|Year : 2023 | Volume
| Issue : 1 | Page : 36
Analysis of varying micrornas as a novel biomarker for early diagnosis of preeclampsia: A scoping systematic review of the observational study
Muhammad Mikail Athif Zhafir Asyura1, Maria Komariah2, Shakira Amirah1, Emir G Faisal1, Sidik Maulana3, Hesti Platini4, Tuti Pahria4
1 Undergraduate Medical Education, Faculty of Medicine, Universitas Indonesia, Indonesia
2 Department of Fundamental in Nursing, Faculty of Nursing, Universitas Padjadjaran, Indonesia
3 Professional Nursing Program, Faculty of Nursing, Universitas Padjadjaran, Indonesia
4 Department of Medical-surgical Nursing, Faculty of Nursing, Universitas Padjadjaran, Indonesia
|Date of Submission||04-May-2022|
|Date of Acceptance||03-Oct-2022|
|Date of Web Publication||21-Mar-2023|
Department of Fundamental in Nursing, Faculty of Nursing, Universitas Padjadjaran, Bandung
Source of Support: None, Conflict of Interest: None
Background: Preeclampsia (PE) is a pregnancy-related syndrome with moderate mortality. Early diagnosis of the condition remains difficult, with the current diagnostic modalities being ineffective. The varying microRNAs (miRNAs) as a novel biomarker pose an alternative solution with their potential to be reviewed. Methods: This study follows the Preferred Reporting Item for Systematic Review and Meta-Analysis Extended for Scoping Review (PRISMA-ScR). PubMed/MEDLINE, CENTRAL/Cochrane, ProQuest, Science Direct, and Wiley Online Library were used for this review. We only include observational studies. A critical appraisal was assessed in this study using QUADAS-2. Results: We retrieved 30 observational studies fulfilling the set criteria. Data extracted were synthesized qualitatively based on miRNAs that are more prominent and their area-under-the-curve (AUC) values. In total, 109 distinct dysregulated miRNAs were identified in comparison to healthy controls, with 10 of them (mir-518b, mirR-155, mirR-155-5p, miR-122-5p, miR-517-5p, miR-520a-5p, miR-525-5p, miR-320a, miR-210, and miR-210-3p) being identified in two or more studies. A brief look at the results shows that 49 miRNAs are downregulated and 74 miRNAs are upregulated, though the fold change of the dysregulation in all studies is not available due to some studies opting for a visual representation of the differences using whisker plots, bar charts, and heat map diagrams to visualize the difference from the reference control. Conclusions: This study has analyzed the potential of varying miRNAs as potential diagnostic biomarkers and how they might be used in the future. Despite this, potent miRNAs identified should be more emphasized in future research to determine their applicability and connection with the pathogenesis.
Keywords: Biomarkers, early diagnosis, microRNAs, preeclampsia, pregnancy
|How to cite this article:|
Zhafir Asyura MM, Komariah M, Amirah S, Faisal EG, Maulana S, Platini H, Pahria T. Analysis of varying micrornas as a novel biomarker for early diagnosis of preeclampsia: A scoping systematic review of the observational study. Int J Prev Med 2023;14:36
|How to cite this URL:|
Zhafir Asyura MM, Komariah M, Amirah S, Faisal EG, Maulana S, Platini H, Pahria T. Analysis of varying micrornas as a novel biomarker for early diagnosis of preeclampsia: A scoping systematic review of the observational study. Int J Prev Med [serial online] 2023 [cited 2023 Jun 8];14:36. Available from: https://www.ijpvmjournal.net/text.asp?2023/14/1/36/372270
| Introduction|| |
Preeclampsia (PE) is a pregnancy-related syndrome with a prevalence of 5–8% in the world. PE is characterized by high blood pressure and proteinuria, which leads to various pathological processes as a major cause of maternal, fetal, and neonatal mortality and morbidity. Each year, about 76,000 women and 500,000 infants die from PE. PE has also been associated with an increased risk of diabetes mellitus and cardiovascular complications in the mother and later on in the child.
