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Diagnostics
Protocol
Predictive value of miR-210 as a novel biomarker for pre-eclampsia: a systematic review protocol
  1. Pooneh Nikuei1,
  2. Nahid Davoodian2,3,
  3. Iman Tahamtan4,
  4. Abbas Ali Keshtkar5
  1. 1Molecular Medicine Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
  2. 2Stem Cell and Cell Therapy Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
  3. 3Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
  4. 4School of Information Sciences, College of Communication and Information, University of Tennessee, Knoxville, Tennessee, USA
  5. 5Department of Health Sciences Education Development, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
  1. Correspondence to Dr Nahid Davoodian; Nahid.Davoodian{at}hums.ac.ir

Abstract

Introduction Pre-eclampsia (PE) is a serious condition affecting 3–5% of all pregnancies worldwide. However, underlying molecular pathogenesis of this disease has largely remained unknown. Recently, several studies have indicated the possibility role of microRNAs, especially miR-210, in the aetiology of PE. The aim of this systematic review is to assess the possible role of miR-210 as a novel biomarker for the prediction of PE.

Methods and analysis Using a combination of mesh terms ‘preeclampsia’, ‘microRNA’ and their equivalents, an electronic search will be performed for all observational studies (cross sectional, case–control and cohort) in PubMed, Web of Science, Scopus, Embase, Cochrane, LILACS and OvidSP MEDLINE from January 2005 to December 2015. Furthermore, other sources are searched, including grey literature, reference lists of relevant primary studies as well as key journals. Study selection, data extraction and quality assessment of studies will be performed independently by 2 reviewers, and any disagreement will be resolved by consensus. If sufficient data are available, it will be combined by either fixed or random effects models. We will investigate the source)s(and degree of heterogeneity using ‘Heterogeneity χ2’ and I2. Heterogeneity would be investigated through either subgroup analysis or metaregression. Stata V.11.1 will be used for data analysis.

Ethics and dissemination The results of this study are disseminated in peer-reviewed journal articles and academic presentations. Formal ethical approval is not required, since the secondary data will be collected.

Trial registration number CRD42015032345.

  • preeclampsia
  • miR-210
  • Predictive value

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/bmjopen-2016-011920

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    Strengths and limitations of this study

    • This systematic review, for the first time, will assess the predictive value of miR-210 in patients with pre-eclampsia.

    • Study selection, data extraction and quality assessment of studies will be conducted independently by two reviewers.

    • Subgroup analysis or metaregression will be used for investigation of the observed statistical heterogeneity.

    Background

    Pre-eclampsia (PE) is a human pregnancy-specific disorder characterised by a new onset of hypertension. It affects 3–5% of all pregnancies worldwide and remains as a leading cause of maternal and neonatal mortality and morbidity.1 Risk factors for PE are obesity, prior hypertension, maternal age, kidney disease, autoimmune diseases and diabetes mellitus.2 Although the aetiology of PE is largely unknown, the placenta in general and trophoblast in particular are prerequisites for the development of this disease. It is characterised by incomplete trophoblast invasion and aberrant spiral arterial remodelling, leading to decreased uteroplacental perfusion, placental ischaemia and hypoxia.3 Diagnostic criteria for PE include the presence of hypertension, developing after 20 weeks of gestation, and the coexistence of one or more of the following new-onset conditions: proteinuria, maternal organ dysfunction and uteroplacental dysfunction.4 Early-onset PE is usually defined as PE that develops before 34 weeks of gestation, while late-onset PE develops at or after 34 weeks of gestation.5

    PE is considered severe when systolic blood pressure is higher than 160 mm Hg or diastolic blood pressure is higher than 110 mm Hg. HELLP syndrome (platelet level <100 000/dL, alanine aminotransferase or aspartate aminotransferase elevation of twofold the upper limit of normal, and haemolysis with elevated lactate dehydrogenase twofold the upper reference limit or >650 IU/L) is severe complications of PE.5

