Research ArticleAlterations of Several Serum Parameters Are Associated withPreeclampsia and May Be Potential Markers for the Assessment ofPE Severity

Zhongliang Duan ,1 Cui Li,1 Wing Ting Leung,2,3,4 Jiangnan Wu ,5 Mingyan Wang,1

Chunmei Ying ,1 and Ling Wang 2,3,4

1Department of Clinical Laboratory, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China2Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, Shanghai Medical College,Fudan University, Shanghai, China3The Academy of Integrative Medicine, Fudan University, Shanghai, China4Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China5Department of Clinical Epidemiology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China

Correspondence should be addressed to Chunmei Ying; ycmzh2012@163.com and Ling Wang; dr.wangling@fudan.edu.cn

Received 10 September 2019; Revised 21 November 2019; Accepted 31 December 2019; Published 14 January 2020

Guest Editor: Ioannis Kosmas

Copyright © 2020 Zhongliang Duan et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

The precise pathophysiological mechanisms of preeclampsia (PE) and preventative strategies remain unknown. Laboratorymarkers which can help in identifying PE patients from pregnant women and assessing the severity of PE during pregnancyare worthy to be explored. In this study, a retrospective case-control study was designed to assess whether the serum levels ofalbumin (ALB), total protein (TP), prealbumin (PA), alkaline phosphatase (ALP), lactic dehydrogenase (LDH), D-dimer,fibrinogen (Fbg), platelet (PLT) count, mean platelet volume (MPV), and platelet distribution width (PDW) can help inassessing PE and evaluate its severity. 256 pregnant women were enrolled and classified into 3 groups: mild preeclampsia(mPE, n = 85), severe preeclampsia (sPE, n = 78), and healthy normotensive controls (control, n = 93). Our result showed thatthe serum levels of ALP, LDH, and D-dimer were significantly higher in mild or severe PE patients compared with the healthycontrols (66 (52.5-76.5) vs. 168 (141.5-201.25) vs. 182.5 (120-191.5), 152 (139.75-166.25) vs. 183.5 (163.25-307) vs. 282(215.25-306), 1.05 (0.65-1.57) vs. 3.05 (2.25-4.08) vs. 5.65 (2.29-7.71)), while ALB, TP, and PA are lower (38 (37-42) vs. 31.5(25.5-34.5) vs. 28.5 (24-33), 65 (63-68.25) vs. 56.5 (52-61) vs. 51.5 (49-58), 219:14 ± 68:25 vs. 167:88 ± 52:21 vs. 143:22 ± 50:46).On the other hand, compared with the mPE group, the sPE group showed significantly lower PLT count but higher level ofLDH, D-dimer, and Fbg. No significant differences in MPV or PDW were found between any of the two groups. In conclusion,the above markers except for the MPV and PDW may be correlated with PE severity in this patient cohort, indicating possiblevalues of these potential biomarkers in auxiliary diagnosis and severity assessment of PE.

1. Introduction

Preeclampsia (PE) is a pregnancy-specific disease character-ized by new-onset hypertension and proteinuria after 20weeks of gestation associated with placental hypoperfusion.It is one of the major causes for fetal growth restriction,and in severe cases, it can progress into maternal multiorgandysfunction or even mortality of both the mother and the

newborn [1]. PE affects approximately 5–10% of pregnanciesworldwide [2]. Pregnant women diagnosed with PE are oftenat a higher risk of future cardiovascular or cerebrovasculardiseases [3]. The exact pathogenesis of PE remains contro-versial, while abnormal inflammation and immune responses[4, 5] and impaired coagulation-fibrinolysis systems [6, 7] areoften mentioned. Among a number of possible causes ofPE, the abnormal gestational trophoblast cell invasion

HindawiDisease MarkersVolume 2020, Article ID 7815214, 7 pageshttps://doi.org/10.1155/2020/7815214

and endothelial cell injuries are also widely studied. Deficienttrophoblastic invasion into maternal myometrial spiral arte-riole leads to the inadequate remodeling of the spiral arteries;the resulting abnormal implantation reduces the placentalperfusion, thus causing the downstream hypoxia and mater-nal symptoms [8, 9]. The placental hypoperfusion may resultin a state of hypoxia, yielding a state of excessive oxidativestress, angiogenic responses, and the release of antiangio-genic proteins and other inflammatory mediators whichcan lead to vascular endothelial damage and coagulation sys-tem activation [10]. The abnormal maternal metabolism canalso adversely affect the intrauterine environment, aggravat-ing the outcomes of PE [11]. Additionally, the roles of pertur-bation of the renin-aldosterone-angiotensin II axis, immuneadaption, and genetic susceptibility are also being investi-gated by many studies [12–14].

