Abstract

Background: Endocan, a novel protein involved in inflammation and endothelial dysfunction, has been suggested to be related to preeclampsia, although the results of previous studies were not consistent. The aim of the study was to evaluate the potential difference of circulating endocan in women with preeclampsia and those with normal pregnancy.

Methods: Matched case–control studies evaluating the difference of circulating endocan between women with preeclampsia and those with normal pregnancy were identified via systematic search of PubMed and Embase databases. A random-effect model or a fixed-effect model was used to pool the results according to the heterogeneity. Subgroup analysis was performed to evaluate whether the timing of preeclampsia onset affected the outcome.

Results: Overall, eight matched case–control studies, including 451 women with preeclampsia and 442 women with normal pregnancy were included. Significant heterogeneity was detected among the included studies (P for Cochrane’s Q test = 0.006, I2 = 65%). Meta-analysis with a random-effect model showed that women with preeclampsia had significantly higher circulating level of endocan compared with women with normal pregnancy (standardized mean difference = 0.37, 95% confidence interval: 0.13–0.62, P = 0.003). Subsequent subgroup analyses showed that the difference of circulating endocan between women with early onset preeclampsia and those with normal pregnancy was not statistically different from that between women with late-onset preeclampsia and those with normal pregnancy (P for subgroup difference = 0.81).

Conclusions: Women with preeclampsia have higher circulating endocan than those with normal pregnancy.

Introduction

Preeclampsia refers to a severe complication during pregnancy that is characterized of hypertension and proteinuria after 20 weeks of gestation in pregnant women with no evidence of previous hypertension [1–3]. Women with preeclampsia are at higher risk for the development of cardiovascular diseases during pregnancy and after delivery [4–6]. Moreover, preeclampsia has been identified as a risk factor of maternal and perinatal morbidity and mortality worldwide [1]. However, effective treatments for preeclampsia remain limited, and the only cure for preeclampsia may be premature delivery when it occurs [3]. In addition, since some prophylactic measures such as aspirin [7] have been proved to be effective to reduce the incidence preeclampsia if it is administered early (e.g. within 16 weeks of gestation), it is important for the early recognition of women who are at higher risk to develop preeclampsia during pregnancy [8,9].

The pathogenesis of preeclampsia is multifactorial [3]. According to previous studies, endothelial dysfunction and systematic inflammatory response are among the main pathophysiological mechanisms for preeclampsia [10–12]. Endocan, also known as endothelial cell-specific molecule 1 (ESM-1), is a circulation-detectable soluble dermatan sulfate proteoglycan that is secreted by vascular endothelial cells of many tissue, including placenta [13]. Accumulating studies suggest that endocan has been involved in angiogenesis, endothelial dysfunction, and inflammation, and accordingly, changes of circulating endocan has been observed in patients with cardiovascular diseases, including hypertension [14–16]. A recent study in a rat model of connective tissue disease related pulmonary arterial hypertension (CTD-PAH) showed that knockdown of endocan attenuated the severity of PAH and related cardiac dysfunction, accompanied with the inhibition of tumor necrosis factor-α (TNF-α) signaling pathways [17]. These results suggest that endocan may be a functional protein rather than a simple biomarker. Interestingly, it has also been suggested that change of circulating endocan may be a marker of women with preeclampsia [18–25]. However, results of previous pilot studies are inconsistent [18–25]. Some studies showed that circulating endocan may be higher in women with preeclampsia than those with normal pregnancy [18,20,22,24], while others did not find a significant difference regarding the circulating endocan between pregnant women with and without preeclampsia [19,21,23,25]. Since the sample sizes of these studies are generally small, some studies may be statistically underpowered to detect a significant difference of circulating endocan between women with preeclampsia and those with normal pregnancy. Therefore, in the present study, we performed a meta-analysis to synthesize the results of the previous studies in order to systematically evaluate the potential difference of circulating endocan in women with and without preeclampsia. Moreover, since it has been demonstrated that women with early- and late-onset preeclampsia may have different risk factors and outcomes [26], we also performed subgroup analyses to evaluate whether circulating endocan was changed in both the early- and late-onset preeclampsia compared with that in women with normal pregnancy.