PE which is classified into early-onset PE (EOPE) and late-onset PE (LOPE) may appear after 20 weeks of gestation. In early-onset PE (EOPE), the clinical symptoms experienced by the mother will appear before 33 gestational weeks, whereas in late-onset PE (LOPE), they appear at and after 34 weeks., EOPE itself is responsible for the most maternal and fetal mortality and morbidity rates. The placenta plays an integral role in the development of PE. To explain the occurrence of PE, there are pathophysiological differences between EOPE and LOPE. In EOPE, there is a transformation of the spiral arteries resulting in placental hypoperfusion followed by a decrease in nutrients that will be delivered to the fetus. This will also be a sign of fetal growth restriction (FGR). In contrast to EOPE, in LOPE, there is little or no modification of the spiral arteries, which in some cases causes hyperperfusion of the placenta. The high mortality rate in mothers and infants indicates that preventive measures arising from effective diagnostic tools or treatment for PE patients remain sub-optimal. The only cure available is to reduce proinflammatory agents in the maternal cardiovascular system through the delivery of the fetus. Until now, the cause of PE is still not fully understood and several studies have been conducted to investigate it. Therefore, it is necessary to develop (bio)markers that can be used to accurately diagnose PE patients early, even before extensive treatment is needed.
Recently, several studies have focused on identifying molecules named microRNAs (miRNAs). miRNAs are small non-coding ribonucleic acid (RNA) molecules containing approximately 22 nucleotides that regulate biological functions within cells, including apoptosis, cell development, and cell differentiation by binding to specific regions of the 3′-untranslated regions (3′-UTR). Various pieces of research evidence indicate that miRNAs play an important role in the process of placental development as well as pregnancy, which play a pivotal role in the pathophysiology of PE. Empirical findings and comparisons show some differentially expressed miRNAs in comparison to controls or true-normal subjects. A previous study in the meta-analysis found that miRNA biomarkers may be potentially important to PE diagnosis. However, the evidence has limited included studies. Moreover, we need to find varying miRNAs than their included studies retrieved. Following that thought process, this study will investigate the potential and variation of miRNA as a diagnostic biomarker for PE with more extensive evidence than in previous studies and contribute toward the realization of sustainable development goals (SDGs) 3.4, which is to reduce premature mortality from non-communicable diseases (NCDs) through prevention and treatment and promote mental health and well-being.
| Methods|| |
This study was conducted following the Preferred Reporting Item for Systematic Review and Meta-analysis for Scoping Review (PRISMA-ScR) [see Supplementary File 1]. This study aimed to investigate the potential of miRNA as a diagnostic biomarker for PE.
To obtain the relevant studies, the following keywords were used: “mirna” OR “microRNA” OR “mir-” OR “non coding RNA”) AND (”preeclampsia” OR “Toxemias” OR “pregnancy: Gestosis”), altogether with known synonyms and applying the use of medical subject heading (MeSH) terms where appropriate. The search strategy was carried out in five databases, namely, PubMed/MEDLINE, CENTRAL/Cochrane, ProQuest, Science Direct, and Wiley Online Library for records that were published until August 15, 2021.
Inclusion and exclusion criteria
Throughout the creation of this review, we applied the inclusion criteria as follows: (1) observational study design which includes case controls and cohorts, (2) the population being female patients identified with PE or any other specific classifications of PE, (3) index test measured being the alteration of miRNA identified, (4) controls being healthy pregnant patients, and (5) outcome in terms of the type of miRNA studied accompanied with the alteration identified and fold change if available. The exclusion criteria applied were (1) pieces of literature with irretrievable full text, (2) articles that include reviews, letters, commentaries, and conference abstracts, and (3) studies written in languages other than Bahasa Indonesia or English.
Data collection and study outcome
Three independent reviewers carried out data extraction, with any discrepancies later on adjudicated through consensus together. The details extracted from reviewed studies include: (1) authors and the year of publication, (2) population characteristics which include size, characteristics, and age of the sample, (3) study characteristics including the location and study design, (4) biological source of miRNA used, (5) platform of analysis used, and (6) type of miRNA studied accompanied with its alteration and fold change. Secondary outcomes for studies were also extracted for discussions such as the area under the curve (AUC).
