https://orcid.org/0000-0003-2235-921X
Figures
Abstract
Background
Preeclampsia (PE) is a pregnancy-specific disorder characterized by endothelial dysfunction, and activation of the coagulation system. Alteration of PLT parameters is the common hematological abnormality observed in women with PE. The main aim of this study was to systematically review previous studies from around the world to generate evidence about the relationship between platelet count (PC) and PE, as well as mean platelet volume (MPV) and PE, by calculating the pooled weighted mean difference (WMD) of PC and MPV between PE and normotensive (NT) groups.
Methods
Relevant articles which were published in the English language from January 10, 2011, to January 10, 2021, were systematically searched through PubMed, Web of Science, and African journals online. In addition, reference probing of published articles searching was employed through Google Scholar and Google for searching grey literature. The methodological qualities of articles were assessed using Joana Brigg’s institute critical appraisal checklist. A random-effects model was used to estimate pooled WMD of PLT parameters between the two groups with the respective 95% confidence intervals (CI) using Stata version 11.0. The I2 statistics and Egger’s regression test were used to assess heterogeneity and publication bias among included studies, respectively.
Results
A total of 25 articles were included in this systematic review and meta-analysis. Of which, 23 studies were used in each PC and MPV analysis. The overall pooled WMD of PC and MPV between PE and NT groups were -41.45 × 109/L [95% CI; -51.8, -31.0] and 0.98 fl [95% CI; 0.8, 1.1], respectively. The pooled WMD revealed that PC decreased significantly in the PE group compared to the NT group while MPV increased significantly in the PE group.
Citation: Walle M, Gelaw Y, Getu F, Asrie F, Getaneh Z (2022) Preeclampsia has an association with both platelet count and mean platelet volume: A systematic review and meta-analysis. PLoS ONE 17(9): e0274398. https://doi.org/10.1371/journal.pone.0274398
Editor: Dermot Cox, Royal College of Surgeons in Ireland, IRELAND
Received: December 13, 2021; Accepted: August 26, 2022; Published: September 14, 2022
Copyright: © 2022 Walle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data supporting the findings are within the paper.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: BP, Systolic Blood Pressure; CBC, Complete Blood Count; DBP, Diastolic blood pressure; GW, Gestational Week; IQR, Interquartile Range; JBI, Joanna Brigg Institute; Mesh, Medical Subject Headings; MPV, Mean Platelet Volume; NT, Normotensive; PC, Platelet Count; PE, Preeclampsia; PlGF, Placental Growth Factor; PLT, Platelet; PRISMA, Preferred Reporting Items for Systematic Review and Meta-Analysis; PROSPERO, International Prospective Register of Systematic Reviews; SBP, Blood Pressure; SD, Standard Deviation; SE, Standard Error; sEng, Soluble Endoglin; sFlt-1, Soluble fms-like Tyrosine Kinase 1; TGFβ, Transforming Growth Factor-β; VEGF, Vascular Endothelial Growth Factor; WMD, Weighted Mean Difference
Introduction
Preeclampsia (PE) is a pregnancy-specific medical disorder that is characterized by activation of the coagulation system, and endothelial cell dysfunction [1]. It is diagnosed by elevated blood pressure (BP), a systolic BP (SBP) of at least 140 mmHg, or a diastolic BP (DBP) of 90 mmHg after 20th GW with proteinuria ≥ 1+ in urine dipstick [2]. Women with PE present diverse signs and symptoms associated with multiple organ systems, including headache, thrombocytopenia, severe hypertension, chest pain, pulmonary edema, low oxygen saturation, and abnormal liver and kidney function [3].This disorder is a major cause of maternal and fetal morbidity and mortality [4]. Around 5% of pregnancies are complicated by PE worldwide [5]. World Health Organization (WHO) estimated that the incidence of PE is higher in developing countries than in developed countries [6].
The placenta has always been a central figure in the etiology of PE [4].A two-stage model was developed to easily explain its complex pathogenesis [7]. First, deficient spiral artery remodeling in the uterus is caused by inadequate fetal trophoblast invasion of uterine tissue. The resulting abnormal implantation reduces maternal blood flow to the placenta and fetus, ultimately leading to the development of placental ischemia and an increase in oxidative stress [8, 9]. The second stage of PE starts when the placenta responds to progressive ischemia or hypoxia; the placenta may secret and release reactive oxygen species, chemokines, pro-inflammatory cytokines, and anti-angiogenic factors into the maternal circulation that contribute to endothelial damage [7, 10, 11].
Among the potential mediators, the balance between pro-angiogenic factors and anti-angiogenic factors is particularly clinically important [12].The disproportionate levels of pro-angiogenic factors like vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and transforming growth factor-β (TGFβ), and anti-angiogenic factors such as soluble endoglin (sEng) and soluble fms-like tyrosine kinase-1 (sFlt-1) are believed to cause generalized maternal endothelial dysfunctions [4]. For instance, the elevated levels of sFlt are thought to bind and reduce the bioavailability of VEGF, impairing their endogenous production of nitric oxide and causing vasoconstriction. The production of nitric oxide is induced by VEGF which neutralizes reactive oxygen species and vasoconstrictor signaling [13].
Furthermore, the release of Chemokines and pro-inflammatory cytokines induces inflammation in the maternal circulation, and the release of reactive oxygen species contributes to further placental oxidative stress and endothelial dysfunction [14].
