2021) China | Cross-sectional | 18 | 28 | 28 ± 8 vs. 29 ± 6 | Placenta | At the time of delivery After selective pregnancy termination (1st and 2nd trimester controls) | Normal term pregnancies 1st trimester (6–8 GW) controls 2nd trimester (18–21 GW) controls | No | No | NR | NR |
Hayder 2021 (Hayder et al., 2021) Canada | Case-control | 18 Total 14 Pre-term PE 4 Term PE | 30 Total 13 Pre-term 17 Term | Pre-term 30.27 ± 0.36 vs. 29.83 ± 0.51 Term 37.25 ± 0.25 vs. 38.32 ± 0.14 | Placenta | At the time of delivery | Pre-term controls 26–36 GW Term controls 37–40 GW | No | NR | NR | NR |
Jairajpuri 2021 (Jairajpuri et al., 2021) Bahrain | Case-control | 30 15 mPE 15 sPE | 15 | 32 (29–35) mPE 33 (29–37) sPE vs. 30 (25–35) | MPB (plasma) | At the time of delivery | Healthy controls with no previous history of hypertension, cardiovascular disease, hepatitis, kidney disease, diabetes, and any evidence of intrapartum infection or other complications of pregnancy such as fetal anomalies or chromosomal abnormalities in the third trimester | No | NR | Yes | Yes |
Liu 2021 (Liu et al., 2021) China | Cross-sectional | 30 EOPE | 30 | 30.77 ± 5.75 vs. 32.10 ± 4.96 | Placenta | At the time of delivery | Helathy pregnancies who had chosen Caesarean section because of abnormal fetal position, pelvic stenosis, or social factorsetc. | No | No | NR | NR |
Kamali Simsek, 2021 (Kamali Simsek et al., 2021) Turkey | Cross-sectional | 7 | 7 | 31.3 ± 5.02 vs. 28.2 ± 4.7 | Placenta (hDMSC) | At the time of delivery | Healthy pregnant women | Gestational age | NR | NR | NR |
Kolkova 2021 (Kolkova et al., 2021) Slovakia | Case-control | 27 Total 13 mPE 11 sPE 7 EOPE 17 LOPE | 32 (29 used for miRNA analysis) | 27 (21–50) vs. 30 (25–37) | MPB (plasma) | Before delivery | Normal pregnancies with no pregnancy complications, such as artificial insemination, threatened abortion, premature rupture of membranes and/or premature birth, placenta praevia, and foetal macrosomia | No | NR | NR | Yes |
Liao 2021 (Liao et al., 2021) China | Case-control | 70 EOPE 33 sEOPE 37 mEOPE | 35 | 28.6 ± 2.2 sEOPE 27.9 ± 3.1 mEOPE vs. 28.2 ± 2.9 | MPB (serum) | Before delivery | Normal pregnant women | No | NR | NR | Yes |
Luizon 2021 (Luizon et al., 2021) Brasil | Nested case-control | 5 sPE | 5 | 29.8 ± 2.0 vs. 28.8 ± 2.6 | MPB (plasma) | Before delivery | Healthy pregnancies | No | NR | NR | Yes |
Mao 2021 (Mao et al., 2021) China | Case-control | 24 | 21 | 32.21 ± 4.51 Vs. 34.23 ± 3.29 | Placenta | At the time of delivery | Normal pregnancies | Maternal age, maternal weight, systolic blood pressure mmHg, diastolic blood pressure mmHg, proteinuria g/day, body weight of infant g, Gestational age | NR | Yes | NR |
Martinez-Fierro 2021 (Martinez-Fierro and Garza-Veloz, 2021) Mexico | Nested case-control | 16 | 18 | 23.5 ± 5.1 vs. 23.4 ± 5.8 | MPB (serum) | Before delivery (12, 16, 20 GW) At the time of PE diagnosis | Healthy pregnancies without complications | No | No | NR | Yes |
Peng 2021 (Peng et al., 2021) China | Cross-sectional | 30 | 30 | 30.2 ± 5.1 vs. 30.5 ± 4.8 | Placenta | At the time of delivery | Normal pregnant women | No | NR | NR | Yes |
Witvrouwen 2021* (Witvrouwen et al., 2021) Belgium | Cross-sectional | 24 EOPE | 30 | 28.5 (26.7–30.9) vs. 29.2 (27.4–32.5) | MPB (plasma) | At the time of PE diagnosis (22–36 GW) | Healthy pregnancies free from medication and did not have a history of PE, (pregnancy-induced) hypertension, cardiovascular disease or other chronic conditions | No | No | No | No |
Xu 2021 (Xu et al., 2021) China | Cross-sectional | 35 Total 20 EOPE 15 sPE | 38 | 30.92 ± 1.89 EOPE 31.27 ± 3.85 sPE vs. 30.67 ± 2.56 | Placenta | At the time of delivery | Healthy pregnant women | No | NR | NR | NR |