    Several angiogenic and antiangiogenic factors, including placental growth factor (PlGF), soluble fms-related tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng), have recently been suggested for detection of PE.6–9 However, there is controversy over using these factors, as most of them are not sensitive or specific enough to be used for clinical diagnosis.10 ,11 Early diagnosis would allow medical management/intervention, resulting in the improvement of outcomes for the mother and fetus.12 Currently, several studies have identified the expression of microRNAs (miRNAs) in placenta tissue, which may be involved in pregnancy-associated disorders, such as PE.12–15

    miRNAs are small non-coding RNAs, playing important roles in regulating gene expression by degradation or translation repression of mRNAs. miRNAs have several biofunctions, including development, differentiation and apoptosis, as well as oncogenesis.1 Recently, miRNAs have generated great interest as potential novel diagnostic biomarkers for cancer,16 ,17 tissue injury18 and PE.12 Aberrant expression of miRNAs has been recently reported in PE placenta and serum.13 ,15 ,19–22 The most commonly identified placental miRNA in PE is miR-210, which is well known as a hypoxia-responsive miRNA.14 ,23 ,24 The level of miR-210 increases in response to low oxygen tension in many different cell types, and it is upregulated in hypoxia-associated diseases, such as cancer and PE.14 ,23 Although many researchers have published their data on the predictive value of miR-210 in PE, and have raised concerns about the efficiency of miR-210 as a biomarker, this issue remains questionable.

    So far, a few narrative reviews have discussed the role of miR-210 in PE, confirming its involvement in the pathogenesis of this disease.1 ,12 ,25 ,26 To the best of our knowledge, a systematic review has not yet been conducted to evaluate the predictive value of miR-210 for PE.

    Objectives

    The purpose of this systematic review is to evaluate the predictive value of miR-210 in pre-eclamptic patients.

    Methods

    This systematic review adheres to the PRISMA-P guidelines.27 The systematic review protocol is registered in ‘International Prospective Register for Systematic Reviews’ (PROSPERO) and its trial registration number is CRD42015032345.28

    Eligibility criteria

    Types of studies

    All observational studies (cross-sectional, case–control and cohort) will be included if they meet the following criteria: (1) the studies reporting miR-210 expression level in serum, plasma and placenta of women affected to PE; (2) studies describing PE according to ISSHP. However, if a study does not mention the ‘PE definition’, it will be assessed by authors, and if PE is the outcome of interest, the study will be included; (3) the results on the occurrence of PE should be described by ‘means’ and ‘SD’. Animal studies and review articles are excluded.

    Participants

    Women who developed PE after 20 weeks of gestation are included in the study. The term healthy pregnant women are considered as controls.

    miR-210

    miRNAs are a class of non-coding RNA, which negatively regulate gene expression.1 miR-210 is the most commonly identified placental miRNA found to be upregulated in pre-eclamptic patients. Using microarray and real-time PCR, several studies have reported overexpression of this miRNA in the throphoblast cells under hypoxia condition, which is thought to be one of the important causes of PE.14 ,23 ,24

    In the current review, studies evaluating the relationship between miR-210 expression level and PE are included.

    Outcomes

    According to the ‘International Society for the Study of Hypertension in Pregnancy’ (ISSHP),4 PE is defined as: hypertension developing after 20 weeks of gestation and the coexistence of one or more of the following new-onset conditions:

    1. Proteinuria

    2. Other maternal organ dysfunction:

      • renal insufficiency (creatinine >90 µmol/L)

      • liver involvement (elevated transaminases and/or severe right upper quadrant or epigastric pain)

      • neurological complications (examples include eclampsia, altered mental status, blindness, stroke, or more commonly hyperreflexia when accompanied by clonus, severe headaches when accompanied by hyperreflexia, and persistent visual scotomata)

      • haematological complications (thrombocytopenia, disseminated intravascular coagulation, haemolysis)

    3. Uteroplacental dysfunction

    4. fetal growth restriction

    As definitions and diagnosis criteria for PE may vary, when PE is the outcome of interest, the study will be eligible for inclusion.

    Search strategy

    With no language restriction, literature search will be performed in PubMed, Web of Science, Scopus, Embase, Cochrane, LILACS and OvidSP MEDLINE, using a combination of mesh terms ‘preeclampsia’, ‘microRNA’ and their equivalents, from January 2005 to December 2015. The search strategy for OvidSP MEDLINE is shown in table 1. This search strategy can be modified as required for other electronic databases.