The contact of platelet (PLT) with the injured endothelium activates the coagulation system which leads to an increase in PLT consumption and production [15]. Activation of the coagulation system with increased PLTs aggregation leads to multisystem dysfunction in PE [16, 17]. The elevated consumption of PLTs due to the abnormal coagulation system and PLT activation leads to thrombocytopenia which can be used as an important sign of PE [15, 18]. Mean platelet volume (MPV) is one of the groups of PLT parameters that is mainly related to PLT morphology and proliferation kinetics [19]. It is a marker of PLT size, function, and activation as the number and size of pseudopodia increases during PLT activation [20]. The increased consumption of PLTs obligated the bone marrow to produce and release young and large PLTs [15, 21] leading to an increase in MPV in PE patients [22, 23]. There were studies conducted on the association of PLT parameters with PE, however, the findings were controversial. For instance, several studies [17, 24, 25] found a significant association between PE and platelet count (PC), as well as PE and MPV; on the other hand, some studies [26–28] found non-significant differences in these parameters between PE and NT groups. Therefore, the primary goal of this systematic review and meta-analysis was to determine the pooled weighted mean difference (WMD) of PC and MPV between PE and normotensive (NT) groups and generate evidence about the association between PC and PE, and MPV and PE.
Materials and methods
Study design
This systematic review and meta-analysis was performed based on an updated preferred reporting item for systematic review and meta-Analysis (PRISMA) guideline 2020 [29]. This systematic review and meta-analysis analyzed findings from published articles to evaluate the pooled WMD of some PLT parameters between preeclamptic and NT pregnant women globally.
Eligibility criteria
Studies that met the following criteria were considered eligible for inclusion in this study.
Types of studies.
We include all published original studies with cross-sectional, case-control, and cohort study designs. There were language restrictions; studies published only in the English language were included. Moreover, we have included studies that were published from January 10, 2011, to January 10, 2021.
Types of participants.
We included studies that were carried out on the pregnant woman with a primary clinical diagnosis of PE and also having a control NT group.
Types of outcome measures.
The primary outcome of the study was determining the WMD of PC and MPV between PE and NT groups. Studies reported the outcome of interest (PC and MPV) and express the results as mean and standard deviation (SD) or median and interquartile range (IQR) for both PE and NT groups were included in this study.
Publication condition.
Studies that meet the eligibility criteria were included regardless of their publication status (published, unpublished and grey literature, etc.).
After a thorough screening of the abstracts and the full texts of the studies, articles having methodological problems were excluded. Studies that did not report the value of PC and MPV in both groups were excluded. Studies whose entire text was not available for free were also excluded. Furthermore, studies conducted among pregnant women, but who had co-morbidities like; HIV/AIDS, malaria, hypertension, and coagulation disorder were excluded from the study.
Information source
Data were collected through searching previous literature on electronic databases such as PubMed, Science direct, and African journals online using search terms. In addition, reference probing of published articles searching was employed through Google Scholar and Google for searching grey literature.
Search strategy
This was done independently by three reviewers (MW, ZG, and YG). A systematic search of published articles was performed on electronic databases using search terms. The search terms were developed following the Medical Subject Headings (Mesh) thesaurus in combination with free text key terms, and they were used in combination using Boolean operators like “OR” or “AND”. The searching terms used in electronic databases were “platelet parameter”, “platelet indices”, “platelet count”, “thrombocytes count”, “mean platelet volume”, “mean platelet size”, “MPV”, and “preeclampsia”. During the literature search, the results were limited by study population, language, availability of full text, and date of publication. Relevant articles which were written in the English language and published from January 10, 2011, to January 10, 2021, were systematically searched.
Selection process
After studies are identified through extensive searching, the search results were imported into EndNote X9 (Thomson Reuters, New York, USA) to organize and remove duplicated articles. After the removal of the duplicates, two authors (MW and YG) independently and meticulously screened the title and abstract of each of the retrieved articles for eligibility. In case of disagreement, consensus on which articles to screen full-text was reached by discussion. If necessary, the third reviewer (ZG) was consulted to make the final decision. Next, the two reviewers independently screened full-text articles for inclusion. Again, in case of disagreement, the consensus was reached on inclusion or exclusion by a discussion with the third reviewer.
Data collection process
We designed a data extraction form, which two review authors (MW and FA) used to extract data from eligible studies. Reviewers worked independently to extract study details. A third reviewer (ZG) reviewed data extraction, and resolve conflicts. The mean±SD values of PC and MPV in each group were extracted. The results of these parameters that were expressed as median (IQR) were also extracted and changed to mean and SD using a formula that was recommended by Wan et al. [30]. Additionally, the first author’s name, publication year, study country, study design, the sample size of the PE group, the sample size of the NT group, and PE severity status among PE groups were extracted. Moreover, the standard error (SE) of WMD was calculated to do Egger’s test and funnel plot. Extracted data were compared, with any discrepancies being resolved through discussion. Then, MW entered the extracted data into a Microsoft Excel spreadsheet.
Data item.
- PC: is a laboratory test to measure the number of PLTs per microliter of blood.
- MPV: is a laboratory test used to measure a PLT volume that reflects the bone marrow activity [31].
- PE severity: PE cases are divided into two categories based on the severity of the condition: mild PE and severe PE. Preeclamptic patients can be considered with mild PE when the BP ranged from 140/90-160/110 mmHg, and proteinuria ≥ 1 on a urine dipstick while severe PE when BP is ≥ 160/110 mmHg with proteinuria >3+ on a urine dipstick and edema and other major symptoms [2]. We extracted this data as mild or severe directly from the included studies. If the studies did not classify them as mild and severe, they were taken as undefined PE.