Yu 2021 (Yu et al., 2021) China | Case-control | 40 sPE | 40 | NR | Placenta | At the time of delivery | Control pregnancies | No | NR | NR | Yes |
Zhao X 2021a* (Zhao et al., 2021a) China | Cross-sectional | 10 | 10 | 29.73 ± 4.2 vs. 28.85 ± 3.9 | Placenta | At the time of delivery | normal pregnant women were: 1) healthy subjects; 2) successful pregnancy, normal blood pressure and negative proteinuria | No | NR | NR | Yes |
Zhao X 2021b (Zhao et al., 2021b) China | Case-control | 25 | 25 | 28.91 ± 5.42 vs. 26.73 ± 4.34 | Placenta | At the time of delivery | Normal pregnant women | No | NR | NR | Yes |
Zhu 2021 (Zhu and Liu, 2021) China | Cross-sectional | 21 | 21 | 34.1 ± 5 vs. 33.5 ± 4 | MPB (serum) | NR | Normal pregnant women defined as i) Healthy subjects; ii) delivery after 37 weeks; iii) successful pregnancy without any complications, normal blood pressure and negative proteinuria | No | NR | NR | Yes |
Zolfaghari 2021 (Zolfaghari et al., 2021) Iran |
Case-control | 25 | 25 | 29.2 ± 4.38 vs. 28.12 ± 3.84 | MPB (mononuclear cells) | Before delivery | Healthy age-matched pregnant women at 28–38 weeks of gestation with no sign of historical disorders were engaged for this study | Maternal age | NR | NR | Yes |
Expressed as mean ± sd, mean ± sd (min-max), mean (min-max), mean ± se, med (min-max), med (25–75 percentile), med (Q1; Q3), or as individual data, as stated in the original article.
GW, gestational week; mPE, mild PE; sPE, severe PE; MPB, maternal peripheral blood; mEOPE, mild early onset PE; sEOPE, severe early onset PE; mLOPE, mild late onset PE; sLOPE, severe late onset PE; BMI, body mass index; MSC, mesenchymal stem cells; UC, umbilical cord; NR, not reported; UCMSC, umbilical cord mesenchymal stem cells; UCB, umbilical cord blood; hDMSC, decidual derived mesenchymal stem cells; GHTA, gestational hypertension; Lbs, pounds; HELLP, Hemolysis, elevated Liver enzymes and Low Platelets; HTA, hypertension; GDM, gestational diabetes mellitus; CVS, chorionic villus sampling.
Disease severity was reported in 70/229 publications. Details regarding PE definitions and the diagnostic criteria used in the original articles are presented in Supplementary Tables S2, S3. qRT-PCR as the detection method with U6 as an internal control was utilized in almost all studies, and the details regarding quantification methods and housekeeping genes used are presented in Supplementary Table S4. A list of all explored miRNAs from the included publications according to PE severity (more severe, less severe, and not-specified PE) is presented in Supplementary Tables S5–S7.
Meta-Analysis
A meta-analysis was performed for the following fourteen miRNAs: miRNA-16, miRNA-17, miRNA-17-5p, miRNA-20b, miRNA-23a, miRNA-29a-3p, miRNA-29b, miRNA-30a-3p, miRNA-155, miRNA-155-5p, miRNA-181a, miRNA-195, miRNA-210, and miRNA-376c.
The expression levels were significantly higher in the placentas of women with PE compared to women without PE for miRNA-16 (SMD = 1.51, 95%CI = 0.55–2.46, p = 0.002) (Figure 2), miRNA-20b (SMD = 0.89, 95%CI = 0.33–1.45, p = 0.002) (Figure 3), miRNA-23a (SMD = 2.02, 95%CI = 1.25–2.78, p < 0.001) (Figure 4), miRNA-29b (SMD = 1.37, 95%CI = 0.36–2.37, p = 0.008) (Figure 5), miRNA-155 (SMD = 2.99, 95%CI = 0.83–5.14, p = 0.007) (Figure 6) and miRNA-210 (SMD = 1.63, 95%CI = 0.69–2.58, p < 0.001) (Figure 7). Subgroup analysis showed increased levels of miRNA-210 expression in placentas of women with more severe (SMD = 2.01, 95%CI = 0.31–3.71, p = 0.020), but not in women with a less severe form of PE (SMD = 0.39, 95%CI = –8.14 = 8.92, p = 0.930), compared to women without PE (Figure 7). The expression levels in placenta were significantly lower in women with PE compared to women without PE for miRNA-376c (SMD = –4.86, 95%CI = –9.51 to –0.20, p = 0.040) (Figure 8).