Timely and accurate identification of the pregnantwomen who are at risk of developing PE is crucial as theyrequire close prenatal monitoring and treatment to achievebetter pregnancy outcomes. PE is typically diagnosed usingclinical criteria which is based on nonspecific markers andclinical presentation. Currently, there is no screening or stan-dard diagnostic test approved for clinical use [15]. Besides,PE may exist atypically, present individual difference, orresemble other conditions. Therefore, in recent years,attempts have been made to find specific and practical labo-ratory markers for PE prediction and assessment. Researchhas shown that the angiogenic pathway in early gestation isaltered and excess angiogenic factors are released by the pla-centa into maternal blood. Maternal soluble endoglin (sEng)and soluble fms-like tyrosine kinase-1 (sFlt1) may be possiblemarkers in early gestational age for prediction of PE [16–18].There are also studies suggesting that MPV was significantlyhigher in preeclamptic women than in healthy pregnantwomen and thus may be a promising biomarker for the PEdetection and follow-up [19]. Systemic immune inflamma-tion indices such as neutrophil-lymphocyte ratio (NLR) andmonocyte-lymphocyte ratio (MLR) are also reported to beeffective in clinical assessment, disease severity evaluation,and prognosis evaluation of PE [20]. Changes of serum traceelements like Ca, Cu, and Mg are reported to be associatedwith PE, while serum ceruloplasmin [21] and soluble LIGHT[22] are reported to have predictive value in PE.

There have been controversies regarding the value ofseveral hematological parameters (such as D-dimer, Fbg,PLT, MPV, and PDW) and biochemical tests (such asALB, TP, PA, ALP, and LDH) in PE prediction or in theevaluation of PE severity. For example, the value of plateletcount and platelet indices in PE is supported by several stud-ies; however, there are also studies that found no significance[23–25]. The significance of ALB in assessing the onset andseverity of preeclampsia is also controversial [26, 27].

Our study is aimed at providing further data and out-comes on these topics in Chinese population. We hypothe-size that the altered levels of biological makers take part inclinical assessment, disease severity evaluation, and progno-sis of PE during pregnancy. The primary aim of this studyis to compare the ten serum parameters (ALB, TP, PA,ALP, LDH, D-dimer, Fbg, PLT, MPV, and PDW) of mild

and severe preeclampsia patients at the time point they metdiagnosis criteria with the normotensive controls, in orderto investigate whether these parameters are correlated withPE or have a significant difference between sPE and mPEpatients. Our study also hopes to provide further insight intothe investigation of laboratory markers for PE clinical assess-ment and disease severity evaluation.

2. Methods

2.1. Patients and Controls. Data collection was approved bythe Ethics Committee of the Obstetrics & Gynecology Hospi-tal affiliated to Fudan University, and written informed con-sents were obtained from all cases. In this case-controlretrospective study, a total of 256 pregnant women including163 PE patients and 93 normotensive healthy controls wererecruited from the obstetric outpatient clinic and inpatientdepartment of the Obstetrics & Gynecology Hospital affili-ated to Fudan University, during the time from June 2017to June 2018. The recruitment of PE patients was consecu-tive. The enrolled controls were normal in blood pressureand immune system profile and were matched with the PEpatients in gestational age and maternal prepregnancy bodyweight. Only pregnant women who have received all theirantenatal examinations and delivered in our hospital wereincluded in this study. PE is diagnosed according to the2002 Practice Bulletin of American College of Obstetricsand Gynecology (ACOG) guidelines [28]. PE patients werefurther classified as mild preeclampsia (n = 85) and severepreeclampsia (n = 78). Preeclampsia is considered severe ifsystolic blood pressure (SBP) is ≥160mm Hg or diastolicblood pressure (DBP) is ≥110mm Hg or at least one of thefollowing clinical symptoms occurred: renal insufficiency,pulmonary edema, microvascular disease, thrombocytope-nia, impaired liver function, and peripheral severe organinvolvement (visual impairment and headache) [29]. Patientswere considered to have mild PE if they met the diagnosticcriteria of preeclampsia but not the criteria for severe PE.Patients presented with other obstetric or systemic diseaseswere excluded from this study, which includes chronichypertension, preexisting renal disease, immunological dis-eases, and multiple pregnancies HELLP syndrome. Pregnantwomen with other known medical complications which canaffect the level of examined serum biomarkers, such as repro-ductive tract infections, recurrent spontaneous abortion,immunological diseases, and genetic diseases, were alsoexcluded from this study.