Methods

Literature search

We followed the instructions of Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines [27] and the Cochrane’s Handbook for Systematic Review [28] throughout the design, implementation, analysis, and reporting for the present study. The electronic databases of PubMed and Embase were searched for relevant records, using the terms of ‘endocan’ OR ‘endothelial cell-specific molecule 1’ OR ‘ESM-1’, combined with ‘preeclampsia’ OR ‘pre-eclampsia’ OR ‘eclampsia’ OR ‘pregnancy-induced hypertension’ OR ‘PIH’ OR ‘toxemia’ OR ‘edema-proteinuria-hypertension gestos’ OR ‘EPH’. The search was limited to human studies published in English or Chinese. We also analyzed the reference lists of original and review articles using a manual approach. The final literature search was performed on June 25, 2019.

Study selection

Studies were included for analysis if they met the following criteria: (1) published as full-length article; (2) included cases of women with preeclampsia and controls of women with normal pregnancy, at least matched for gestational age (GA); (3) serum or plasma level of endocan was measured in women with preeclampsia and women with normal pregnancy at the diagnosis of preeclampsia; and (4) reported circulating levels of endocan in cases and controls as means and standard deviations (SDs) or these data could be estimated. The diagnosis of preeclampsia was consistent with the American College of Obstetricians and Gynecologists criteria [29], which was classified as new onset (after 20 weeks of gestation) elevated systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg and proteinuria (≥ 300 mg of protein in a 24-h urine collection); or as hypertension plus one of the following: (1) thrombocytopenia (platelet count <100,000 per microliter), (2) impaired liver function (twice the normal concentration of liver transaminases), (3) new renal insufficiency (>1.1 mg/dl or doubling of serum creatinine), (4) pulmonary edema and (5) new-onset cerebral or visual disturbances. Reviews, editorials, abstracts, preclinical studies or repeated reports of the same studies were excluded.

Data extraction and quality assessment

Two authors performed the literature search, data extraction and quality assessment independently according to the inclusion criteria. Discrepancies were resolved by consensus. For each included study, data on first author’s name, year of publication, country of the study, maternal age, numbers of cases and controls, GA of blood sampling, and methods for endocan measurements were extracted. The study quality evaluation was performed according to the Newcastle–Ottawa Scale (NOS) [30], which varies from 1 to 9 stars, and 9 stars indicate the high quality of the study. This scale judges each study on three broad categories, including selection of the study groups; the comparability of the groups; and the ascertainment of the outcome of interest; 9 stars.

Statistical analyses

Because different methods were used for the measurement of endocan in the included studies, and the values of endocan varied significantly (more than 10 folds) among these studies, standardized mean differences (SMD) with 95% confidence intervals (CI) were chosen as the measurement of difference for the circulating endocan in women with preeclampsia and in women with normal pregnancy as indicated by the Cochrane’s Handbook [28]. Inter-study heterogeneity was formally tested using Cochrane’s test, and significant heterogeneity was considered existing if P value was <0.10 [31]. The I2 statistic was also calculated, and a value of I2 > 50% indicated significant heterogeneity [32]. A random-effect model was applied to combine the data if significant heterogeneity was detected; otherwise, a fixed-effect model was used. Sensitivity analysis by omitting one study at a time was performed to evaluate the stability of the outcome [28]. Stratified analyses was performed to evaluate whether women with early- and late-onset preeclampsia both had higher circulating endocan compared with women with normal pregnancy. Predefined subgroup analyses were also performed to evaluate the influences of other study characteristics on the outcome, including study location, maternal age, sample size, type of blood sample, and NOS. Early-onset preeclampsia was defined as preeclampsia occurred at ≤33 weeks of gestation, while those occurred after 33 weeks of gestation was defined as late-onset preeclampsia [33]. The medians of continuous variables were chosen as the cutoff values for stratification. Potential publication bias was estimated by the visual inspection for the symmetry of the funnel plots complemented with the Egger’s regression test [34]. The statistical analysis was performed with RevMan software (Version 5.3; Cochrane Collaboration, Oxford, U.K.) and Stata software (version 12.0; Stata Corporation, College Station, TX, U.S.A.).