FIGURE 2.
Meta-analysis of differences in expression level of miRNA-16 in placenta between women with vs. without preeclampsia.
FIGURE 3.
Meta-analysis of differences in expression level of miRNA-20b in placenta between women with vs. without preeclampsia.
FIGURE 4.
Meta-analysis of differences in expression level of miRNA-23a in placenta between women with vs. without preeclampsia.
FIGURE 5.
Meta-analysis of differences in expression level of miRNA-29b in placenta between women with vs. without preeclampsia.
FIGURE 6.
Meta-analysis of differences in expression level of miRNA-155 in placenta between women with vs. without preeclampsia.
FIGURE 7.
Meta-analysis of differences in expression level of miRNA-210 in placenta between women with vs. without preeclampsia.
FIGURE 8.
Meta-analysis of differences in expression level of miRNA-376c in placenta between women with vs. without preeclampsia.
The expression level was significantly higher in the maternal peripheral blood of women with PE compared to women without PE for miRNA-155 (SMD = 2.06, 95CI = 0.35–3.76, p = 0.020) (Figure 9), but it was lower for miRNA-16 (SMD = –0.47, 95%CI = –0.91 to –0.03, p = 0.040) (Figure 10).
FIGURE 9.
Meta-analysis of differences in expression level of miRNA-155 in peripheral blood between women with vs. without preeclampsia.
FIGURE 10.
Meta-analysis of differences in expression level of miRNA-16 in peripheral blood between women with vs. without preeclampsia.
The functional roles of all significant miRNAs are presented in detail in Table 2. Although the roles of the evaluated miRNAs are confusing, special emphasis should be placed on the interpretation of the miRNAs known roles in controlling trophoblast proliferation, migration, invasion, apoptosis, differentiation, cellular metabolism, and angiogenesis.
TABLE 2.
Functional roles of significant miRNAs.
Placental expression levels were not significantly different in women with PE compared to women without PE for miRNA-17 (SMD = 0.22, 95%CI = -1.35 to –1.79, p = 0.790) (Supplementary Figure S1), miRNA-30a-3p (SMD = 1.00, 95%CI = –0.50–2.50, p = 0.190) (Supplementary Figure S2), miRNA-181a (SMD = 0.05, 95%CI = –0.99–1.08, p = 0.930) (Supplementary Figure S3), and miRNA-195 (SMD = –0.16, 95%CI = –1.35–1.02, p = 0.780) (Supplementary Figure S4). The expression level was not significantly different in maternal peripheral blood in women with PE compared to women without PE for miRNA-17-5p (SMD = 0.08, 95%CI = –0.74–0.90, p = 0.850) (Supplementary Figure S5), miRNA-29a-3p (SMD = –0.29, 95%CI = –1.22–0.64, p = 0.540) (Supplementary Figure S6), miRNA-155-5p (SMD = –0.37, 95%CI = –1.07–0.33, p = 0.300) (Supplementary Figure S7), miRNA-181a (SMD = 0.22, 95%CI = –0.42–0.86, p = 0.500) (Supplementary Figure S8), and miRNA-210 (SMD = 0.48, 95%CI = –0.66–1.62, p = 0.410) (Supplementary Figure S9).
The same results were obtained when sensitivity analyses were performed to exclude studies with unspecified types of PE, to replace expression data obtained from the chorionic plate with those obtained from the basal plate, including/excluding different forms (more/less severe) of PE where possible (Supplementary Figures S10–S22).