A risk of bias (ROB) assessment was conducted based on the Quality Assessment of Diagnostic Accuracy Studies –2 (QUADAS 2). Each study is evaluated based on a number of domains that measures the eligibility of patient selection, index test, reference standard, flow, and timing. Each domain is equipped with 3–4 signaling questions to determine the final score being the low, high, or unclear ROB. The first three domains would also be evaluated for concerns regarding the applicability of the research question. The assessments were performed by all reviewers (EGF and SA), with discrepancies resolved by consensus and adjudicated by a third reviewer (MMAZA).
| Results|| |
| Search results|| |
Literature searching according to the PRISMA flow diagram [Figure 1] resulted in 6145 studies from 5 different databases. Initial screening based on title and abstract relevancy yielded 41 records for full-text screening. After 5 duplicates were excluded, 36 studies were eligible for full-text screening. Six studies were further excluded due to five having incompatible study designs conducted in vivo and one study in Chinese. In total, we had 30 studies that fulfilled the set criteria and would be further analyzed by tabulation of extracted data for comparison and qualitative synthesis based on the miRNA's dysregulation between patients identified with PE and healthy pregnant females.
Characteristics of the included study
Careful screening by three independent reviewers (MMAZ, EGF, and SA) resulted in 27 case-control[13–39] and 3 cohort studies[40–42] being included in this review. The studies were carried out in mostly affluent countries in Asia, Europe, and the Americas with half of the studies (n = 15) conducted in China. Most of the studies recruited samples ranging from 10 to 40 PE females, accompanied by control groups ranging from 30 to 40 participants, except for a case-control study conducted by Kim et al., which recruited a total of 92 PE patients and an equal number of controls. The mean age of the samples was within the range of 25–46 years [Table 1].
Critical appraisal results of the included studies are shown in [Figure 2] according to QUADAS-2. Based on the four domains assessing for bias, high and unclear risks of bias are mostly identified in the domain assessing for patient selection. Risks arising from this domain are due to most studies having a case-control study design, and no randomization occurred among the sample group for the index test and reference standard, again due to the nature of the study design. Furthermore, bias was also identified in the flow and timing domain, in which some studies did not include all patients for analysis or did not explicitly state the number of subjects receiving the reference standard. However, the majority (or even all) of the studies show a low ROB for the index test and reference standard used. Moreover, the same could be said for domains that were assessed for their applicability, which all showed a low ROB in terms of concerns relating to the initial research question implemented.
In terms of outcome extracted, there were three biological sources for miRNA identified: Plasma (n = 15), placenta (n = 11), and peripheral blood (n = 6) with most of the samples analyzed using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and microarray analysis. In total, there were 109 unique dysregulated miRNAs identified in comparison to the healthy controls, with 10 of them (mir-518b, mirR-155, mirR-155-5p, miR-122-5p, miR-517-5p, miR-520a-5p, miR-525-5p, miR-320a, miR-210, and miR-210-3p) identified in two or more included studies [Table 2]. A brief look at the outcome shows 49 miRNAs being downregulated and 74 miRNAs being upregulated, although fold change of the dysregulation of all studies is not available due to some opting for a visual representation of the differences using whisker plots, bar charts, and heat map diagrams to visualize the difference from the reference control. Other than quantifiable fold change, studies conducted by Hromadnikova (2017) et al., Li et al., Timofeeva et al., Jelena et al., Kim et al., Demirer et al., and Hromadnikova (2019) et al. further examined the parameters using receiving operative characteristics (ROC) and AUC to determine the overall sensitivity and specificity of the diagnostic biomarker.,,,,,, Studies with the AUC would be evaluated qualitatively separate from the qualitative analysis carried out on the fold change of the miRNA dysregulations. The summary of all included studies can be seen in [Table 3] (see supplementary materials), whereas a summary of AUC values is shown in [Table 4] and would further be discussed in this review.
| Discussion|| |
PE is defined as new-onset gestational hypertension associated with at least one proteinuria, maternal organ dysfunction, or uteroplacental dysfunction in or after 20 weeks of gestation. Additionally, PE may develop either intrapartum or postpartum for the first time. To confirm hypertension, blood pressure has to be measured on two occasions with an appropriate tool. Other diagnosing methods such as detecting proteinuria could also be used for diagnosing PE. The current method and golden standard for diagnosing proteinuria is via a 24-hour urine analysis. However, this method has several disadvantages, such as its time-consuming nature, the requirement of refrigeration, and often incomplete samples. Other laboratories and imaging tests of women with de novo hypertension require hemoglobin, platelet count, serum creatinine, liver enzymes, and uric acid serum in determining the presence of any maternal organ dysfunction and the diagnosis of PE. In the pathogenesis of PE, levels of sFlt-1 and lower levels of PlGF are subtle before the onset of the disease. Therefore, screening of these components has shown to have great sensitivity and specificity in diagnosing PE. Trials conducted by Fox et al. showed that PIGF screening for PE diagnosis is significantly faster and safer in terms of maternal adverse events and morbid neonatal outcomes. With the difficulties in predicting and diagnosing PE, several studies started to investigate other marker algorithms for predicting PE. These markers employ the same diagnostic capabilities such as identifying dysregulation in (1) A (PAPP-A), (2) disintegrin and metalloproteinase 12 (ADAM12), (3) placental growth factor (PIGF), (4) placental protein 12, (5) angioprotein 1/2, (6) inhibin & activin A, (7) soluble endoglin, (8) soluble fms-like tyrosine kinase 1 (sFLt-1), and (9) human chorionic gonadotropin (hCG).