Results

Literature search results

The study selection process was shown in Figure 1. Overall, 103 citations were identified through initial database searching, of which 91 were excluded mainly because they were not relevant to the purpose of the study. The remaining 12 studies underwent full-text review, and eight studies were finally included [18–25]. The other four studies were excluded because circulating endocan was not measured in one study, two studies were repeated reports of the included studies, and another one was a conference abstract of an included study.

Flowchart of database search

Figure 1
Flowchart of database search
Figure 1
Flowchart of database search

Study characteristics

Three inconsistencies regarding data extraction and one inconsistency in quality evaluation occurred, and the consensus was achieved via reviewing the literature by the two authors together. The characteristics of included studies are shown in Table 1. All of the included studies were matched case–control studies published after 2015. The sample size of the included studies varied from 22 to 232. The mean maternal ages of the women varied from 24 to 31 years. In five studies, serum endocan was measured [19,21–23,25]; while for the remaining three studies, plasma endocan was measured [18,20,24]. For all the studies, an enzyme-linked immunosorbent assay (ELISA) was used to measure circulating endocan except for one study, of which a Milliplex Assay was applied [20]. The NOS of the included studies ranged between 7 and 8 stars.

Table 1
Characteristics of the included studies
Author Country Study design Maternal age Diagnosis of PE No. of PE No. of Control GA at sampling Endocan sample Methods for endocan measurement NOS 
   Years    Weeks    
Yuksel 2015 Turkey Matched CC 30.5 ACOG 49 32 At diagnosis (mean: 32) Serum ELISA 
Hentschke 2015 Brazil Matched CC 26 ACOG 50 67 At diagnosis (28–36) Plasma Milliplex assay 
Chang 2015 China Matched CC 29.9 ACOG 12 10 At diagnosis Serum ELISA 
Adekola 2015 US Matched CC 24.3 ACOG 102 130 At diagnosis Plasma ELISA 
Cakmak 2016 Turkey Matched CC 28.3 ACOG 99 30 At diagnosis (mean: 34) Serum ELISA 
Wang 2017 China Matched CC 29.7 ACOG 41 43 At diagnosis Serum ELISA 
Schuitemaker 2018 the Netherlands Matched CC 28.1 ACOG 38 51 At diagnosis (30–36) Plasma ELISA 
Gozdziewicz 2019 Poland Matched CC 31 ACOG 60 59 At diagnosis (30–38) Serum ELISA 
Author Country Study design Maternal age Diagnosis of PE No. of PE No. of Control GA at sampling Endocan sample Methods for endocan measurement NOS 
   Years    Weeks    
Yuksel 2015 Turkey Matched CC 30.5 ACOG 49 32 At diagnosis (mean: 32) Serum ELISA 
Hentschke 2015 Brazil Matched CC 26 ACOG 50 67 At diagnosis (28–36) Plasma Milliplex assay 
Chang 2015 China Matched CC 29.9 ACOG 12 10 At diagnosis Serum ELISA 
Adekola 2015 US Matched CC 24.3 ACOG 102 130 At diagnosis Plasma ELISA 
Cakmak 2016 Turkey Matched CC 28.3 ACOG 99 30 At diagnosis (mean: 34) Serum ELISA 
Wang 2017 China Matched CC 29.7 ACOG 41 43 At diagnosis Serum ELISA 
Schuitemaker 2018 the Netherlands Matched CC 28.1 ACOG 38 51 At diagnosis (30–36) Plasma ELISA 
Gozdziewicz 2019 Poland Matched CC 31 ACOG 60 59 At diagnosis (30–38) Serum ELISA 

Abbreviations: ACOG, American College of Obstetricians and Gynecologists; CC, case–control; ELISA, enzyme-linked immunosorbent assay; GA, gestational age; NOS, the Newcastle–Ottawa Scale; PE, preeclampsia.