2.2. Sample Collection and Analysis. Blood samples were col-lected as soon as the diagnosis of PE was confirmed and weretested within 2 hours. 2mL of venous blood sample was col-lected into a test tube with EDTA-K-2 anticoagulant and wastested for whole blood count using Sysmex XN1000 hematol-ogy analyzer (Sysmex Corporation, Japan). Blood coagulativefunction was performed on a Sysmex CS5100 hematologyanalyzer (Sysmex Corporation, Japan) with another 2mL ofvenous blood collected. 3mL of venous blood sample wascollected without anticoagulants for biochemical test andwas tested by using Hitachi 7600 automatic analyzer (Hitachi

2 Disease Markers

Corporation, Japan). The above tests were conducted accord-ing to the manufacturer’s instructions. The test results ofserum ALB, TP, PA, ALP, LDH, D-dimer, Fbg, PLT, MPV,and PDW were all recorded. All these laboratory parameterswere tested in our clinical laboratory, according to theISO15189 standards.

2.3. Statistical Analysis Approach. The demographic andmedical information of all enrolled pregnant women wereobtained from medical records. The normality was analyzedby the Shapiro-Wilk test. The data of continuous variableswere represented as X ðmeanÞ ± SD ðstandard deviationÞ ormedian and interquartile range. The categorical data wererepresented as percentage (%). Continuous data were com-pared within groups by the independent-samples t-test,one-way ANOVA, or Kruskal-Wallis test. The categoricaldata were analyzed by the chi-square test. Correlationsbetween the parameters and the onset of PE were evaluatedby the Pearson correlation coefficient (r). These biomarkers’values to evaluate PE were calculated by a receiver operatingcharacteristic (ROC) curve. The area under curve (AUC) wascalculated to evaluate the predictive powers. Each cutoffpoint was assessed by searching for the maximum Youden’sindex (sensitivity + specificity – 1). SPSS 19.0 software wasused for statistical analysis. p < 0:05 was considered statisti-cally significant.

3. Results

3.1. Maternal Clinical and Demographic CharacteristicsComparison between the mPE, sPE, and Control Groups. Atotal of 256 pregnant women were included in this study.Patients were divided into three groups: sPE (n = 78), mPE(n = 85), and healthy normotensive (control, n = 93) groups.Demographic and essential features of the three groupsincluding age, gravidity, gestational age, vaginal delivery,and cesarean section rates are shown in Table 1. The average

age of the sPE group patients is 32:22 ± 2:71, while the aver-age age of the mPE group and healthy control group is28:06 ± 2:84 and 29:38 ± 5:14 years, respectively. Comparedto the control and mPE groups, women who developed sPEare higher in age (p < 0:05). There is no significant differenceamong the three groups with respect to gravidity (p > 0:05).Moreover, delivery time of the sPE group is significantlyearlier than the control and mPE groups (p < 0:05). It isnotable that compared with the control group, the sPEand mPE groups have higher rate of cesarean delivery, thatis, lower rate of vaginal delivery (p < 0:001). There is a sig-nificant difference between the mPE and sPE groups regard-ing gestational age at delivery and delivery mode of vaginalor cesarean delivery.

3.2. Analysis of Biochemical Markers in the Three Groups.The levels of each tested serum parameter are shown inTable 2. The comparisons between the three groups are pre-sented as p values demonstrated. As shown in Table 2, theALB, TP, PA, ALP, LDH, and D-dimer levels of the controlgroup are significantly different from those of the sPE andmPE groups. Specifically, the ALB, TP, and PA serum levelsof the control group are higher than the sPE and mPEgroups. On the contrary, for the ALP, LDH, and D-dimer,the control group is significantly lower. No significance isfound by the comparison of ALB, TP, PA, and ALP levelsbetween the mPE and sPE groups. The LDH and D-dimerof either the mPE or the sPE group are significantly higherthan the control group, and the sPE group is higher thanthe mPE group. We also measured the serum level of Fbg,PLT, MPV, and PDW of the three groups. The result showsno significant difference between the control group and themPE group in the levels of four parameters. However, bycomparing the sPE patients with the healthy controls ormPE patients, the Fbg level is significantly higher and PLTis significantly lower in sPE patients. Significant differenceof MPV level is found only between the control and sPE

Table 1: Summary of maternal characteristics of the control, mild preeclampsia, and severe preeclampsia groups.