    View this table:
    Table 1

    Search strategy used in OvidSP MEDLINE

    Other resources

    Grey literature, reference lists of relevant primary studies as well as key journals will be searched for additional studies.

    Data collection and analysis

    All retrieved documents will be transferred to EndNote software (X6) and duplicated articles will be removed from the Endnote library. Then, the title and abstract of the found documents will be evaluated to exclude non-relevant studies. Afterward, according to the inclusion and exclusion criteria of this study, the eligibility of the full texts of the remaining articles will be assessed independently by two reviewers. At this step, any disagreement will be resolved by consensus between the two authors.

    The required data will be extracted by two reviewers from relevant studies, independently. The data include: (1) setting and study design, (2) author, (3) publication year, (4) type of disease (mild or severe), (5) occurrence time of disease (early or late), (6) mode of delivery (normal vaginal or caesarean), (7) ethnicity, (8) type of sample (placenta or serum), (9) methods used for the evaluation of expression (microarray and real-time PCR), (10) key measures for meta-analysis, including: relative risk, mean difference, standard mean difference and sample size.

    If data from the same study are reported in multiple publications, they will be considered as one study. We will also attempt to contact authors of the studies with possibly relevant but unpublished data. If no response is received from the author(s) of such publications, they will be contacted in the intervals of 15 days for three times. In cases where no responses are received, they will be excluded from the study. Any disagreement will be resolved by consensus between the two authors.

    Assessment of methodological quality

    Quality assessment of primary studies will be independently conducted according to a modified version of ‘Strengthening the Reporting of Observational Studies in Epidemiology’ guideline (STROBE), by two reviewers.29 The questions will be answered as yes with 1 point, and no or unclear with zero. After the assessment of each article, its total score will be calculated. Afterward, the studies will be categorised into three levels: low risk, high risk and unclear risk of bias. Disagreements between the two authors will be resolved by consensus.

    Statistical analysis and data synthesis

    Stata software, V.11.1 (StataCorp LP, College Station, Texas, USA), will be used to analyse the extracted data. The meta-analysis will be used to assess the effectiveness of miR-210 for the prediction of PE. If meta-analysis is not feasible, narrative synthesis may be conducted. The main key measures (sample size, mean difference and standard mean difference) will be combined with fix or random models. Forest plot will be used for graphics. The p value of <0.05 will be interpreted as statistically significant.

    Heterogeneity assessment

    The source)s (and degree of heterogeneity will be investigated by ‘Heterogeneity χ2’ and I2. I2 value <50% will be considered as there is no heterogeneity, while I2 value higher than 50% shows the existence of source(s) of heterogeneity, which would be investigated through either subgroup analysis or metaregression if sufficient studies were available.27 Likely sources of heterogeneity would be severity of disease (mild or severe), occurrence time of disease (early or late), mode of delivery (normal vaginal or caesarean), ethnicity, type of sample (placenta or serum), primiparity or multiparity and the method (microarray and real-time PCR) used for the expression evaluation.

    Assessment of reporting bias

    Finally, reporting of publication bias will be assessed by using ‘Funnel Plot’, ‘Begg's and Egger's test’ or ‘Plot Fill and Trim method’.

    Discussion

    miRNAs have generated great interest for their potential roles as diagnostic and prognostic biomarkers in various diseases.30–32 Recently, several studies have demonstrated the aberrant expression of miRNAs between placenta of women affected to PE and normal placenta.33–35 Findings of these studies suggest miRNA's contribution in the pathogenesis of PE, especially by altering the development of placenta.21 ,33 ,36 As a sensor of hypoxia, miR-210 has most frequently been identified to be overexpressed in PE.14 ,23 ,24 It is likely that miR-210 involves in the development of trophoblast cells.14 ,23 ,24 Moreover, several studies have reported the striking role of miR-210 in repression of trophoblast migration, invasion and angiogenesis.3 ,14 ,34 Therefore, the dysregulation of this miRNA may be responsible for the limited proliferation and shallow invasion of trophoblast cells as well as the insufficient remodelling of maternal spiral arteries. Based on the aforementioned results, this study will assess the predictive value of miR-210 as a novel biomarker for PE.