Circulating endocan in women with preeclampsia: main study and subgroup analyses

Overall, our meta-analysis included 451 women with preeclampsia and 442 women with normal pregnancy from eight case–control studies [18–25]. The heterogeneity among the included studies was significant (P for Cochrane’s Q test = 0.006, I2 = 65%). Results of meta-analysis with a random-effect model showed that women with preeclampsia had significantly higher circulating level of endocan compared with women with normal pregnancy (SMD = 0.37, 95% CI: 0.13–0.62, P = 0.003; Figure 2A). Sensitivity analyses by omitting data from one comparison at a time did not significantly change the results (SMD = 0.26–0.41, P < 0.05), indicating that the result of the meta-analysis was stable. Stratified analyses showed that circulating endocan was significantly higher in women with late-onset preeclampsia than those with normal pregnancy (P = 0.04) but the difference became insignificant when comparing between women with early-onset preeclampsia and normal controls (P = 0.12; Figure 2B). However, the difference between the subgroup was not significant (P = 0.81). Subsequent subgroup analyses showed that study characteristics such as study locations, sample sizes, types of blood samples, or NOS did not significantly affect the results (P for subgroup analyses all > 0.05; Table 2), while maternal age may significantly affect the outcome (P for subgroup analysis = 0.02). It seemed that the difference of circulating endocan between women with preeclampsia and normal pregnancy was mainly driven by studies with maternal age ≤ 29 years, but not for those with maternal age > 29 years (Table 2).

Forest plots for the meta-analysis

Figure 2
Forest plots for the meta-analysis

Forest plots for the meta-analysis comparing circulating endocan between women with preeclampsia and those with normal pregnancy; (A) main analyses; and (B) stratified analyses by the timing of preeclampsia onset; PE, preeclampsia. For each figure, mean and SD indicate the mean values and SD of circulating endocan (μg/ml) in women from each group, and total indicate the total number of women in each group.

Figure 2
Forest plots for the meta-analysis

Forest plots for the meta-analysis comparing circulating endocan between women with preeclampsia and those with normal pregnancy; (A) main analyses; and (B) stratified analyses by the timing of preeclampsia onset; PE, preeclampsia. For each figure, mean and SD indicate the mean values and SD of circulating endocan (μg/ml) in women from each group, and total indicate the total number of women in each group.

Table 2
Subgroup analyses for the difference between endocan between PE and normal pregnant women
Characteristics Dataset number SMD (95% CI) of pentraxin-3 P for subgroup effect I2 P for subgroup difference 
Study countries 
 Others 0.41 [0.11, 0.70] 0.007 73%  
 China 0.19 [-0.19, 0.58] 0.32 0% 0.39 
Mean maternal age (years) 
 ≤29 0.58 [0.22, 0.93] 0.001 73%  
 >29 0.09 [-0.13, 0.32] 0.42 0% 0.02 
Sample size 
 >100 0.42 [-0.06, 0.90] 0.09 72%  
 ≤100 0.34 [0.04, 0.63] 0.03 65% 0.77 
Blood sample 
 Plasma 0.65 [0.16, 1.13] 0.009 82%  
 Serum 0.16 [-0.03, 0.36] 0.11 0% 0.07 
NOS 
 7 0.22 [0.01, 0.44] 0.04 0%  
 8 0.45 [0.07, 0.83] 0.02 77% 0.30 
Characteristics Dataset number SMD (95% CI) of pentraxin-3 P for subgroup effect I2 P for subgroup difference 
Study countries 
 Others 0.41 [0.11, 0.70] 0.007 73%  
 China 0.19 [-0.19, 0.58] 0.32 0% 0.39 
Mean maternal age (years) 
 ≤29 0.58 [0.22, 0.93] 0.001 73%  
 >29 0.09 [-0.13, 0.32] 0.42 0% 0.02 
Sample size 
 >100 0.42 [-0.06, 0.90] 0.09 72%  
 ≤100 0.34 [0.04, 0.63] 0.03 65% 0.77 
Blood sample 
 Plasma 0.65 [0.16, 1.13] 0.009 82%  
 Serum 0.16 [-0.03, 0.36] 0.11 0% 0.07 
NOS 
 7 0.22 [0.01, 0.44] 0.04 0%  
 8 0.45 [0.07, 0.83] 0.02 77% 0.30 

Abbreviations: CI, confidence interval; NOS, the Newcastle–Ottawa Scale; PE, preeclampsia; SMD, standard mean difference.

Publication bias

The funnel plot was symmetrical on visual inspection, indicating low risk of publication bias (Figure 3). The result of Egger’s regression test also indicated no significant publication bias (P = 0.419).