Control (n = 93) mPE (n = 85) sPE (n = 78) p value

Age 29:38 ± 5:14 28:06 ± 2:84 32:22 ± 2:71 ∗ <0.05Parity 1:14 ± 0:62 1:20 ± 0:68 1:06 ± 0:55 >0.05Gestational age at sampling (weeks) 34:06 ± 4:62 33:12 ± 4:46 34:93 ± 4:13 >0.05Gestational age at delivery (weeks) 39:04 ± 2:53 37:57 ± 3:44 35:69 ± 4:68# <0.05Highest SBP (mmHg) 118:22 ± 10:18∗∗ 140:18 ± 18:34 155:41 ± 20:15 <0.01Highest DBP (mmHg) 78:45 ± 11:29 ∗ 94:35 ± 9:76 103:2 ± 10:18 <0.05Renal function

Blood urea nitrogen (mmol/L) 3:94 ± 1:16 4:13 ± 1:65 4:33 ± 1:58 >0.05Uric acid (μmol/L) 344:21 ± 57:17 405:91 ± 86:74 452:69 ± 93:33 ∗ <0.05Creatinine (μmol/L) 43:68 ± 10:23 48:38 ± 9:74 50:25 ± 9:66 >0.05

Urine albumin (g/24 h) 0:19 ± 0:12∗∗∗ 1:92 ± 1:08 3:25 ± 1:12 <0.001Vaginal delivery rate (%) 69∗∗∗ 47 25 <0.001Cesarean rate (%) 31∗∗∗ 53 75 <0.001Compared with the other two groups: ∗p < 0:05, ∗∗p < 0:01, ∗∗∗p < 0:001; compared with the control group: #p < 0:05.

3Disease Markers

groups. There is no significant finding by comparing thePDW among the three groups.

3.3. Value of PE Evaluation by These Biomarkers. Correlationbetween these biomarkers and PE was evaluated by the

Pearson correlation coefficient. The Pearson correlation coef-ficient and p values are shown in Table 3. The result suggeststhat PE is significantly positively correlated with biomarkersof ALP, LDH, and D-dimer and negatively correlated withALB, TP, and PA.

Table 2: Serum markers’ values in different groups.

Marker Control mPE sPE Control vs. mPE Control vs. sPE mPE vs. sPE

ALB 38 (37-42) 31.5 (25.5-34.5) 28.5 (24-33) <0.001 <0.001 0.2113

TP 65 (63-68.25) 56.5 (52-61) 51.5 (49-58) 0.0002 <0.001 0.4046

PA 219:14 ± 68:25 167:88 ± 52:21 143:22 ± 50:46 0.0002 <0.001 0.0555

ALP 66 (52.5-76.5) 168 (141.5-201.25) 182.5 (120-191.5) 0.0009 0.0001 0.4291

LDH 152 (139.75-166.25) 183.5 (163.25-307) 282 (215.25-306) 0.0022 <0.001 0.0444

D-dimer 1.05 (0.65-1.57) 3.05 (2.25-4.08) 5.65 (2.29-7.71) <0.001 <0.001 0.0115

Fbg 3:58 ± 1:22 3:51 ± 1:15 4:12 ± 2:33 0.3969 0.0484 0.0470

PLT 232 (197-252.25) 211 (178-279) 169 (158-191.25) 0.4932 <0.001 0.0066

MPV 10:54 ± 2:03 10:69 ± 1:14 11:04 ± 2:51 0.2419 0.0137 0.1031

PDW 12:87 ± 3:54 13:5 ± 3:17 13:03 ± 4:26 0.1365 0.3810 0.2640

Data are presented as mean ± standard deviation ðSDÞ when the parameters’ distributions were normal distribution or median and interquartile rangeswhen skewed.

Table 3: Correlation between biomarkers and PE.

ALB TP PA ALP LDH D-dimer Fbg PLT MPV PDW

Pearson correlation coefficient -0.770 -0.665 -0.622 0.560 0.571 0.628 0.183 -0.181 0.156 0.044

p value 0.000 0.000 0.000 0.000 0.000 0.000 0.092 0.096 0.152 0.686

ROC curve

0.2

0.4

0.6

0.8

1.0

0.00.0 0.2 0.4 0.6 0.8 1.0

1 − specificity

Sens

itivi

ty

ALPLDHD-dimer

FbgMPVPDW

Figure 1: ROC curve of each positively correlated biomarker. ROCcurve was used to estimate each significantly positively correlatedbiomarker visually. The AUC of ALP, LDH, and D-dimer wasmore than 0.700. The AUC of Fbg, MPV, and PDW was less than0.700.

ROC curve

0.2

0.4

0.6

0.8

1.0

0.00.0 0.2 0.4 0.6 0.8 1.0

1 − specificity

Sens

itivi

ty

ALBTP

PAPLT

Figure 2: ROC curve of each negatively correlated biomarker. ROCcurve was used to estimate each significantly negatively correlatedbiomarker visually. The AUC of ALB, TP, and PA was more than0.700. The AUC of PLT was less than 0.700.