Risk of bias assessment
The methodological qualities of included studies were appraised in detail using the Joana Brigg’s institute (JBI) tool [32] by two reviewers (FA and FG). The tool consists of 8 items to assess the internal and external validity for cross-sectional studies, 10 items for case-control studies, and 11 items for cohort studies. Each item was assessed as 0 for “not done”, 1 for “done”, UC for “unclear”, and NA for “not applicable”. Any disagreements during the review process were resolved by consensus and when the disagreements continue after discussion, a third person (ZG) was consulted to finally settle the discrepancy. Finally, the overall qualities of the study were scored according to the number of done items per study quality assessment items. Articles with an average score of 50% and above were included in this meta-analysis study.
Effect measures
We planned to analyze the pooled WMD of PC and MPV and their 95%confidence interval (CI) between PE and NT groups in pair-wise meta-analyses by extracting the value of these parameters in each group from the report of previous studies.
Statistical analysis and interpretation
After the relevant data had been extracted from the studies using Microsoft excel format, the authors then analyzed the results by using STATA version 11.0 (STATA Corporation, College Station, TX, USA), and it was performed by MW and FG together. The original studies were summarized and presented by using a table and the forest plot. The random-effects model was used for pooling WMD analysis of PLT parameters between groups with the respective 95% CIs.
Heterogeneity between included studies was determined using Higgin’s I-squared statistics. The I2 values of 25%, 50%, and 75% were considered as low, medium, and high heterogeneity, respectively [33]. To explore the potential source of heterogeneity, subgroup analysis was carried out by study area, study design, and PE severity. Sensitivity analysis was performed to evaluate the influence of each study on the pooled measures by omitting one single study in each turn and recalculating the pooled WMD for the remainders. Publication bias was evaluated by inspection of funnel plots and Egger’s test (a statistical analog for funnel plots) [34]. All analyses were performed using Stata 11.0 (StataCorp LP, College Station, TX, USA), and P < 0 05 was considered to be statistically significant.
Results
Search and study selection
A total of 1, 496 studies were identified through database searching and Google search which were done on pregnant women and published from January 10, 2011, to January 10, 2021, in the English language. After removing duplicates, a total of 675 studies remained for screening. Out of which, 650 articles were excluded after reading their title (626 articles) and full-text (24 articles).Among 24 studies that were excluded after reading the full text, 19of them did not report the outcome variable (PLT parameters) in both groups clearly [1, 10, 18, 22, 35–49], and three studies did not report the criteria to diagnose PE [50–52], and the remaining two studies had not clearly described the study design [53, 54]. Finally, after excluding non-relevant articles, a total of 25 studies that reported the outcome of interest in terms of mean±SD or median (IQR) were included and used for the final analysis (Fig 1).
Study characteristics
In this systematic review and meta-analysis, a total of 25 articles were included. Out of 25 articles, three were conducted in China [38, 50, 55], four in India [17, 56–58], four in Turkey [16, 26, 27, 59], two in Korea [24, 60], two in Saudi-Arabia [61, 62], two in Egypt [25, 63], two in Sudan [64, 65], two were in Ethiopia [66, 67] and the other four studies were from Bangladesh [68], Brazil [69], Pakistan [70], and Mexico [28]. Of the included studies, 20 of them expressed the result of the outcome with mean±SD and the rest five [24, 26, 58, 59, 61] expressed the results with median (IQR).
A total of 27 studies were included for pooled WMD analysis of PC (Table 1). Of them, eight studies were included by splitting four studies [24, 25, 60, 67] into two based on PE severity. The included studies for PC analysis comprised a total of6, 250 pregnant women (1,943 PE and 4, 307NT). Of preeclamptic women, 319 women were with mild PE, 480 with severe PE and the rest 1,144 had undefined PE.A total of 29 studies were included for the pooled WMD analysis of MPV, with six of them [24, 25, 38, 59, 60, 67] being split into two studies depending on the severity of PE (Table 2).The included studies comprised a total of 6, 609 pregnant women (2,034PE and 4,575NT).
The association of platelet count with preeclampsia
We performed a random-effect meta-analysis of pooled WMD for PC on the extracted 27 studies. The overall pooled WMD revealed that PC decreased significantly in the PE group compared to the NT group [WMD: -41.5×109/L, 95% CI; -51.8×109/L, -31.0×109/L] (Fig 2).The estimated pooled mean of PC in PE and NT groups was 190.1×109/L [95% CI;164.2×109/L, 216.1×109/L] and 232.6×109/L [95% CI;144.2× 109/L, 321.1×109/L], respectively.
The association of mean platelet volume with preeclampsia
The random-effects meta-analysis for MPV showed that the estimated pooled mean of MPV in PE patients and NT pregnant women was 9.8fl [95% CI; 9.6fl, 10.1fl] and 8.8fl [95% CI; 8.7fl, 8.9fl], respectively. The overall pooled WMD analysis revealed that MPV values were significantly increased in the PE group when compared with the NT group [WMD: 0.98fl; 95%CI; 0.8, 1.1] (Fig 3).
Heterogeneity and publication bias analysis
The existence of heterogeneity and publication bias was determined within included studies. The heterogeneity of the included study was high according to Higgin’s I-squared statistics (I2 = 99.7%; p<001 for PC and I2 = = 97.7%; p<001 for MPV). The heterogeneity indicated that there was a high variation of studies which lead us to subgroup analysis. The subgroup analyses were performed based on the year of publication, PE severity, and region where the studies were conducted. However, there was no significant reduction in heterogeneity.
The Egger’s test was used to determine the presence of publication bias for the analysis of pooled WMD of PLT parameters between PE and NT pregnant women. The P-value in Egger’s test showed that the publication bias was marginally insignificant in all PLT parameter analyses [P = 0.565 for PC and P = 0.811 for MPV]. All the values were greater than 5%; indicating no evidence of publication bias within included studies (Tables 3 & 4) and no need for trim and fill analysis. Besides, a funnel plot was also depicted to illustrate the presence/absence of publication bias in all PC (Fig 4) and MPV (Fig 5) analyses.