Funnel plots for the meta-analysis

Figure 3
Funnel plots for the meta-analysis

Funnel plots for the meta-analysis comparing circulating endocan between women with preeclampsia and those with normal pregnancy. Each box in the figure indicates an included study of the meta-analysis, and the plots were constructed by the effect size for each study (SMD) and its standard error (SE). The plots were symmetrical on visual inspection, suggesting low risk of publication bias for this meta-analysis.

Figure 3
Funnel plots for the meta-analysis

Funnel plots for the meta-analysis comparing circulating endocan between women with preeclampsia and those with normal pregnancy. Each box in the figure indicates an included study of the meta-analysis, and the plots were constructed by the effect size for each study (SMD) and its standard error (SE). The plots were symmetrical on visual inspection, suggesting low risk of publication bias for this meta-analysis.

Discussion

In this meta-analysis, we found that women with preeclampsia have higher circulating endocan compared with women who are matched for gestational age with normal pregnancy. Subsequent analyses showed that study characteristics including the timing of study locations, sample sizes, types of blood samples, or study quality score did not significantly affect the outcome, while mean maternal age may have significant influence on the outcome. Stratified analyses showed that circulating endocan was significantly higher in women with late-onset preeclampsia than those with normal pregnancy, but the difference became insignificant when comparing between women with early-onset preeclampsia and normal controls. Moreover, results showed that the difference of circulating endocan between women with preeclampsia and normal pregnancy was mainly driven by studies including younger women (≤29 years), but not for those including older women (>29 years). Taken together, these results demonstrated that circulating endocan is higher in women with preeclampsia as compared with women with normal pregnancy. Future studies are needed to determine whether endocan was involved in the pathogenesis and progression or preeclampsia.

To the best of our knowledge, our meta-analysis is the first study to evaluate the potential difference of circulating endocan in women with preeclampsia and in women with normal pregnancy. We included matched case–control studies and the pooled results demonstrated that women with preeclampsia have higher circulating endocan than those with normal pregnancy. The robustness of the finding was further confirmed by the results of sensitivity and subgroup analyses, which showed that the outcome was not significantly affected by any single included study or study characteristics including study locations, sample sizes, types of blood samples, or study quality score. However, it remains undetermined whether up-regulated circulating endocan plays a role in the pathogenesis of preeclampsia. The initial pathophysiological change in preeclampsia is the impaired trophoblast invasion of the maternal spiral arteries [35]. The above change causes placental hypoxia, which further enhanced the overproduction and release of placenta derived anti-angiogenic and inflammatory factors, thereby contributing to the systematic manifestation of preeclampsia [3]. Endocan is an indicator of endothelial function, which is produced and secreted human endothelial cells of many organs [36]. Previous studies showed that endocan may participate in many processes related with endothelium, including cell adhesion, angiogenesis, inflammation and endothelial dysfunction [36], which have all been confirmed to be involved in the pathogenesis of preeclampsia [37–39]. Moreover, it has been shown that the endocan protein in placenta tissue is significantly up-regulated in women with preeclampsia [15,19], which also highlights the potential role of endocan in the pathogenesis of preeclampsia. To the best of our knowledge, no experimental studies have been performed to investigate the function of endocan in the pathogenesis of preeclampsia. Since it has been shown that knockdown of endocan attenuate the PAH related changes in a rat model of CTD-PAH via inhibition of TNF-α related inflammation pathways [17], it could be hypothesized that endocan may participate in the pathogenesis of preeclampsia via enhancing inflammation related endothelial dysfunction. Future studies are needed to determine the molecular pathways through that endocan may mediate the pathogenesis of preeclampsia.

Previous studies indicated that women with early-onset and late-onset preeclampsia may have different profiles of risk factors as well as different clinical outcomes [26]. A previous study showed that angiogenic factors are detectable before and at the time of clinical diagnosis of early-onset preeclampsia, whereas alterations were observed only at the time of diagnosis in women with late-onset preeclampsia [40]. Our stratified analyses showed that circulating endocan was significantly higher in women with late-onset preeclampsia than those with normal pregnancy, but the difference became insignificant when comparing between women with early-onset preeclampsia and normal controls, suggesting that timing of preeclampsia onset may affect the difference of circulating endocan between women with preeclampsia and normal pregnancies. Moreover, our subgroup analyses indicated that the difference of circulating endocan between women with preeclampsia and normal pregnancy was mainly driven by studies including younger women. This should be interpreted with caution since the variations for the age group in the included studies are limited, and the number of the included studies for each subgroup is relatively small.