4 Disease Markers

The ROC curve is used to estimate the AUC of ALP,LDH, D-dimer, Fbg, MPV, and PDWwhich positively corre-lated with PE (Figure 1) and ALB, TP, PA, and PLT thatnegatively correlated with PE (Figure 2). The AUC in the pre-diction for PE of each marker is shown in Table 4.

4. Discussion

PE is a pregnancy complication characterized by new-onsethypertension and signs of abnormal metabolism or organdysfunction. PE can lead to severe or even fatal complicationsfor both the mother and the fetus. The pathogenesis of PEremains controversial.

In clinical practice, the laboratory index that can beobtained easily could help medical practitioners in monitor-ing PE directly. Thus, practical laboratory markers which canhelp in assessing the onset and severity of PE remain to bestudied. In recent years, an increasing number of studiesare giving attentions to the correlation between serummarkers and severity of PE [30–32]. Soluble endoglin andsoluble fms-like tyrosine kinase-1 [16], serum ceruloplasmin[21], and soluble LIGHT [22] in the early phrase of preg-nancy are often reported to have possible value in PE predic-tion. However, so far, there is no reliable means. The onset ofpreeclampsia is considered a complicated pathophysiologicprocess associated with angiogenesis, hypoxia, oxidativestress, perturbation of the renin-aldosterone-angiotensin IIaxis, inflammation, immune maladaptation, and genetic sus-ceptibility [15]. Thus, besides the definition of PE as the com-bination of high blood pressure and albuminuria in apregnant woman, more clinical markers are needed for com-prehensive assessment of PE.

In this retrospective study, we found more clinicalmarkers that may be correlated with the onset and severityof PE, and they were easily measurable and available. We alsofound that the average age of the severe PE group was olderthan the other two groups, suggesting women that conceiveat older age are at higher risk of developing PE. This is con-sistent with Sun et al.’s report [33]. Besides, we also found asignificant difference in levels of ALB, TP, PA, ALP, LDH,and D-dimer between the healthy control group and eitherthe mild or the severe PE group, suggesting that these bio-markers might have potential values in identifying PEpatients from the pregnant women. PE often presents withproteinuria, which might lead to the low levels of ALB, TP,and PA in serum, and these markers may be useful for mon-itoring the progression of PE. The changes in the coagulation

system and endothelial injury may lead to the abnormalexpression of D-dimer, Fbg, and PLT in serum. The levelsof LDH, D-dimer, Fbg, and PLT in the severe PE group weresignificantly different from the mild PE group, indicatingpotential value of auxiliary diagnosis in distinguishing mildand severe PE patients.

Platelet indices such as PLT, MPV, and PDW are widelyavailable and cost-effective, facilitating its investigations inthe prediction of PE [34, 35]. Freitas et al. [36] found thatsPE patients had a significantly higher MPV. Dogan et al.[31] suggested that the increasing platelet turnover causes adecrease in the PLT, and an increase of MPV value and adecrease in PC/MPV ratio may play an important role in pre-dicting the risk of PE. Our study showed similar resultsregarding the alterations of MPV and PLT in PE patientsbut different in the PDW level. The inconsistence in resultsmay be due to the racial or methodological differences, whichis worthy to be further studied. Consistent with previousstudies [7, 37], D-dimer is significantly higher in PE patients,indicating a possible role of D-dimer in the pathology of PE.

The ROC curves and the Pearson correlation coefficientshow significant positive correlation between PE and ALP,LDH, and D-dimer and negative correlation between PEand ALB, TP, and PA, which may be useful in daily clinicalpractice to predict the risk of PE.

Potential limitations of this study include that it is asingle-center and retrospective study that still lacks evidencefor use in clinical practice. Larger and multicenter prospec-tive studies are still waited to be done to further verify theroles of the examined markers in assessment of PE severityand pregnancy outcomes.

In conclusion, the alterations of ALB, TP, PA, ALP, LDH,and D-dimer may have a role in the pathogenesis of PE orfunction in the development of PE. Our data suggest thatthese markers may have potential value in evaluating the riskand severity of PE. The serum parameters we studied can bereadily derived and thus may be practical in daily clinicalpractice. Future large-scale prospective studies should furtherclarify the roles played by these parameters in the predictionof risk and severity of PE.

Data Availability

All my data in this manuscript were collected from patientsof my hospital and approved by the Ethics Committee ofthe Obstetrics & Gynecology Hospital of Fudan University.

Table 4: ROC curve of significant markers for evaluation of preeclampsia.