Subgroup analysis
Subgroup analysis in estimated pooled weighted mean difference of platelet count between Preeclampsia and normotensive groups.
In the subgroup analysis by PE severity, the pooled WMD was less evident among women with mild PE and NT pregnant women [WMD: -39.7×109/L; 95%CI: -73.9,-5.4] compared to the difference between severe PE and NT pregnant women [WMD: -67.3×109/L; 95%CI: -105.0, -29.5], the difference in both cases was statistically significant (Fig 6). The subgroup analysis by study continent showed that PC decreased significantly in PE groups in Asia and Africa with pooled WMD of -37.5×109/L [95% CI; -52.2×109/L, -22.9× 109/L:I2 = 99.9%] and -65.6×109/L [95% CI; -65.6×109/L, -42.9×109/L: I2 = 90.9%], respectively. However, the pooled WMD of PC was not significant in the Europe region [WMD: -8.8×109/L; 95% CI;-30.7×109/L, 12.9×109/L] (Fig 7). Moreover, the subgroup analysis by study design showed that there was a significant decrement of PC in the PE group compared to the NT group in case-control and cross-sectional studies with a pooled WMD of -43.5×109/L [95% CI; -60.3×109/L, -26.7×109/L] and -53.1×109/L [95% CI; -70.1× 109/L,-36.0× 109/L], respectively. However, there was no significant difference among the groups in cohort studies with WMD -20.1×109/L [95% CI; -42.1×109/L, 1.9×109/L] in the retrospective cohort and -15.3×109/L [95% CI; -34.5× 109/L, 4.0× 109/L] in prospective cohort studies (Fig 8).
Subgroup analysis in estimated pooled weighted mean difference of mean platelet volume between preeclampsia and normotensive groups.
The subgroup analysis of MPV by PE severity revealed that the pooled WMD of MPV between severe PE group and NT group was smaller [WMD: 1.7fl; 95%CI; 0.9fl, 2.6fl] compared to the WMD between mild PE and NT groups [WMD: 1.2fl; 95%CI; 0.6fl, 1.8fl], the difference was significant in both subgroups (Fig 9). The subgroup analysis by continent showed that there was a significant difference of MPV between groups in Asia, Europe, and Africa with a pooled WMD of 0.6fl [95% CI; 0.5fl, 0.8fl], 0.6fl [95% CI; 0.3fl, 1fl], and 1.9fl [95% CI; 1.2fl, 2.6fl], respectively (Fig 10). Furthermore, the subgroup analysis by study design revealed that the pooled WMD among the groups in all study designs were significant with a pooled WMD of 0.9fl [95% CI; 0.6fl, 1.2fl], 1.2fl [95% CI; 0.1fl, 2.3fl], 0.9fl [95% CI; 0.6fl, 1.1fl], and 0.9fl [95% CI; 0.2fl, 1.6fl] in case-control, cross-sectional, retrospective cohort and prospective cohort studies, respectively (Fig 11).
Sensitivity analysis
Sensitivity analysis was carried out on the pooled WMD of PC and MPV among PE and NT pregnant women. The analysis was done to evaluate the effect of each study on the estimated pooled WMD. The result showed that omitted studies did not show a significant effect on the pooled estimated WMD of PC analysis among PE and NT pregnant women (Fig 12). However, the sensitivity statistics on the pooled WMD of MPV analysis indicated that one study [70] has a determinant effect on the pooled estimated WMD of MPV with an estimate WMD of 1.13 which was out of the overall pooled estimated range [WMD: 0.98; 95% CI; 0.84, 1.124] (Fig 13).
Discussions
During a normal pregnancy, the level of PC drops physiologically due to hemodilution, increased PLT consumption in peripheral tissue, and increased PLT aggregation as a result of increased levels of thromboxane A2 [71]. This Pregnancy-induced thrombocytopenia is mild and has no negative consequences for the mother or fetus, however, significant thrombocytopenia is associated with medical conditions and can have serious maternal-fetal consequences [72]. These changes may aggravate pregnancy-related disorders like PE. In established PE, changes in the coagulation system lead to a decrease in PC [24], which suggests an early sign of the disease [72]. Moreover, the progression of PE to the severe stage leads to increased turnover of PLTs [48]. The main objective of this systematic review and meta-analysis was to assess the association between PE and PC, PE and MPV. The association was determined by the pooled weighted mean difference. Accordingly, the majority of the included studies showed that PC was significantly lower in PE pregnant women than NT pregnant women [16, 17, 24, 25, 50, 57, 60, 61, 63, 65, 66, 68–70]. However, some studies showed that PC had not a significant difference between PE and NT pregnant women [26–28, 55, 56, 58, 62, 64]. Moreover, in the majority of the included studies, MPV was significantly higher in PE pregnant women than NT pregnant women [16, 17, 24, 25, 38, 50, 55, 56, 58, 60, 63–66, 68, 70]. Indeed, some studies showed MPV had no significant difference between PE and NT pregnant women [26, 28, 57, 59, 62, 69]. The reason for the discrepancy might be the difference in sample size, study design, diagnostic method, geographical location, and/or variation in gestational week between cases and controls.