Our study has some limitations which should be considered when interpreting the results. First, moderate heterogeneity was detected among the included studies. Although we performed subgroup analyses to explore the potential source of heterogeneity, it seems that none of the following study characteristics could adequately explain the potential heterogeneities, including study locations, sample sizes, types of blood samples, or study quality score. Since circulating endocan may be affected by factors which have impact on endothelial function, some remaining confounding factors may contribute to the heterogeneity, such as concurrent medications or some nutritional supplements during pregnancy. Second, it remains unknown whether up-regulated endocan participates in the pathogenesis of preeclampsia or it is simply just a marker of impaired endothelial function and activated inflammatory response. Third, future studies are needed to determine whether up-regulation of circulating endocan occurs before the onset of preeclampsia. Finally, a standardized protocol for measuring of circulating endocan has not been validated (from plasma or serum, the specific method, and the cut-off values). Therefore, it may be too early to propose that endocan could be used as a marker of preeclampsia at current state. However, results of our study demonstrated an increased circulating endocan in women with preeclampsia compared with those with normal control. Future studies are needed to determine whether endocan was involved in the pathogenesis and progression or preeclampsia.

In conclusion, results of meta-analysis showed that women with preeclampsia have higher circulating endocan than those with normal pregnancy. Future studies are needed to determine whether endocan was involved in the pathogenesis and progression or preeclampsia.

Author Contribution

Zhaoming Liu designed the study. Both authors performed literature search, data extraction, quality evaluation, and statistical analyses. Xia Lan wrote the manuscript. Both authors reviewed and revised the manuscript, and approved the manuscript for submission.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

The authors declare that there are no sources of funding to be acknowledged.

