Skip to main content

Advertisement

SpringerLink
Log in

The Role of Biomarkers and Imaging to Predict Preeclampsia and Subsequent Cardiovascular Dysfunction

  • Reproductive Health and Cardiovascular Disease (G Sharma, Section Editor)
  • Published:
Current Treatment Options in Cardiovascular Medicine Aims and scope Submit manuscript

Abstract

Purpose of review

Preeclampsia is a major cause of maternal morbidity and mortality worldwide. Despite decades of research, the ability of clinicians to accurately predict the onset of preeclampsia prior to the manifestation of symptoms has not significantly improved. In this review, we will examine the pathophysiology underlying preeclampsia and discuss the role of potential biomarkers for early prediction and diagnosis. In addition, we will explore imaging modalities in the detection of early myocardial and vascular endothelial dysfunction associated with preeclampsia.

Recent findings

Circulating angiogenic and antiangiogenic biomarkers have emerged as key factors in the pathophysiology of the condition. However, single serological biomarkers have limited sensitivity to accurately predict preeclampsia; thus, a combination of clinical information along with urine or blood biomarkers is needed.

Summary

The combined use of biomarker assays and new imaging modalities could enhance the predictive tools for this devastating disease and the development of cardiovascular sequelae. In the future, advances in proteomics, metabolomics, and other techniques may allow the identification of biomarkers with high enough predictive and prognostic information to be translated into clinical practice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Phipps EA, Thadhani R, Benzing T, Karumanchi SA. Pre-eclampsia: pathogenesis, novel diagnostics and therapies. Nat Rev Nephrol. 2019;15(5):275–89. https://doi.org/10.1038/s41581-019-0119-6.

    Article  PubMed  PubMed Central  Google Scholar 

  2. • ACOG. Gestational hypertension and preeclampsia. Obstet Gynecol. 2020;135(6):1492–5. https://doi.org/10.1097/AOG.0000000000003892 ACOG Practice Bulletin Number 222 (2020) - Gestational Hypertension and Preeclampsia. Discusses updated criteria for diagnosis of preeclampsia.

    Article  Google Scholar 

  3. • Mehta LS, Warnes CA, Bradley E, et al. Cardiovascular considerations in caring for pregnant patients: a scientific statement from the American Heart Association. Circulation. 2020;141(23):e884–903. https://doi.org/10.1161/CIR.0000000000000772 Mehta 2020 Circulation: AHA Scientific Statement on Cardiovascular Considerations in Caring for Pregnant Patients.

    Article  PubMed  Google Scholar 

  4. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;74(10):1376–414. https://doi.org/10.1016/j.jacc.2019.03.009.

    Article  PubMed  Google Scholar 

  5. Maynard SE, Venkatesha S, Thadhani R, Karumanchi SA. Soluble Fms-like tyrosine kinase 1 and endothelial dysfunction in the pathogenesis of preeclampsia. Pediatr Res. 2005;57(5):1R–7R. https://doi.org/10.1203/01.PDR.0000159567.85157.B7.

    Article  PubMed  Google Scholar 

  6. Faiz S. Renal biomarkers of preeclampsia. In: Kidney Biomarkers: Elsevier; 2020. p. 289–317. https://doi.org/10.1016/b978-0-12-815,923-1.00009-2.

  7. Aplin JD, Myers JE, Timms K, Westwood M. Tracking placental development in health and disease. Nat Rev Endocrinol. 2020;16(9):479–94. https://doi.org/10.1038/s41574-020-0372-6.

    Article  CAS  PubMed  Google Scholar 

  8. Kanter D, Lindheimer MD, Wang E, et al. Angiogenic dysfunction in molar pregnancy. Am J Obstet Gynecol. 2010;202(2):184.e1-184.e5. https://doi.org/10.1016/j.ajog.2009.09.005.

    Article  CAS  PubMed Central  Google Scholar 

  9. Roberts JM, Hubel CA. The two stage model of preeclampsia: variations on the theme. Placenta. 2009;30(SUPPL.):32–7. https://doi.org/10.1016/j.placenta.2008.11.009.

    Article  CAS  Google Scholar 

  10. James JL, Whitley GS, Cartwright JE. Pre-eclampsia: fitting together the placental, immune and cardiovascular pieces. J Pathol. 2010;221(4):363–78. https://doi.org/10.1002/path.2719.

    Article  CAS  PubMed  Google Scholar 

  11. Gatford KL, Andraweera PH, Roberts CT, Care AS. Animal models of preeclampsia: causes, consequences, and interventions. Hypertension. 2020;75(6):1363–81. https://doi.org/10.1161/HYPERTENSIONAHA.119.14598.

    Article  CAS  PubMed  Google Scholar 

  12. Rana S, Lemoine E, Granger J, Karumanchi SA. Preeclampsia: pathophysiology, challenges, and perspectives. Circ Res. 2019;124(7):1094–112. https://doi.org/10.1161/CIRCRESAHA.118.313276.