Nevertheless, in this systematic review and meta-analysis, there was a significant decrement of pooled PC in the PE group compared to the NT group [WMD:-41.45 × 109/L; 95% CI; -51.8, -31.0]. This could be due to increased consumption of PLT due to an abnormal coagulation system along with PLT activation [15, 18]. In preeclamptic women, plasma PLTs activation markers like β-thrombomodulin and PLT factor-4 significantly increased [69]. The increment of plasma PLTs activation markers like β-thrombomodulin and PLT factor-4 [73, 74]and the expression of activation markers on the PLTs surface confirm PLT activation [75, 76]. The activation of PLTs leads to PLT consumption. Besides, impaired endothelial synthesis of Prostacyclin and nitric oxide has been related to PE [69, 77]. Both Prostacyclin and nitric oxide relax blood vessels and inhibit PLT activation [78]. Therefore the impairment of the synthesis of these molecules in PE may cause blood vessel constriction and leads to PLT activation and consumption [15, 24].
Moreover, this systematic review and meta-analysis revealed that the overall pooled WMD of MPV values was significantly increased in the PE group when compared with the NT group [WMD: 0.98fl; 95%CI; 0.8, 1.1]. This demonstrated that PE is associated with a significant increase in MPV. The finding was in agreement with a systematic review and meta-analysis done by Bellos et al. which claimed that MPV was significantly higher in preeclamptic patients than the NT pregnant women [79]. This could be due to the increased PLT synthesis in the bone marrow and release of large PLTs as a result of increased PLT consumption and destruction, increasing MPV in PE [80].
In the subgroup analysis by PE severity, the pooled WMD of all PLT parameters was smaller among women with mild PE and NT pregnant women compared to the difference between severe PE and NT pregnant women. This might be due to the increased activation of the coagulation system as the disease progresses from mild to severe stage [1]. So, it makes the WMD of PLT parameters in severe PE higher and more significant. The subgroup analysis by study design showed that the pooled WMD of PC was not significant in both retrospective and prospective cohort studies while MPV was not significant only in retrospective cohort studies. Moreover, Subgroup analysis based on continent showed the pooled WMD of MPV was significant in all regions while the pooled WMD of PC between PE and NT groups was significant in Asia and Africa regions.
Strengths and limitations of the study
The present review summarizes the current literature regarding the association of PC and MPV with PE which may give a clue to use these PLT parameters in the diagnosis of PE. It is based on a large number of studies for each parameter and included all relevant articles done around the globe. A comprehensive search using a different database and different searching strategies were the strength of this study. Moreover, the review was done in accordance with the protocol of the PRISMA statement. Nevertheless, most of the included studies had a case-control design; thus, selection bias cannot be excluded and studies that were published other than in English languages were not included. Even though subgroup analysis was performed the heterogeneity was still observed in all analyses.
Conclusions
The pooled data from our systematic review and meta-analysis suggest that PE is associated with a lowering PC and increasing MPV. Thus, the measurement of PLT parameters, like PC and MPV, among pregnant women can be used as easily available, economical, and inexpensive clinical indicators in the assessment of PE. As a result, combining PLT Parameters with BP is more important than utilizing BP alone. However, the predictive performances like cut-off value, sensitivity, and specificity of these parameters have to be explored for the early diagnosis of PE. Further, multicenter longitudinal studies are required to evaluate their role at various GW of pregnancy.
Supporting information
S2 File. The risk of bias assessment of included studies.
https://doi.org/10.1371/journal.pone.0274398.s002
(DOCX)
Acknowledgments
We appreciate all of the authors of the studies we used in our systematic review and meta-analysis.
References
- 1. Ammar K, El A, Gehad A, Mohamed I. Evaluation of platelet indices and their significance in Preeclampsia. Nature Science. 2014;12(3):147–53.
- 2. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ task force on hypertension in pregnancy. Obstetrics and gynecology. 2013;122(5):1122–31.
- 3. Fondjo L, Boamah V, Fierti A, Gyesi D, Owiredu E-W. Knowledge of preeclampsia and its associated factors among pregnant women: a possible link to reduce related adverse outcomes. BMC pregnancy childbirth. 2019;19(1):456. pmid:31791264
- 4. Gathiram P, Moodley J. Pre-eclampsia: its pathogenesis and pathophysiolgy. Cardiovascular journal of Africa. 2016;27(2):71. pmid:27213853
- 5. Abalos E, Cuesta C, Grosso AL, Chou D, Say L. Global and regional estimates of preeclampsia and eclampsia: a systematic review. European Journal of Obstetrics Gynecology Reproductive Biology. 2013;170(1):1–7. pmid:23746796
- 6.
Dolea C, AbouZahr C. Global burden of hypertensive disorders of pregnancy in the year 2000. World Health Organization, Geneva; 2003.
- 7. Phipps E, Prasanna D, Brima W, Jim B. Preeclampsia: updates in pathogenesis, definitions, and guidelines. Clinical Journal of the American Society of Nephrology. 2016;11(6):1102–13. pmid:27094609
- 8. Behram M, Oğlak SC, Doğan Y. Evaluation of BRD4 levels in patients with early-onset preeclampsia. Journal of Gynecology Obstetrics Human Reproduction. 2021;50(2):101963. pmid:33129979
- 9. Behram M, Oglak SC. The expression of angiogenic protein Cyr61 significantly increases in the urine of early-onset preeclampsia patients. Journal of Contemporary Medicine. 2021;11(5):605–9.
- 10. Mannaerts D, Heyvaert S, De Cordt C, Macken C, Loos C, Jacquemyn Y. Are neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and/or mean platelet volume (MPV) clinically useful as predictive parameters for preeclampsia? The Journal of Maternal-Fetal Neonatal Medicine. 2019;32(9):1412–9. pmid:29179639
- 11. Calvo P, Rodríguez P, Figueroa Q. Update in preeclampsia. Revista Médica Sinergia. 2020;5(01):345.