Discussion
We identified in this study seven differentially expressed miRNAs in the placentas of women with vs without PE. miRNA-16, miRNA-20b, miRNA-23a, miRNA-29b, miRNA-155, and miRNA-210 were significantly increased in the placentas of PE women, while the levels of miRNA-376c were significantly decreased in PE placentas. We found no differences in the expression levels of miRNA-17, miRNA-30a-3p, miRNA-181a, and miRNA-195 in placentas of PE vs. non-PE women. A meta-analysis of the miRNA expression levels in the peripheral blood of PE women compared to women without PE was performed for miRNA-16, miRNA-17-5p, miRNA-29a-3p, miRNA-155, miRNA-155-5p, miRNA-181a and miRNA-210. A significant decrease in miRNA-16 expression levels in maternal peripheral blood of PE women was found, and no differences were found for other evaluated miRNAs. A sensitivity analysis did not change the results of the primary analysis.
Placentation is thought to be the basis for normal physiological pregnancy and is required for fetal growth and development, as well as the expectation of term labor. Several sensitive, precisely dictated, vascular processes involving angiogenesis at the fetal-maternal interface and adequate cytotrophoblast invasion with spiral-artery remodeling are essential for placentation (Weedon-Fekjær et al., 2014). At the very beginning of a pregnancy in which PE will develop, the transformation of proliferative endothelium into invasive endothelium is absent, and the expected extensive invasion of cytotrophoblasts into the spiral arteries does not occur. This results in pathologic remodeling of the placental arterioles, which become narrow, with reduced flow and sclerotic changes in the arteriolar walls (Mouillet et al., 2015). Placental ischemia promotes an inflammatory state that is characterized by increased production of inflammatory cytokines by pro-inflammatory T cells, and a decrease in regulatory and anti-inflammatory cytokines (Hanna et al., 2000). Decreased levels of anti-inflammatory cytokines (IL-10, IL-4) and increased pro-inflammatory cytokines (TNF-α, IL-6) in the circulation and placental tissue support the inflammatory background of preeclampsia (Keiser et al., 2009; Spence et al., 2021). These processes lead to placental malnutrition, and subsequent development of PE. The placenta is known to be an organ in which a large number of miRNAs are expressed (Mouillet et al., 2015). Several miRNAs contribute to the processes of trophoblast proliferation, invasion, and differentiation. miRNA-125b-1-3p and miRNA-210 inhibit trophoblast proliferation and invasion, while miRNA-155 inhibits trophoblast invasion only. In contrast, miRNA-376c enhances trophoblast proliferation and invasion (Mouillet et al., 2015). Fu et al. demonstrated that miR-376c promotes trophoblast cell proliferation, survival, migration, and invasion, and postulated that inhibition of Nodal and TGF-β signaling by miR-376c is important for adequate placentation (Fu et al., 2013). Primate-specific C19MC miRNAs, which are almost exclusively expressed in placenta, were described as important factors influencing adequate trophoblast invasion and arterial remodeling (Hromadnikova et al., 2013; Mouillet et al., 2015). As knowledge of the functional importance of miRNAs in adequate placentation and the development of PE increases (Hayder et al., 2018), it becomes important to determine whether miRNA expression levels are disrupted in PE, and which specific miRNA contributes predominantly to disease pathogenesis.
Meta-analysis in this study revealed significantly higher miRNA-16 expression in the placentas of women with PE compared to those without PE. Confirmation of the possible association between altered expression of miRNA-16 and PE was first described by Hu et al. who showed that there is increased expression of miRNA-16 in the placentas of women with severe PE (Hu et al., 2009). This was followed by Vu et al. who found increased expression of miRNA-16 in the sera of women with PE compared with healthy controls (Wu et al., 2012). The pathologic significance of miRNA-16 lies in its function in regulating the cell cycle. Liu et al. have shown that miRNA-16 stops the cell cycle in G1 phase by regulating the expressions of the CCND3, CCNE1 and CDK6 genes. Based on these physiological roles, it is supposed that miRNA-16 acts as a tumor suppressor (Yan X. et al., 2013). It also is known that the target of miRNA-16 is the Vascular Endothelial Growth Factor (VEGF) gene, whose product is an extremely important protein that initiates vasculogenesis in the placenta and induces proliferation and migration of endothelial cells in blood vessels (Wang and Zhao, 2010). In a study by Wang et al., miRNA-16 was found to have the potential to inhibit proliferation, migration and angiogenesis in mesenchymal stem cells (Wang Y. et al., 2012). The significantly lower miRNA-16 expression levels in the maternal peripheral blood of women with PE compared to those without PE led epigenetic analysis in another direction. It is proposed, but not proven, that miRNA-16 plays a significant role in the progression of human cardiac cell injury in ischemic dilated cardiomyopathy through endoplasmic reticulum stress, inflammation, autophagy, and apoptosis (Calderon-Dominguez et al., 2021). Down regulation of this miRNA, known as an anti-apoptotic factor, also was registered in ischemic myocardial cells, as a reaction to hypoxia in order to protect the tissue (Zhang H. J. et al., 2019). Therefore, miRNA-16 may play a role in both ischemic cardiomyopathy and preeclampsia, which similarly represent hypoxia induced pathological states. Original research articles have reported differing results regarding miRNA-16 levels in pregnancy complications. miRNA-16 levels were elevated in fetal macrosomia, but decreased in severe preeclampsia (Wu et al., 2012; Ge et al., 2015).