    References

    1. ↵
      1. Chen DB,
      2. Wang W
      . Human placental microRNAs and preeclampsia. Biol Reprod 2013;88:130. doi:10.1095/biolreprod.113.107805
      OpenUrlAbstract/FREE Full Text
    2. ↵
      1. Al-Jameil N,
      2. Aziz Khan F,
      3. Fareed Khan F, et al
      . A brief overview of preeclampsia. J Clin Med Res 2013;6:1–7. doi:10.4021/jocmr1682w
      OpenUrl
    3. ↵
      1. Zhang Y,
      2. Fei M,
      3. Xue G, et al
      . Elevated levels of hypoxia-inducible microRNA-210 in pre-eclampsia: new insights into molecular mechanisms for the disease. J Cell Mol Med 2012;16:249–59. doi:10.1111/j.1582-4934.2011.01291.x
      OpenUrlCrossRefPubMed
    4. ↵
      1. Tranquilli A,
      2. Dekker G,
      3. Magee L, et al
      . The classification, diagnosis and management of the hypertensive disorders of pregnancy: a revised statement from the ISSHP. Pregnancy Hypertens 2014;4:97–104. doi:10.1016/j.preghy.2014.02.001
      OpenUrlPubMed
    5. ↵
      1. Tranquilli AL,
      2. Brown MA,
      3. Zeeman GG, et al
      . The definition of severe and early-onset preeclampsia. Statements from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Pregnancy Hypertens 2013;3:44–7. doi:10.1016/j.preghy.2012.11.001
      OpenUrlPubMed
    6. ↵
      1. Chaiworapongsa T,
      2. Romero R,
      3. Korzeniewski SJ, et al
      . Maternal plasma concentrations of angiogenic/antiangiogenic factors in the third trimester of pregnancy to identify the patient at risk for stillbirth at or near term and severe late preeclampsia. Am J Obstet Gynecol 2013;208:287.e1–15. doi:10.1016/j.ajog.2013.01.016
      OpenUrlCrossRef
    7. ↵
      1. Ghosh SK,
      2. Raheja S,
      3. Tuli A, et al
      . Can maternal serum placental growth factor estimation in early second trimester predict the occurrence of early onset preeclampsia and/or early onset intrauterine growth restriction? A prospective cohort study. J Obstet Gynaecol Res 2013;39:881–90. doi:10.1111/jog.12006
      OpenUrlCrossRefPubMed
    8. ↵
      1. Ghosh SK,
      2. Raheja S,
      3. Tuli A, et al
      . Is serum placental growth factor more effective as a biomarker in predicting early onset preeclampsia in early second trimester than in first trimester of pregnancy? Arch Gynecol Obstet 2013;287:865–73. doi:10.1007/s00404-012-2662-2
      OpenUrlCrossRefPubMed
    9. ↵
      1. Kuc S,
      2. Wortelboer EJ,
      3. van Rijn BB, et al
      . Evaluation of 7 serum biomarkers and uterine artery Doppler ultrasound for first-trimester prediction of preeclampsia: a systematic review. Obstet Gynecol Surv 2011;66:225–39. doi:10.1097/OGX.0b013e3182227027
      OpenUrlCrossRefPubMed
    10. ↵
      1. Lehnen H,
      2. Mosblech N,
      3. Reineke T, et al
      . Prenatal clinical assessment of sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio as a diagnostic tool for preeclampsia, pregnancy-induced hypertension, and proteinuria. Geburtshilfe Frauenheilkd 2013;73:440–5. doi:10.1055/s-0032-1328601
      OpenUrl
    11. ↵
      1. Polsani S,
      2. Phipps E,
      3. Jim B
      . Emerging new biomarkers of preeclampsia. Adv Chronic Kidney Dis 2013;20:271–9. doi:10.1053/j.ackd.2013.01.001
      OpenUrlCrossRefPubMedWeb of Science
    12. ↵
      1. Zhao Z,
      2. Moley KH,
      3. Gronowski AM