- 12. Jardim LL, Rios DRA, Perucci LO, de Sousa LP, Gomes KB, Dusse LMS. Is the imbalance between pro-angiogenic and anti-angiogenic factors associated with preeclampsia? Clinica chimica acta. 2015;447:34–8. pmid:25982781
- 13. Jim B, Karumanchi S. Preeclampsia: pathogenesis, prevention, and long-term complications. Seminars in nephrology. 2017;37(4):386–97. pmid:28711078
- 14. Burton G, Redman C, Roberts J, Moffett A. Pre-eclampsia: pathophysiology and clinical implications. BMJ (Clinical research ed). 2019;366:l2381. pmid:31307997
- 15. Juan P, Stefano G, Antonella S, Albana C. Platelets in pregnancy. Journal of prenatal medicine. 2011;5(4):90–2. pmid:22905300
- 16. Doğan K, Guraslan H, Senturk MB, Helvacioglu C, İdil S, Ekin M. Can platelet count and platelet indices predict the risk and the prognosis of preeclampsia? Hypertension in pregnancy. 2015;34(4):434–42. pmid:26362129
- 17. Annam V, Srinivasa K, Yatnatti S, Med S. Evaluation of platelet indices and platelet counts and their significance in pre-eclampsia and eclampsia. Int J Biol Med Res. 2011;2(1):425–8.
- 18. Sultana R, Karim SF, Atia F, Ferdousi S, Ahmed S. Platelet count in preeclampsia. Journal of Dhaka National Medical College Hospital. 2012;18(2):24–6.
- 19. Budak Y, Polat M, Huysal K. The use of platelet indices, plateletcrit, mean platelet volume and platelet distribution width in emergency non-traumatic abdominal surgery: a systematic review. Biochemia medica. 2016;26(2):178–93. pmid:27346963
- 20. Colkesen Y, Muderrisoglu H. The role of mean platelet volume in predicting thrombotic events. Clinical chemistry laboratory medicine. 2012;50(4):631–4. pmid:22112054
- 21. Oğlak SC, Tunç Ş, Ölmez F. First Trimester Mean Platelet Volume, Neutrophil to Lymphocyte Ratio, and Platelet to Lymphocyte Ratio Values Are Useful Markers for Predicting Preeclampsia. Ochsner Journal. 2021;21(4):364–70. pmid:34984051
- 22. Nooh A, Abdeldayem H. Changes in platelet indices during pregnancy as potential markers for prediction of preeclampsia development. Open Journal of Obstetrics Gynecology. 2015;5(12):703.
- 23. Walle M, Asrie F, Gelaw Y, Getaneh Z. The role of platelet parameters for the diagnosis of preeclampsia among pregnant women attending at the University of Gondar Comprehensive Specialized Hospital antenatal care unit, Gondar, Ethiopia. Journal of Clinical Laboratory Analysis. 2022;36(4):e24305. pmid:35202493
- 24. Yang S, Cho S, Kwon H, Sohn I, Hwang H. Significance of the platelet distribution width as a severity marker for the development of preeclampsia. European Journal of Obstetrics Gynecology Reproductive Biology. 2014;175:107–11. pmid:24502873
- 25. Alkholy EA-M, Farag E, Behery M, Ibrahim M. The significance of platelet count, mean platelet volume and platelet width distribution in Preeclampsia. AAMJ. 2013;11(1).
- 26. Kurtoglu E, Kokcu A, Celik H, Bildircin F, Tosun M, Alper T, et al. Validity of platelet indices in predicting the risk of developing preeclampsia. Clinical Research. 2016;33(2):57–61.
- 27. Kurt R, Aras Z, Silfeler D, Kunt C, Islimye M, Kosar O. Relationship of red cell distribution width with the presence and severity of preeclampsia. Clinical Applied Thrombosis/Hemostasis. 2015;21(2):128–31. pmid:23728834
- 28. Gutierrez-Aguirre C, García-Lozano J, Treviño-Montemayor O, Iglesias-Benavides J, Cantú-Rodríguez O, González-Llano O, et al. Comparative analysis of iron status and other hematological parameters in preeclampsia. Hematology. 2017;22(1):36–40. pmid:27558940
- 29. Page M, Moher D, Bossuyt P, Boutron I, Hoffmann T, Mulrow C, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ (Clinical research ed). 2021;372. pmid:33781993
- 30. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC medical research methodology. 2014;14(1):1–13. pmid:25524443
- 31. Ali U, Gibbs R, Knight G, Tsitsikas D. Sex-divided reference intervals for mean platelet volume, platelet large cell ratio and plateletcrit using the Sysmex XN-10 automated haematology analyzer in a UK population. Hematology, transfusion cell therapy. 2019;41:153–7. pmid:31079661
- 32.
Moola S, Munn Z, Tufanaru C, Aromataris E, Sears K, Sfetcu R, et al. Chapter 7: systematic reviews of etiology and risk. In: Aromataris E, Munn Z (Editors). Joanna briggs institute reviewer’s manual. [Internet]. The Joanna Briggs Institute. 2017. https://reviewersmanual.joannabriggs.org.
- 33. Huedo-Medina TB, Sánchez-Meca J, Marín-Martínez F, Botella J. Assessing heterogeneity in meta-analysis: Q statistic or I2 index? Psychological methods. 2006;11(2):193.
- 34. Sterne J, Egger M, Smith G. Systematic reviews in health care: Investigating and dealing with publication and other biases in meta-analysis. BMJ (Clinical research ed). 2001;323(7304):101–5. pmid:11451790
- 35. Mayer-Pickel K, Stern C, Eberhard K, Lang U, Obermayer-Pietsch B, Cervar-Zivkovic M. Comparison of mean platelet volume (MPV) and sFlt-1/PlGF ratio as predictive markers for preeclampsia. The Journal of Maternal-Fetal Neonatal Medicine. 2021;34(9):1407–14. pmid:31257953
- 36. Dadhich S, Agrawal S, Soni M, Choudhary R, Jain R, Sharma S, et al. Predictive value of platelet indices in development of preeclampsia. SAFOG. 2012;4(1):17–21.