Variables Cutoff value Sensitivity Specificity AUC Sig.95% CI

Lower limit Upper limit

ALB 34.000 100% 89.1% 0.954 <0.001 0.906 1.000

TP 59.500 97.5% 82.6% 0.939 <0.001 0.880 0.998

PA 184.500 95% 65.2% 0.882 <0.001 0.812 0.951

ALP 81.000 95.7% 77.5% 0.895 <0.001 0.822 0.968

LDH 183.500 73.9% 92.5% 0.899 <0.001 0.832 0.965

D-dimer 1.765 95.6% 85% 0.919 <0.001 0.858 0.980

5Disease Markers

All these data approved frommy hospital can be provided forreview process if needed.

Conflicts of Interest

The authors declared no potential conflicts of interests withrespect to the authorship and publication of this article.

Authors’ Contributions

Zhongliang Duan, Cui Li, and Wing Ting Leung contributedequally to this work.

Acknowledgments

This work was supported by grants from the NationalNatural Science Foundation of China (nos. 31571196 and30801502 to Ling Wang), the Program to Guide Medicine(“Yixueyindao”) of the Shanghai Municipal Scienceand Technology Commission (nos. 18401902200 and15401932200 to Ling Wang), the Shanghai Program forSupport of Leading Disciplines-Integrative Medicine (nos.20180101 and 20150407), the Research Foundation (“CRSanjiu”) of Obstetrics & Gynecology Committee of ChineseAssociation of Integrated Traditional Chinese and WesternMedicine (CR1901FC01 to Ling Wang), the Shanghai Com-mittee of the China Democratic League (no. 02054 to LingWang), the FY2008 JSPS Postdoctoral Fellowship for ForeignResearchers (P08471 to Ling Wang), and the ShanghaiPujiang Program (no. 11PJ1401900 to Ling Wang).

References

[1] K. M. Baca, H. N. Simhan, R. W. Platt, and L. M. Bodnar, “Lowmaternal 25-hydroxyvitamin D concentration increases therisk of severe and mild preeclampsia,” Annals of Epidemiology,vol. 26, no. 12, pp. 853–857.e1, 2016.

[2] T. Ahsan, S. Banu, Q. Nahar, M. Ahsan, M. N. Khan, and S. N.Islam, “Serum trace elements levels in preeclampsia andeclampsia: correlation with the pregnancy disorder,” BiologicalTrace Element Research, vol. 152, no. 3, pp. 327–332, 2013.

[3] M. C. Brown, K. E. Best, M. S. Pearce, J. Waugh, S. C. Robson,and R. Bell, “Cardiovascular disease risk in women with pre-eclampsia: systematic review and meta-analysis,” EuropeanJournal of Epidemiology, vol. 28, no. 1, pp. 1–19, 2013.

[4] N. Visser, B. B. van Rijn, G. T. Rijkers, A. Franx, and H. W.Bruinse, “Inflammatory changes in preeclampsia: currentunderstanding of the maternal innate and adaptive immuneresponse,” Obstetrical & Gynecological Survey, vol. 62, no. 3,pp. 191–201, 2007.

[5] A. C. Staff, G. M. Johnsen, R. Dechend, and C. W. G. Redman,“Preeclampsia and uteroplacental acute atherosis: immuneand inflammatory factors,” Journal of Reproductive Immunol-ogy, vol. 101-102, pp. 120–126, 2014.

[6] M. B. Pinheiro, K. B. Gomes, and L. M. S. Dusse, “Fibrinolyticsystem in preeclampsia,” Clinica Chimica Acta, vol. 416,pp. 67–71, 2013.

[7] G. Haire, K. Egan, K. Parmar et al., “Alterations in fibrin for-mation and fibrinolysis in early onset-preeclampsia: associa-tion with disease severity,” European Journal of Obstetrics,

Gynecology, and Reproductive Biology, vol. 241, pp. 19–23,2019.

[8] G. J. Burton, A. W. Woods, E. Jauniaux, and J. C. Kingdom,“Rheological and physiological consequences of conversionof the maternal spiral arteries for uteroplacental blood flowduring human pregnancy,” Placenta, vol. 30, no. 6, pp. 473–482, 2009.

[9] E. A. Steegers, P. von Dadelszen, J. J. Duvekot, andR. Pijnenborg, “Pre-eclampsia,” Lancet, vol. 376, no. 9741,pp. 631–644, 2010.

[10] S. E. Maynard and S. A. Karumanchi, “Angiogenic factors andpreeclampsia,” Seminars in Nephrology, vol. 31, no. 1, pp. 33–46, 2011.

[11] M. Scioscia, S. A. Karumanchi, D. Goldman-Wohl, and P. Y.Robillard, “Endothelial dysfunction and metabolic syndromein preeclampsia: an alternative viewpoint,” Journal of Repro-ductive Immunology, vol. 108, pp. 42–47, 2015.