Abbreviations

     
  • ACOG

    American College of Obstetricians and Gynecologists

  •  
  • CC

    case–control

  •  
  • CTD-PAH

    connective tissue disease related pulmonary arterial hypertension

  •  
  • ESM-1

    endothelial cell-specific molecule 1

  •  
  • GA

    gestational age

  •  
  • NOS

    Newcastle–Ottawa Scale

  •  
  • PE

    preeclampsia

  •  
  • TNF-α

    tumor necrosis factor-α

References

References
1.
Jim
B.
and
Karumanchi
S.A.
(
2017
)
Preeclampsia: pathogenesis, prevention, and long-term complications
.
Semin. Nephrol.
37
,
386
397
[PubMed]
2.
Dymara-Konopka
W.
,
Laskowska
M.
and
Oleszczuk
J.
(
2018
)
Preeclampsia - current management and future approach
.
Curr. Pharm. Biotechnol.
19
,
786
796
[PubMed]
3.
Phipps
E.A.
,
Thadhani
R.
,
Benzing
T.
and
Karumanchi
S.A.
(
2019
)
Pre-eclampsia: pathogenesis, novel diagnostics and therapies
.
Nat. Rev. Nephrol.
15
,
275
289
[PubMed]
4.
Lisowska
M.
,
Pietrucha
T.
and
Sakowicz
A.
(
2018
)
Preeclampsia and related cardiovascular risk: common genetic background
.
Curr. Hypertens. Rep.
20
,
71
[PubMed]
5.
Paauw
N.D.
and
Lely
A.T.
(
2018
)
Cardiovascular sequels during and after preeclampsia
.
Adv. Exp. Med. Biol.
1065
,
455
470
[PubMed]
6.
Perry
H.
,
Khalil
A.
and
Thilaganathan
B.
(
2018
)
Preeclampsia and the cardiovascular system: an update
.
Trends Cardiovasc. Med.
28
,
505
513
[PubMed]
7.
Roberge
S.
,
Bujold
E.
and
Nicolaides
K.H.
(
2018
)
Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis
.
Am. J. Obstet. Gynecol.
218
,
287e281
293e281
8.
Henderson
J.T.
,
Thompson
J.H.
,
Burda
B.U.
and
Cantor
A.
(
2017
)
Preeclampsia screening: evidence report and systematic review for the US Preventive Services Task Force
.
JAMA
317
,
1668
1683
[PubMed]
9.
De Kat
A.C.
,
Hirst
J.
,
Woodward
M.
,
Kennedy
S.
and
Peters
S.A.
(
2019
)
Prediction models for preeclampsia: a systematic review
.
Pregnancy Hypertens.
16
,
48
66
[PubMed]
10.
Giachini
F.R.
,
Galaviz-Hernandez
C.
,
Damiano
A.E.
et al.
(
2017
)
Vascular dysfunction in mother and offspring during preeclampsia: contributions from Latin-American Countries
.
Curr. Hypertens. Rep.
19
,
83
[PubMed]
11.
Cornelius
D.C.
,
Cottrell
J.
,
Amaral
L.M.
and
LaMarca
B.
(
2019
)
Inflammatory mediators: a causal link to hypertension during preeclampsia
.
Br. J. Pharmacol.
176
,
1914
1921
[PubMed]
12.
Boeldt
D.S.
and
Bird
I.M.
(
2017
)
Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia
.
J. Endocrinol.
232
,
R27
R44
[PubMed]
13.
Sarrazin
S.
,
Adam
E.
,
Lyon
M.
et al.
(
2006
)
Endocan or endothelial cell specific molecule-1 (ESM-1): a potential novel endothelial cell marker and a new target for cancer therapy
.
Biochim. Biophys. Acta
1765
,
25
37
[PubMed]
14.
Zhao
T.
,
Kecheng
Y.
,
Zhao
X.
et al.
(
2018
)
The higher serum endocan levels may be a risk factor for the onset of cardiovascular disease: a meta-analysis
.
Medicine (Baltimore)
97
,
e13407
[PubMed]
15.
Chew
B.S.
,
Ghazali
R.
,
Othman
H.
et al.
(
2019
)
Endocan expression in placenta of women with hypertension
.
J. Obstet. Gynaecol. Res.
45
,
345
351
[PubMed]
16.
Musialowska
D.
,
Zbroch
E.
,
Koc-Zorawska
E.
,
Musialowski
P.
and
Malyszko
J.
(
2018
)
Endocan concentration in patients with primary hypertension
.
Angiology
69
,
483
489
[PubMed]
17.
Zhao
H.
,
Xue
Y.
,
Guo
Y.
,
Sun
Y.
,
Liu
D.
and
Wang
X.
(
2017
)
Inhibition of endocan attenuates monocrotaline-induced connective tissue disease related pulmonary arterial hypertension
.
Int. Immunopharmacol.
42
,
115
121
[PubMed]
18.
Adekola
H.
,
Romero
R.
,
Chaemsaithong
P.
et al.
(
2015
)
Endocan, a putative endothelial cell marker, is elevated in preeclampsia, decreased in acute pyelonephritis, and unchanged in other obstetrical syndromes
.
J. Matern. Fetal Neonatal Med.
28
,
1621
1632
[PubMed]
19.
Chang
X.
,
Bian
Y.
,
Wu
Y.
,
Huang
Y.
,
Wang
K.
and
Duan
T.
(
2015
)
Endocan of the maternal placenta tissue is increased in pre-eclampsia