- 37. Laskin S, Payne B, Hutcheon J, Qu Z, Douglas M, Ford J, et al. The role of platelet counts in the assessment of inpatient women with preeclampsia. Journal of Obstetrics Gynaecology Canada. 2011;33(9):900–8. pmid:21923987
- 38. Han L, Liu X, Li H, Zou J, Yang Z, Han J, et al. Blood coagulation parameters and platelet indices: changes in normal and preeclamptic pregnancies and predictive values for preeclampsia. PloS one. 2014;9(12):e114488. pmid:25464515
- 39. Rezk M, Gaber W, Shaheen A, Nofal A, Emara M, Gamal A, et al. First versus second trimester mean platelet volume and uric acid for prediction of preeclampsia in women at moderate and low risk. Hypertension in pregnancy. 2018;37(3):111–7. pmid:29893156
- 40. Gupta A, Bindu S, Mishra K, Dubey I. A comparison of platelet count in severe preeclampsia, mild preeclampsia and normal pregnancy. Int J Res Med Sci. 2018;6:671–6.
- 41. Kashanian M, Hajjaran M, Khatami E, Sheikhansari N. Evaluation of the value of the first and third trimester maternal mean platelet volume (MPV) for prediction of pre-eclampsia. An International Journal of Women’s Cardiovascular Health. 2013;3(4):222–6. pmid:26103800
- 42. Sisti G, Faraci A, Silva J, Upadhyay R. Neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and routine complete blood count components in HELLP syndrome: a matched case control study. Medicina. 2019;55(5):123.
- 43. Tzur T, Sheiner E. Is there an association between platelet count during the first trimester and preeclampsia or other obstetric complications later in pregnancy? Hypertension in pregnancy. 2013;32(1):74–82. pmid:23394118
- 44. Vinodhini R, Lavanya K. Evaluation of platelet count as a prognostic index in eclampsia and pre-eclampsia. Int J Modn Res Revs. 2014;2(10):447–52.
- 45. Kanat‐Pektas M, Yesildager U, Tuncer N, Arioz D, Nadirgil‐Koken G, Yilmazer M. Could mean platelet volume in late first trimester of pregnancy predict intrauterine growth restriction and pre‐eclampsia? Journal of Obstetrics Gynaecology Research. 2014;40(7):1840–5. pmid:25056460
- 46. Dundar O, Yoruk P, Tutuncu L, Akyol Erikci A, Muhcu M, Ergur AR, et al. Longitudinal study of platelet size changes in gestation and predictive power of elevated MPV in development of pre‐eclampsia. Prenatal Diagnosis: Published in Affiliation With the International Society for Prenatal Diagnosis. 2008;28(11):1052–6. pmid:18973157
- 47. Altınbas S, Toğrul C, Orhan A, Yücel M, Danısman N. Increased MPV is not a significant predictor for preeclampsia during pregnancy. Journal of clinical laboratory analysis. 2012;26(5):403–6. pmid:23001987
- 48. Özdemirci Ş, Başer E, Kasapoğlu T, Karahanoğlu E, Kahyaoglu I, Yalvaç S, et al. Predictivity of mean platelet volume in severe preeclamptic women. Hypertension in pregnancy. 2016;35(4):474–82. pmid:27314286
- 49. Vilchez G, Lagos M, Kumar K, Argoti P. Is mean platelet volume a better biomarker in pre‐eclampsia? Journal of Obstetrics Gynaecology Research. 2017;43(6):982–90. pmid:28422358
- 50. Zhang H, Zhang Y, Wang Z, Yan J. Platelet count and mean platelet volume predict atypical pre-eclampsia. Pregnancy hypertension. 2019;18:29–34. pmid:31450133
- 51. Maconi M, Cardaropoli S, Cenci A. Platelet parameters in healthy and pathological pregnancy. Journal of clinical laboratory analysis. 2012;26(1):41–4. pmid:24833533
- 52. Vagdatli E, Gounari E, Lazaridou E, Katsibourlia E, Tsikopoulou F, Labrianou I. Platelet distribution width: a simple, practical and specific marker of activation of coagulation. Hippokratia. 2010;14(1):28. pmid:20411056
- 53. Karateke A, Kurt RK, Baloğlu A. Relation of platelet distribution width (PDW) and platelet crit (PCT) to preeclampsia. Ginekologia polska. 2015;86(5).
- 54. Yavuzcan A, Caglar M, Ustun Y, Dilbaz S, Yidiz E, Ozbilgec S, et al. Mean platelet volume, neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in severe preeclampsia. Ginekologia polska. 2014;85(3). pmid:24783431
- 55. Chen Y, Lin L. Potential value of coagulation parameters for suggesting preeclampsia during the third trimester of pregnancy. The American journal of the medical sciences. 2017;354(1):39–43. pmid:28755731
- 56. Gogoi P, Sinha P, Gupta B, Firmal P, Rajaram S. Neutrophil‐to‐lymphocyte ratio and platelet indices in pre‐eclampsia. International Journal of Gynecology Obstetrics. 2019;144(1):16–20. pmid:30362112
- 57. Amita K, Kumar N, Shobha S, Shankar V. The role of platelet parameters as a biomarker in the diagnosis and in predicting the severity of preeclampsia. Indian Journal of Pathology Oncology. 2015;2(2):57–60.