      . Diagnostic potential for miRNAs as biomarkers for pregnancy-specific diseases. Clin Biochem 2013;46:953–60. doi:10.1016/j.clinbiochem.2013.01.026
      OpenUrlCrossRefPubMed
    13. ↵
      1. Li Q,
      2. Long A,
      3. Jiang L, et al
      . Quantification of preeclampsia-related microRNAs in maternal serum. Biomed Rep 2015;3:792–6. doi:10.3892/br.2015.524
      OpenUrl
    14. ↵
      1. Luo R,
      2. Wang Y,
      3. Xu P, et al
      . Hypoxia-inducible miR-210 contributes to preeclampsia via targeting thrombospondin type I domain containing 7A. Sci Rep 2016;6:19588. doi:10.1038/srep19588
      OpenUrlCrossRefPubMed
    15. ↵
      1. Ura B,
      2. Feriotto G,
      3. Monasta L, et al
      . Potential role of circulating microRNAs as early markers of preeclampsia. Taiwan J Obstet Gynecol 2014;53:232–4. doi:10.1016/j.tjog.2014.03.001
      OpenUrl
    16. ↵
      1. Chim SS,
      2. Shing TK,
      3. Hung EC, et al
      . Detection and characterization of placental microRNAs in maternal plasma. Clin Chem 2008;54:482–90. doi:10.1373/clinchem.2007.097972
      OpenUrlAbstract/FREE Full Text
    17. ↵
      1. Gilad S,
      2. Meiri E,
      3. Yogev Y, et al
      . Serum microRNAs are promising novel biomarkers. PLoS ONE 2008;3:e3148. doi:10.1371/journal.pone.0003148
      OpenUrlCrossRefPubMed
    18. ↵
      1. Wang Q,
      2. Huang Z,
      3. Xue H, et al
      . MicroRNA miR-24 inhibits erythropoiesis by targeting activin type I receptor ALK4. Blood 2008;111:588–95. doi:10.1182/blood-2007-05-092718
      OpenUrlAbstract/FREE Full Text
    19. ↵
      1. Fu G,
      2. Ye G,
      3. Nadeem L, et al
      . MicroRNA-376c impairs transforming growth factor-β and nodal signaling to promote trophoblast cell proliferation and invasion. Hypertension 2013;61:864–72. doi:10.1161/HYPERTENSIONAHA.111.203489
      OpenUrlCrossRef
    20. ↵
      1. Hu Y,
      2. Li P,
      3. Hao S, et al
      . Differential expression of microRNAs in the placentae of Chinese patients with severe pre-eclampsia. Clin Chem Lab Med 2009;47:923–9. doi:10.1515/CCLM.2009.228
      OpenUrlCrossRefPubMed
    21. ↵
      1. Mayor-Lynn K,
      2. Toloubeydokhti T,
      3. Cruz AC, et al
      . Expression profile of microRNAs and mRNAs in human placentas from pregnancies complicated by preeclampsia and preterm labor. Reprod Sci 2011;18:46–56. doi:10.1177/1933719110374115
      OpenUrlAbstract/FREE Full Text
    22. ↵
      1. Zhu XM,
      2. Han T,
      3. Sargent IL, et al
      . Differential expression profile of microRNAs in human placentas from preeclamptic pregnancies vs normal pregnancies. Am J Obstet Gynecol 2009;200:661.e1–7. doi:10.1016/j.ajog.2008.12.045
      OpenUrlCrossRefPubMed
    23. ↵
      1. Chan SY,
      2. Loscalzo J
      . MicroRNA-210: a unique and pleiotropic hypoxamir. Cell Cycle 2010;9:1072–83. doi:10.4161/cc.9.6.11006
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      1. Devlin C,
      2. Greco S,
      3. Martelli F, et al
      . miR-210: more than a silent player in hypoxia. IUBMB Life 2011;63:94–100. doi:10.1002/iub.427
      OpenUrlPubMedWeb of Science
    25. ↵
      1. Fu G,
      2. Brkić J,
      3. Hayder H, et al
      . MicroRNAs in human placental development and pregnancy complications. Int J Mol Sci 2013;14:5519–44. doi:10.3390/ijms14035519
      OpenUrlCrossRefPubMed
    26. ↵
      1. Harapan H,
      2. Andalas M,
      3. Mudhakir D, et al