[12] S. D. Burke, Z. K. Zsengellér, E. V. Khankin et al., “Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity inpreeclampsia,” The Journal of Clinical Investigation, vol. 126,no. 7, pp. 2561–2574, 2016.

[13] K. J. Gray, R. Saxena, and S. A. Karumanchi, “Genetic predis-position to preeclampsia is conferred by fetal DNA variantsnear FLT1, a gene involved in the regulation of angiogenesis,”American Journal of Obstetrics and Gynecology, vol. 218, no. 2,pp. 211–218, 2018.

[14] C. Gohner, T. Plosch, and M. M. Faas, “Immune-modulatoryeffects of syncytiotrophoblast extracellular vesicles in preg-nancy and preeclampsia,” Placenta, vol. 60, Suppl 1, pp. S41–S51, 2017.

[15] B. C. Young, R. J. Levine, and S. A. Karumanchi, “Pathogenesisof preeclampsia,” Annual Review of Pathology, vol. 5, pp. 173–192, 2010.

[16] M. U. Baumann, N. A. Bersinger, M. G. Mohaupt, L. Raio,S. Gerber, and D. V. Surbek, “First-trimester serum levels ofsoluble endoglin and soluble fms-like tyrosine kinase-1 asfirst-trimester markers for late-onset preeclampsia,” AmericanJournal of Obstetrics and Gynecology, vol. 199, no. 3,pp. 266.e1–266.e6, 2008.

[17] S. E. Maynard, J. Y. Min, J. Merchan et al., “Excess placentalsoluble fms-like tyrosine kinase 1 (sFlt1) may contribute toendothelial dysfunction, hypertension, and proteinuria in pre-eclampsia,” The Journal of Clinical Investigation, vol. 111,no. 5, pp. 649–658, 2003.

[18] S. Venkatesha, M. Toporsian, C. Lam et al., “Soluble endoglincontributes to the pathogenesis of preeclampsia,” Nature Med-icine, vol. 12, no. 6, pp. 642–649, 2006.

[19] I. Bellos, G. Fitrou, V. Pergialiotis, N. Papantoniou, andG. Daskalakis, “Mean platelet volume values in preeclampsia:a systematic review and meta-analysis,” Pregnancy Hypertens,vol. 13, pp. 174–180, 2018.

[20] J. Wang, Q. W. Zhu, X. Y. Cheng et al., “Assessment efficacy ofneutrophil-lymphocyte ratio and monocyte-lymphocyte ratioin preeclampsia,” Journal of Reproductive Immunology,vol. 132, pp. 29–34, 2019.

[21] Y. Engin-Ustun, Y. Ustun, M. Kamaci, and R. Sekeroglu,“Maternal serum ceruloplasmin in preeclampsia,” Interna-tional Journal of Gynaecology and Obstetrics, vol. 89, no. 1,pp. 51-52, 2005.

[22] C. Hirashima, T. Ohmaru-Nakanishi, S. Nagayama et al.,“Serum soluble LIGHT in the early third trimester as a novel

6 Disease Markers

biomarker for predicting late-onset preeclampsia,” PregnancyHypertens, vol. 14, pp. 174–176, 2018.

[23] C. Monteith, K. Egan, H. O’Connor et al., “Early onset pre-eclampsia is associated with an elevated mean platelet volume(MPV) and a greater rise in MPV from time of booking com-pared with pregnant controls: results of the CAPE study,”Journal of Perinatal Medicine, vol. 46, no. 9, pp. 1010–1015,2018.

[24] S. W. Yang, S. H. Cho, H. S. Kwon, I. S. Sohn, and H. S. Hwang,“Significance of the platelet distribution width as a severitymarker for the development of preeclampsia,” European Jour-nal of Obstetrics, Gynecology, and Reproductive Biology,vol. 175, pp. 107–111, 2014.

[25] M. A. AlSheeha, R. S. Alaboudi, M. A. Alghasham, J. Iqbal, andI. Adam, “Platelet count and platelet indices in women withpreeclampsia,” Vascular Health and Risk Management,vol. 12, pp. 477–480, 2016.

[26] J. Benoit and E. Rey, “Preeclampsia: should plasma albuminlevel be a criterion for severity?,” Journal of Obstetrics andGynaecology Canada, vol. 33, no. 9, pp. 922–926, 2011.

[27] D. M. Dai, J. Cao, H. M. Yang et al., “Hematocrit and plasmaalbumin levels difference may be a potential biomarker todiscriminate preeclampsia and eclampsia in patients withhypertensive disorders of pregnancy,” Clinica Chimica Acta,vol. 464, pp. 218–222, 2017.