- 58. Thalor N, Singh K, Pujani M, Chauhan V, Agarwal C, Ahuja R. A correlation between platelet indices and preeclampsia. Hematology, transfusion cell therapy. 2019;41(2):129–33. pmid:31084762
- 59. Yücel B, Ustun B. Neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, mean platelet volume, red cell distribution width and plateletcrit in preeclampsia. Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health. 2017;7:29–32. pmid:28279444
- 60. Kim MA, Han GH, Kwon JY, Kim YH. Clinical significance of platelet‐to‐lymphocyte ratio in women with preeclampsia. American Journal of Reproductive Immunology. 2018;80(1):e12973. pmid:29781540
- 61. AlSheeha M, Alaboudi R, Alghasham M, Iqbal J, Adam I. Platelet count and platelet indices in women with preeclampsia. Vascular health risk management. 2016;12:477. pmid:27920548
- 62. Elgari M, Khabour O, Alhag S. Correlations between changes in hematological indices of mothers with preeclampsia and umbilical cord blood of newborns. Clinical Experimental Hypertension. 2019;41(1):58–61. pmid:29473761
- 63. Hassan HE-S, Azzam H, Othman M, Hassan M, Selim T. Soluble E-selectin, platelet count and mean platelet volume as biomarkers for pre-eclampsia. Pregnancy hypertension. 2019;17:1–4. pmid:31487622
- 64. Abass A-E, Abdalla R, Omer I, Ahmed S, Khalid A, Elzein H. Evaluation of platelets count and indices in pre-eclampsia compared to normal pregnancies. IOSR J Dent Med Sci. 2016;1(15):5–8.
- 65.
Mohammed F. Platelets Count and Indices as possible predictors for pre-eclampsia in Sudanese Women in Khartoum State Maternity Hospitals: Sudan University of Science & Technology; 2016.
- 66. Sitotaw C, Asrie F, Melku M. Evaluation of platelet and white cell parameters among pregnant women with Preeclampsia in Gondar, Northwest Ethiopia: A comparative cross-sectional study. Pregnancy hypertension. 2018;13:242–7. pmid:30177059
- 67. Tesfay F, Negash M, Alemu J, Yahya M, Teklu G, Yibrah M, et al. Role of platelet parameters in early detection and prediction of severity of preeclampsia: A comparative cross-sectional study at Ayder comprehensive specialized and Mekelle general hospitals, Mekelle, Tigray, Ethiopia. Public Library of Science one. 2019;14(11):e0225536. pmid:31751422
- 68. Mondal B, Paul D, Sultana T, Rahman Q, Ahmed S, Fatema K, et al. Assessment of platelet count and platelet indices in preeclampsia and eclampsia. Am J Innov Res Appl Sci. 2015;1(3):80–4.
- 69. Freitas L, Alpoim P, Komatsuzaki F, Carvalho M, Dusse LM. Preeclampsia: are platelet count and indices useful for its prognostic? Hematology. 2013;18(6):360–4. pmid:23676885
- 70. Mazhar S, Mazhar N, Anwa A. Usefulness of platelet count and mean platelet volume in prediction of preeclampsia. Pakistan Postgraduate Medical Journal. 2014;25(4):118–20.
- 71. Ciobanu AM, Colibaba S, Cimpoca B, Peltecu G, Panaitescu AM. Thrombocytopenia in pregnancy. J Maedica. 2016;11(1):55. pmid:28465752
- 72. Vinodhini R, Lavanya K. Evaluation of platelet count as a prognostic index in eclampsia and pre eclampsia. Int J Modn Res. 2014;2(10):447–52.
- 73. Inglis T, Stuart J, George A, Davies A. Haemostatic and rheological changes in normal pregnancy and pre‐eclampsia. British Journal of Haematology. 1982;50(3):461–5. pmid:6461347
- 74. Trogstad L, Magnus P, Stoltenberg C. Pre-eclampsia: Risk factors and causal models. Best practice & research Clinical obstetrics & gynaecology. 2011;25(3):329–42. pmid:21349772
- 75. Konijnenberg A, Stokkers EW, van der Post JA, Schaapb MC, Boer K, Bleker OP, et al. Extensive platelet activation in preeclampsia compared with normal pregnancy: enhanced expression of cell adhesion molecules. American journal of obstetrics and gynecology. 1997;176(2):461–9. pmid:9065199
- 76. Janes SL, Kyle PM, Redman C, Goodall AH. Flow cytometric detection of activated platelets in pregnant women prior to the development of pre-eclampsia. Thrombosis and haemostasis. 1995;74(10):1059–63.
- 77. Fitzgerald DJ, Entman SS, Mulloy K, FitzGerald GA. Decreased prostacyclin biosynthesis preceding the clinical manifestation of pregnancy-induced hypertension. Circulation. 1987;75(5):956–63. pmid:3552297
- 78. Mitchell JA, Ali F, Bailey L, Moreno L, Harrington LS. Role of nitric oxide and prostacyclin as vasoactive hormones released by the endothelium. Experimental physiology. 2008;93(1):141–7. pmid:17965142
- 79. Bellos I, Fitrou G, Pergialiotis V, Papantoniou N, Daskalakis G. Mean platelet volume values in preeclampsia: a systematic review and meta-analysis. Pregnancy hypertension. 2018;13:174–80. pmid:30177049
- 80. Kaito K, Otsubo H, Usui N, Yoshida M, Tanno J, Kurihara E, et al. Platelet size deviation width, platelet large cell ratio, and mean platelet volume have sufficient sensitivity and specificity in the diagnosis of immune thrombocytopenia. British journal of haematology. 2005;128(5):698–702. pmid:15725092