Despite being repeatedly reviewed, these diagnostic markers are still categorized as insufficient due to the limitation of reliability and validity. Other studies have shown that cffDNA is also dysregulated, thus having the potential as a marker. However, cffDNA usage is again limited because of its low levels after the second trimester, making the biomarker very time-bound in terms of its applicability. Early detection and prediction of PE have been the main focus for prevention, translating the amount of effort being put into early detection tools. Despite these efforts, the sensitivity and predictive value of these markers remain sub-optimal. Therefore, new solutive tools for diagnosing and predicting PE are continuously being sought.
MicroRNAs (miRNAs), are small single-stranded molecules of 22 nucleotides among non-coding RNAs, which are not involved in protein translation and transcription. miRNA is considered a post-transcriptional regulatory molecule with the ability to degrade mRNA and suppress translation. Studies have shown a subtle difference in the expression of miRNA in PE. This pattern of miRNA is detected in the placenta, peripheral blood, mesenchymal stem cells (MCs), umbilical cord blood, and umbilical vein endothelial cells. This indicates the availability of miRNAs or circulating miRNAs in biological sources relevant to PE and the importance of source location which could have a varying correlation with expression profiles, either upregulated or downregulated. In PE, altered miRNA expression may indicate the severity and its involvement in metabolic changes and other essential mechanisms.[51–53] However, the definite difference (between women with PE and healthy pregnant women) is in the regulation of trophoblast function, angiogenesis, and mesenchymal stem cell function as a predictor for diagnosis. Moreover, the detection of nucleic acid molecules is proven to be essential and even necessary to screen for congenital abnormalities such as PE.
As mentioned before, from the 109 dysregulated miRNAs identified, 10 were reported across 15 studies, thus indicating a higher probable significance in terms of their applicability [Table 2].,,,,,,,,,,,, However, caution should be taken for qualitative synthesis, and numbers alone should be a sole comparator for its significance. This is definitely true for two studies conducted by Hromadnikova et al. in 2017 and 2019,, with the latter identifying the same miRNA sequence in the previous study. Other than times identified, the easiness of a miRNA as a potent biomarker could potentially be identified based on their margin difference.,, Based on fold change alone, the analysis could be carried out by identifying the miRNA sequence based on the greatest fold change identified for the respective source [Table 3]. For miRNAs acquired from the plasma of a PE-suspect patient, the highest fold change identified was ±33 × for miR-210-3p and miR-517c-3p from a case-control study conducted by Nejad et al. On the contrary, hsa-miR-188-3p was identified with a greater downregulation of 0.26×. Interestingly, only plasma-sourced studies explicitly stated the fold change of the miRNA identified, with an exception of Niu et al.'s study which showed an upregulation of 2.36× for miR-30a-3p and Youssef et al.'s study with both miR-210 and miR-155 showing upregulation of more than 2×. However, similar to the number of miRNAs identified, fold change should not be taken slowly as a basis of recommendation due to its vague statistical significance. Carrying on from that statement, the authors decided to do another subset analysis on included studies, where AUC is defined and presented for the identified miRNA.
By definition, AUC or area under the ROC curve signifies the aggregate performance measure of the stated classification threshold, or in this context, the specificity and sensitivity of the respective miRNA as a biomarker for PE. Of the 30 included studies, only 8 studies were completed by Hromadnikova et al. in 2017 and 2019, Li et al.,2015 Li et al.,2020 Timofeeva et al., Jelena et al., Kim et al., and Demirer et al. [Table 4].,,,,,,, AUC values close to 1.0 signify a higher aggregation of sensitivity and specificity, thus signifying a better probability score of that respective miRNA to be used as a biomarker., Following these terms, miR-31-5p should be identified as the most prospective and consistent miRNA for PE. However, a more interesting analysis could be carried out by combining the AUC values and the consistency the respective miRNA has based on the number of times the miRNA has been identified across the included studies.