[28] ACOG Committee on Obstetric Practice, “ACOG practicebulletin. Diagnosis and management of preeclampsia andeclampsia. Number 33, January 2002. American College ofObstetricians and Gynecologists,” International journal ofgynaecology and obstetrics: the official organ of the Interna-tional Federation of Gynaecology and Obstetrics, vol. 77,no. 1, pp. 67–75, 2002.

[29] A. L. Tranquilli, M. A. Brown, G. G. Zeeman, G. Dekker, andB. M. Sibai, “The definition of severe and early-onset pre-eclampsia. Statements from the International Society for theStudy of Hypertension in Pregnancy (ISSHP),” PregnancyHypertens, vol. 3, no. 1, pp. 44–47, 2013.

[30] L. J. Sun, G. F. Xu, M. Lv, H. Zhou, H. F. Huang, and Q. Luo,“Predictive value of maternal serum biomarkers for pre-eclampsia and birth weight: a case-control study in Chinesepregnant women,” Journal of Women’s Health (2002),vol. 27, no. 12, pp. 1519–1524, 2018.

[31] K. Dogan, H. Guraslan, M. B. Senturk, C. Helvacioglu, S. Idil,and M. Ekin, “Can platelet count and platelet indices predictthe risk and the prognosis of preeclampsia?,” Hypertension inPregnancy, vol. 34, no. 4, pp. 434–442, 2015.

[32] Y. Einbinder, T. Biron-Shental, M. Agassi-Zaitler et al., “High-density lipoproteins (HDL) composition and function in pre-eclampsia,” Archives of Gynecology and Obstetrics, vol. 298,no. 2, pp. 405–413, 2018.

[33] F. Sun, W. Qian, C. Zhang, J. X. Fan, and H. F. Huang, “Cor-relation of maternal serum homocysteine in the first trimesterwith the development of gestational hypertension and pre-eclampsia,” Medical Science Monitor, vol. 23, pp. 5396–5401,2017.

[34] P. Juan, G. Stefano, S. Antonella, and C. Albana, “Plateletsin pregnancy,” Journal of Prenatal Medicine, vol. 5, no. 4,pp. 90–92, 2011.

[35] P. von Dadelszen, L. A. Magee, R. M. Devarakonda et al., “Theprediction of adverse maternal outcomes in preeclampsia,”Journal of Obstetrics and Gynaecology Canada, vol. 26,no. 10, pp. 871–879, 2004.

[36] L. G. Freitas, P. N. Alpoim, F. Komatsuzaki, M. G. Carvalho,and L. M. S. Dusse, “Preeclampsia: are platelet count and indi-ces useful for its prognostic?,” Hematology, vol. 18, no. 6,pp. 360–364, 2013.

[37] M. Bozkurt, A. E. Yumru, L. Sahin, and S. Salman, “Troponin Iand D-dimer levels in preeclampsia and eclampsia: prospectivestudy,” Clinical and Experimental Obstetrics & Gynecology,vol. 42, no. 1, pp. 26–31, 2015.

7Disease Markers

Stem Cells International

Hindawiwww.hindawi.com Volume 2018

Hindawiwww.hindawi.com Volume 2018

MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of

Hindawiwww.hindawi.com Volume 2018

Hindawiwww.hindawi.com Volume 2018

Disease Markers

Hindawiwww.hindawi.com Volume 2018

BioMed Research International

OncologyJournal of

Hindawiwww.hindawi.com Volume 2013

Hindawiwww.hindawi.com Volume 2018

Oxidative Medicine and Cellular Longevity

Hindawiwww.hindawi.com Volume 2018

PPAR Research

Hindawi Publishing Corporation http://www.hindawi.com Volume 2013Hindawiwww.hindawi.com

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwww.hindawi.com Volume 2018

Journal of

ObesityJournal of

Hindawiwww.hindawi.com Volume 2018

Hindawiwww.hindawi.com Volume 2018

Computational and Mathematical Methods in Medicine

Hindawiwww.hindawi.com Volume 2018

Behavioural Neurology

OphthalmologyJournal of

Hindawiwww.hindawi.com Volume 2018

Diabetes ResearchJournal of

Hindawiwww.hindawi.com Volume 2018

Hindawiwww.hindawi.com Volume 2018

Research and TreatmentAIDS

Hindawiwww.hindawi.com Volume 2018

Gastroenterology Research and Practice

Hindawiwww.hindawi.com Volume 2018

Parkinson’s Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwww.hindawi.com

Submit your manuscripts atwww.hindawi.com