Increased expressions of miRNA-20b and miRNA-29b in the placentas of women with PE compared to women without PE were also found in our study. It is well known that the target gene for both miRNA-20 and miRNA-16 is VEGF, thus affecting placental vasculogenesis (Hayder et al., 2018). miRNA-20b binds to the Ephrin Type-B Receptor 4 (EPHB4) and Ephrin Type-B Receptor 2 (EPHB2), important receptors for intercellular communication, which have functions in the regulation of cellular morphology, binding, migration, proliferation, differentiation, and survival. These processes are assumed to be involved in the miRNA-20b contribution to placental blood vessel remodeling (Pasquale, 2005; Lisabeth et al., 2013). miRNA-29b is involved in the processes of trophoblast proliferation and invasion (Harapan and Andalas, 2015). miRNA-29b contributes to preeclampsia through dysregulation of the extracellular signal-regulated protein kinase and focal adhesion kinase (ERK/FAK) signaling pathway that allows the expression of matrix metalloproteinase-2 (MMP2), which is in turn an important factor for migration and invasion of trophoblast cells. Increased expression of miRNA-29b in severe PE has been previously shown to be associated with reduced expressions of MMP2 and integrin β1(ITGβ1) (Li H. et al., 2013).
The increased miRNA-23a levels in PE placentas support previously reported results that the level of this miRNA is upregulated in conditions related to abnormal angiogenesis (Chhabra et al., 2010). The main role of miRNA-23a, as part of the miR-23a∼27a∼24–2 cluster, is to mediate blood vessel genesis. It is included, except in PE, in pathological states such as muscle atrophy, cardiac hypertrophy, and cancers (Chhabra et al., 2010). Data in vitro, as well as in vivo, indicate that miRNA-23a and miR-23b may have opposite roles, with the former regulating angiogenesis and cellular junctions, and hence inhibiting vascular permeability, while miRNA-23b promotes permeability (Li et al., 2016).
MiRNA-155 expression levels were significantly increased in the placentas and maternal peripheral blood of women with PE compared to those without PE. The increased expression of miRNA-155 and resultant lower levels of cysteine-rich protein 61 (CYR61) and cyclin D1, have been associated with the inhibition of trophoblast invasion (Zhang et al., 2010; Dai et al., 2012). It also has been previously demonstrated that a significant increase in miRNA-155 decreases endothelial nitric oxide synthase (eNOS) expression and thus contributes to development of severe PE (Li X. et al., 2014). This result is consistent with findings from previous studies (Zhang et al., 2010; Gan et al., 2017). This immunomodulatory miRNA, induced in activated T lymphocytes, B lymphocytes and macrophages (Bernstein et al., 2003), is also disrupted in maternal peripheral blood. Its increased expression level was associated with a decreased level of pro-angiogenic factor, VEGF, in an experimental rat model of PE (Cheng et al., 2011). Newly performed studies have reported significantly higher levels of miRNA-155 in the maternal peripheral blood of women with compared to women without PE (Ayoub et al., 2019; Youssef and Marei, 2019; Witvrouwen et al., 2021).
MiRNA-210 has been the most evaluated small non-coding RNA. It is known that miRNA-210 is induced under hypoxic conditions which exist prior to, as well as during the clinical manifestations of PE. Hypoxia stimulates the production of NF-kB 1 (nuclear factor kappa-B 1) and HIF-1A (hypoxia inducible factor 1 α), which induce the expression of miRNA-210 (Muralimanoharan et al., 2012). Previous research has confirmed significantly increased expression of miRNA-210 in both the placentas and sera of women with PE and suggests that miRNA-210 obtained from serum may be a useful biomarker even months before diagnosis (Anton et al., 2013). Micro RNA-210 plays a role in several processes, such as inhibition of cytotrophoblast migration and invasion, differentiation, apoptosis, inflammation, angiogenesis, as well as in the regulation of cellular metabolism. miRNA-210 partially inhibits trophoblast invasion via the ERK/MAPK signaling pathway (Anton et al., 2012). Cell metabolism is dictated by miRNA-210 in that increased expression leads to decreased mitochondrial respiration and vice versa (Hayder et al., 2018). miRNA-210 also plays a role as a suppressor of EFNA3, a member of the ephrin ligand family which is important for cell migration, and HOXA9, an important angiogenesis regulator (Zhang et al., 2012; Luo et al., 2014). Overall, inadequate trophoblast invasion and impaired cellular metabolism are confirmed factors that can lead to the development of PE. Anton et al. found that for each 5-U increase in miR-210 in sera of previously healthy women at the beginning of the second trimester, the odds of PE development later in pregnancy increased fourfold (Anton et al., 2013).