Cross-analysis of both parameters yielded miR-210 (and miR-210-3p), miR-525-5p, and miR-518b.,,,,,,, Despite the limited literature, both miR-525-5p and miR-518b have a direct association with PE; miR-210 (forward: 5′CUGUGCGUGUGACAGCGGCUGA-3′ and reverse: 5′ AGCCGCUGUCACACGCACAGUU-3′) has frequently been reported to show association with the pathogenesis of PE. This association was further developed within the included studies, in which the overexpression of miR-210 had a significant correlation with urea increase and even higher significance in correlation with systolic, diastolic, mean arterial blood pressure (MAP), and creatine levels of more deteriorated cases of PE on both maternal and fetal parameters. Furthermore, overexpression of miR-210 was also inversely correlated with gestational age and fetal birth weight. Hence, both observations imply how miR-210 could be directly involved in PE and its more severe progressions. However, a conclusion based only on correlation is considerably not clinically feasible; thus, more causative study designs on miR-210 and the other two potential miRNAs should be considered to further coin miRNA for the diagnosis of PE.,,,
However, there are challenges in using miRNA as a diagnostic feature and detecting PE. Some of the challenges are principally associated with the small size, low expression level, and similar sequence among tissue during developmental stage expression. The method in screening studies such as droplet digital PCR, microarrays, quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), and deep sequencing has their limitation, method, and factor affecting the output of the study. The most common quantification method of miRNA is qRT-PCTR. Therefore, as said before, the lack of different expressions from plasma or serum is concerning. The normalization of controls and methods is variable, impacting the effectiveness of the reaction. However, using different normalization methods in studies leads to inconsistent results. Therefore, a reliable normalization of control and method in each cell, tissue, and condition is demanded. In contrast to the challenges, the implementation of miRNA is related to next-generation sequencing (NGS) in detecting the presence of exosome miRNA in most PE cases. This highly sensitive method of quantifying miRNA expression has been used to detect and identification of novel and altered levels of miRNA. NGS is cost-effective because it is a high ability in capacities. Nevertheless, NGS has some contrary detection because of the low input amount due to extracellular detection. On the overall implementation of detecting PE using miRNA, it can be concluded that miRNA is a potential biomarker and, with the contrast and issues stated before, methodologies and comparisons to in silico prediction models are needed for a more precise role of miRNA in broad conditions and suitable biomarkers, especially for PE.
Objectively, this study has its own limitations based on the review methodology and also several factors the included studies possess. Firstly, the large number of dysregulated miRNAs identified may instead signify the inconsistency of actually finding the same miRNA sequence being dysregulated from the sample source. However, provided the robust data of this review, some miRNA sequences have been identified to be dysregulated in multiple studies, even from different sources. Hence, this review would lie on its recommendation potential for the best miRNA used for diagnosis. Furthermore, the sample-to-PE ratio remained consistent throughout all included studies, with most of them tested around the same range. This implies a fairer and equal comparison in terms of the size effect of the included studies. Moreover, all studies included are human-based, thus improving their applicability potential with minor adjustments and testing if needed for public implementation. However, based on the study characteristics, most of the studies were conducted in developed or affluent countries. This however may affect its applicative potential in lower-middle-income countries (LMICs), considering the socio-demographic differences and freely available analysis and diagnostic tools. Moreover, despite being a secondary outcome, the strength and reliability of this review are heavily influenced by AUC values in determining the specificity and sensitivity of the proposed miRNA for diagnosing PE.
| Conclusions|| |
The crux of the problem of PE lies in its underlying difficult diagnosis. This study has analyzed the potential of varying miRNAs as potential diagnostic biomarkers and their potential prolonged use in the future. Despite varying sequences of miRNA being identified, some sequences (such as miR-210) that are repeatedly identified for dysregulation should have a higher diagnostic value and, potentially, a higher correlation with the pathogenesis of PE. Potent miRNAs identified should be more emphasized in future research to determine their applicability and connection with pathogenesis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]