      . Micro RNA: new aspect in pathobiology of preeclampsia? Egypt J Med Hum Genet 2012;13:127–31. doi:10.1016/j.ejmhg.2011.09.002
      OpenUrl
    27. ↵
      1. Shamseer L,
      2. Moher D,
      3. Clarke M, et al
      . Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 2015;349:g7647. doi:10.1136/bmj.g7647
      OpenUrlAbstract/FREE Full Text
    28. ↵
      1. Davoodian N,
      2. Nikuei P,
      3. Tahamtan I, et al
      . Predictive value of miR-210 as a novel biomarker for predicting preeclampsia: a systematic review protocol. PROSPERO International prospective register of systematic reviews. 2015.
    29. ↵
      1. von Elm E,
      2. Altman DG,
      3. Egger M, et al
      . The Strengthening the Reporting of Observational Studies in Epidemiology [STROBE] statement: guidelines for reporting observational studies. Gac Sanit 2008;22:144–50. doi:10.1157/13119325
      OpenUrlCrossRefPubMedWeb of Science
    30. ↵
      1. Chandrasekaran K,
      2. Karolina DS,
      3. Sepramaniam S, et al
      . Role of microRNAs in kidney homeostasis and disease. Kidney Int 2012;81:617–27. doi:10.1038/ki.2011.448
      OpenUrlCrossRefPubMedWeb of Science
    31. ↵
      1. Fan HM,
      2. Sun XY,
      3. Guo W, et al
      . Differential expression of microRNA in peripheral blood mononuclear cells as specific biomarker for major depressive disorder patients. J Psychiatr Res 2014;59:45–52. doi:10.1016/j.jpsychires.2014.08.007
      OpenUrlPubMed
    32. ↵
      1. Reid G,
      2. Kirschner MB,
      3. van Zandwijk N
      . Circulating microRNAs: association with disease and potential use as biomarkers. Crit Rev Oncol Hematol 2011;80:193–208. doi:10.1016/j.critrevonc.2010.11.004
      OpenUrlCrossRefPubMed
    33. ↵
      1. Enquobahrie DA,
      2. Abetew DF,
      3. Sorensen TK, et al
      . Placental microRNA expression in pregnancies complicated by preeclampsia. Am J Obstet Gynecol 2011;204:178.e12–21. doi:10.1016/j.ajog.2010.09.004
      OpenUrlCrossRefPubMed
    34. ↵
      1. Pineles BL,
      2. Romero R,
      3. Montenegro D, et al
      . Distinct subsets of microRNAs are expressed differentially in the human placentas of patients with preeclampsia. Am J Obstet Gynecol 2007;196:261.e1–6. doi:10.1016/j.ajog.2007.01.008
      OpenUrlCrossRefPubMed
    35. ↵
      1. Xu P,
      2. Zhao Y,
      3. Liu M, et al
      . Variations of microRNAs in human placentas and plasma from preeclamptic pregnancy. Hypertension 2014;63:1276–84. doi:10.1161/HYPERTENSIONAHA.113.02647
      OpenUrl
    36. ↵
      1. Wang W,
      2. Feng L,
      3. Zhang H, et al
      . Preeclampsia up-regulates angiogenesis-associated microRNA (ie., miR-17,-20a, and-20b) that target ephrin-B2 and EPHB4 in human placenta. J Clin Endocrinol Metab 2012;97:E1051–E9. doi:10.1210/jc.2011-3131
      OpenUrlCrossRefPubMedWeb of Science

    Footnotes

    • Contributors ND and PN contributed to the study design, initial drafting and data extraction. IT developed the search strategy and revised the manuscript. AAK critically revised the manuscript, and provided important intellectual input. All authors approved the final version of the manuscript for publication.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement This study is a systematic review protocol, assessing miR-210 as a novel biomarker for prediction of pre-eclampsia, from January 2005 to December 2015.