MiRNA-376c plays a role in trophoblast proliferation and differentiation (Hayder et al., 2018). We found significantly lower levels of expression in the placentas of women with PE compared to women without PE, which is consistent with the findings of other studies (Fu et al., 2013; Yang H.-l. et al., 2019). Only Yang et al. showed no significant difference in the levels of miRNA-376c expression in the placentas of women with preterm preeclampsia and gestational age matched controls without PE (Yang H.-l. et al., 2019). Fu at al. showed that a decrease in miR-376c expression results in excessive apoptosis, insufficient cell proliferation, and shallow invasion of trophoblasts in the uterus in preeclampsia (Fu et al., 2013).
In summary, our results clearly identify a subset of miRNAs that are dysregulated in preeclampsia and clearly point towards the underlying mechanisms that may be contributing to the pathophysiology of preeclampsia. Our results set the stage for several venues for future research with an overall goal to facilitate early diagnosis and optimize fetal and maternal outcomes. First, given the clinical heterogeneity of preeclampsia (severe vs. mild, late vs. early, and “placental” vs. “maternal”), adequately designed and powered studies may detect differences in miRNA and related specific underlying mechanisms responsible for specific clinical subtypes. Second, clinical studies may identify a marker (or set of markers) with either predictive or diagnostic role. Third, further discovery of signaling pathways affected by miRNA may lead to mechanism-based therapies.
Our study has several limitations. They originate from the unavailability of all/some data from the original publications, uninformative figures presented in the articles, and selection of the housekeeping gene used for internal controls. The consequences of the data unavailability are possible exclusion of relevant data and a smaller number of included studies, as well as miRNAs, in the meta-analysis that may lead to an overestimation/underestimation of the effects of miRNA expression level on PE development. The importance of adequate selection of the housekeeping gene should be emphasized to standardize miRNA evaluation methodology and to provide comparability between studies. The definition of PE is not the same in each of the included studies which may lead to inclusion of heterogeneous cases that can change the assessment of the effect. Through the systematic review, it was realized that cases and controls were rarely matched for gestational age at the time of sampling. It is necessary to highlight the importance of comparing matched groups because it is known that there are physiological changes in miRNAs expression levels throughout pregnancy. The miRNA source in plasma may be maternal, fetal, or both, yet only a small number of studies reported these data.
Conclusion
MiRNAs play an important role in the pathophysiology of PE. The functional roles of the microRNAs found to be disrupted in preeclamptic pregnancies include control of trophoblast proliferation, migration, invasion, apoptosis, differentiation, cellular metabolism, and angiogenesis. The identification of differentially expressed miRNAs in maternal blood creates an opportunity to define an easily accessible biomarker of PE. A better understanding of the role of microRNAs in the development of PE offers great potential for developing diagnostic and therapeutic targets for PE.
Data Availability Statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.
Author Contributions
Conceptualization: AC, VG, ZM, DS, NM; Data curation: AC, JM, MS, NR, JK, NA, TS, VP, DS, NM; Formal analysis: AC, JM, MS, NR, DS, NM; Investigation: AC, VG, JM, OM, MS, NR, JK, NA, NM, TS, VP, DS, NM; Methodology: AC, VG, JM, DS, NM; Project administration: VG, DS, NM; Supervision: VG, DS, NM; Visualization: AC, JM, MS, DS, NM; Writing – original draft: AC, VG, JM, OM, MS, NR, NA, TS, JK, VP, DS, NM; Writing – review & editing: AC, VG, JM, OM, MS, NR, NA, NM, TS, JK, VP, DS, NM. All authors read and approved the final manuscript.
Funding
Funding: NIH R01-HL136348 (VG).
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.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fbioe.2021.782845/full#supplementary-material
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