.
Int. J. Clin. Exp. Pathol.
8
,
14733
14740
[PubMed]
20.
Hentschke
M.R.
,
Lucas
L.S.
,
Mistry
H.D.
,
Pinheiro da Costa
B.E.
and
Poli-de-Figueiredo
C.E.
(
2015
)
Endocan-1 concentrations in maternal and fetal plasma and placentae in pre-eclampsia in the third trimester of pregnancy
.
Cytokine
74
,
152
156
[PubMed]
21.
Yuksel
M.A.
,
Tuten
A.
,
Oncul
M.
et al.
(
2015
)
Serum endocan concentration in women with pre-eclampsia
.
Arch. Gynecol. Obstet.
292
,
69
73
[PubMed]
22.
Cakmak
M.
,
Yilmaz
H.
,
Baglar
E.
et al.
(
2016
)
Serum levels of endocan correlate with the presence and severity of pre-eclampsia
.
Clin. Exp. Hypertens.
38
,
137
142
[PubMed]
23.
Wang
H.Z.
,
Jin
Y.
,
Wang
P.
,
Han
C.
,
Wang
Z.P.
and
Dong
M.Y.
(
2017
)
Alteration of serum endocan in normal pregnancy and preeclampsia
.
Clin. Exp. Obstet. Gynecol.
44
,
419
422
[PubMed]
24.
Schuitemaker
J.H.N.
,
Cremers
T.
,
Van Pampus
M.G.
,
Scherjon
S.A.
and
Faas
M.M.
(
2018
)
Changes in endothelial cell specific molecule 1 plasma levels during preeclamptic pregnancies compared to healthy pregnancies
.
Pregnancy Hypertens.
12
,
58
64
[PubMed]
25.
Szpera-Gozdziewicz
A.
,
Kosicka
K.
,
Gozdziewicz
T.
et al.
(
2018
)
Serum endocan concentration and its correlation with severity of hypertensive disorders in pregnancy
.
J. Matern. Fetal Neonatal Med.
2
,
1
7
26.
Lisonkova
S.
and
Joseph
K.S.
(
2013
)
Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease
.
Am. J. Obstet. Gynecol.
209
,
544e541
544e512
27.
Stroup
D.F.
,
Berlin
J.A.
,
Morton
S.C.
et al.
(
2000
)
Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group
.
JAMA
283
,
2008
2012
28.
Higgins
J.
and
Green
S.
(
2011
)
Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0
.
The Cochrane Collaboration
,
www.cochranehandbook.org, 10 August 2019
29.
(
2013
)
Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy
.
Obstet. Gynecol.
122
,
1122
1131
[PubMed]
30.
Wells
G.A.
,
Shea
B.
,
O’Connell
D.
et al.
(
2010
)
The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses
.
31.
Higgins
J.P.
,
Thompson
S.G.
,
Deeks
J.J.
and
Altman
D.G.
(
2003
)
Measuring inconsistency in meta-analyses
.
BMJ
327
,
557
560
[PubMed]
32.
Higgins
J.P.
and
Thompson
S.G.
(
2002
)
Quantifying heterogeneity in a meta-analysis
.
Stat. Med.
21
,
1539
1558
[PubMed]
33.
Raymond
D.
and
Peterson
E.
(
2011
)
A critical review of early-onset and late-onset preeclampsia
.
Obstet. Gynecol. Surv.
66
,
497
506
[PubMed]
34.
Egger
M.
,
Davey Smith
G.
,
Schneider
M.
and
Minder
C.
(
1997
)
Bias in meta-analysis detected by a simple, graphical test
.
BMJ
315
,
629
634
[PubMed]
35.
Karumanchi
S.A.
and
Granger
J.P.
(
2016
)
Preeclampsia and pregnancy-related hypertensive disorders
.
Hypertension
67
,
238
242
[PubMed]
36.
Balta
S.
,
Mikhailidis
D.P.
,
Demirkol
S.
,
Ozturk
C.
,
Celik
T.
and
Iyisoy
A.
(
2015
)
Endocan: A novel inflammatory indicator in cardiovascular disease?
Atherosclerosis
243
,
339
343
[PubMed]
37.
Wang
Y.
and
Nie
G.
(
2016
)
High levels of HtrA4 observed in preeclamptic circulation drastically alter endothelial gene expression and induce inflammation in human umbilical vein endothelial cells
.
Placenta
47
,
46
55
[PubMed]
38.
Al-Ofi
E.A.
and
Anumba
D.O.
(
2017
)
Ligands of toll-like receptors 2/4 differentially alter markers of inflammation, adhesion and angiogenesis by monocytes from women with pre-eclampsia in co-culture with endothelial cells
.
J. Reprod. Immunol.
121
,
26
33
[PubMed]
39.
O’Brien
M.
,
Baczyk
D.
and
Kingdom
J.C.
(
2017
)
Endothelial dysfunction in severe preeclampsia is mediated by soluble factors, rather than extracellular vesicles
.
Sci. Rep.
7
,
5887
[PubMed]
40.
Perni
U.
,
Sison
C.
,
Sharma
V.
et al.
(
2012
)
Angiogenic factors in superimposed preeclampsia: a longitudinal study of women with chronic hypertension during pregnancy
.
Hypertension
59
,
740
746
[PubMed]
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).