    Article  CAS  PubMed  Google Scholar 

  13. Agarwal I, Karumanchi SA. Preeclampsia and the anti-angiogenic state. Pregnancy Hypertens. 2011;1(1):17–21. https://doi.org/10.1016/j.preghy.2010.10.007.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Chen DB, Zheng J. Regulation of placental angiogenesis. Microcirculation. 2014;21(1):15–25. https://doi.org/10.1111/micc.12093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chau K, Hennessy A, Makris A. Placental growth factor and pre-eclampsia. J Hum Hypertens. 2017;31(12):782–6. https://doi.org/10.1038/jhh.2017.61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350(7):672–83. https://doi.org/10.1056/nejmoa031884.

    Article  CAS  PubMed  Google Scholar 

  17. Levine RJ, Lam C, Qian C, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med. 2006;355(10):992–1005. https://doi.org/10.1056/nejmoa055352.

    Article  CAS  PubMed  Google Scholar 

  18. • Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111(5):649–58. https://doi.org/10.1172/JCI17189 Maynard 2003 JCI: Report shows sFlt-1 being tied to pathogenesis of preeclampsia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rajakumar A, Cerdeira AS, Rana S, et al. Transcriptionally active syncytial aggregates in the maternal circulation may contribute to circulating soluble fms-like tyrosine kinase 1 in preeclampsia. Hypertension. 2012;59(2):256–64. https://doi.org/10.1161/HYPERTENSIONAHA.111.182170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lecarpentier E, Zsengellér ZK, Salahuddin S, et al. Total versus free placental growth factor levels in the pathogenesis of preeclampsia. Hypertension. 2020;76(3):875–83. https://doi.org/10.1161/HYPERTENSIONAHA.120.15338.

    Article  CAS  PubMed  Google Scholar 

  21. Thadhani R, Hagmann H, Schaarschmidt W, et al. Removal of soluble fms-like tyrosine kinase-1 by dextran sulfate apheresis in preeclampsia. J Am Soc Nephrol. 2016;27(3):903–13. https://doi.org/10.1681/ASN.2015020157.

    Article  CAS  PubMed  Google Scholar 

  22. Mutter WP, Karumanchi SA. Molecular mechanisms of preeclampsia. Microvasc Res. 2008;75(1):1–8. https://doi.org/10.1016/j.mvr.2007.04.009.

    Article  CAS  PubMed  Google Scholar 

  23. Venkatesha S, Toporsian M, Lam C, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. 2006. https://doi.org/10.1038/nm1429.

  24. Kusanovic JP, Romero R, Chaiworapongsa T, et al. The Journal of Maternal-Fetal & Neonatal Medicine A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia. J Matern Neonatal Med. 2009;22(11):1021–38. https://doi.org/10.3109/14767050902994754.

    Article  CAS  Google Scholar 

  25. • Kleinrouweler C, Wiegerinck M, Ris-Stalpers C, et al. Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia: a systematic review and meta-analysis. BJOG An Int J Obstet Gynaecol. 2012;119(7):778–87. https://doi.org/10.1111/j.1471-0528.2012.03311.x Kleinrouweler 2012 BJOG, Meta-analysis reviewing studies on angiogenic markers and analyzes their predictive values in preeclampsia.

    Article  CAS  Google Scholar 

  26. Widmer M, Cuesta C, Khan KS, et al. Accuracy of angiogenic biomarkers at ≤20 weeks’ gestation in predicting the risk of pre-eclampsia: A WHO multicentre study. Pregnancy Hypertens. 2015;5(4):330–8. https://doi.org/10.1016/j.preghy.2015.09.004.

    Article  PubMed  Google Scholar 

  27. • Zeisler H, Llurba E, Chantraine F, et al. Predictive Value of the sFlt-1:PlGF Ratio in women with suspected preeclampsia. N Engl J Med. 2016;374(1):13–22. https://doi.org/10.1056/nejmoa1414838 Zeisler 2016 NEJM, A landmark trial validating the role of sFlt-1/PIGF ratio in predicting preeclampsia.

    Article  CAS  PubMed  Google Scholar 

  28. Bian X, Biswas A, Huang X, et al. Short-term prediction of adverse outcomes using the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio in Asian women with suspected preeclampsia. Hypertension. 2019;74(1):164–72. https://doi.org/10.1161/HYPERTENSIONAHA.119.12760.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Perales A, Delgado JL, de la Calle M, et al. sFlt-1/PlGF for prediction of early-onset pre-eclampsia: STEPS (Study of Early Pre-eclampsia in Spain). Ultrasound Obstet Gynecol. 2017;50(3):373–82. https://doi.org/10.1002/uog.17373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Smith GCS, Stenhouse EJ, Crossley JA, Aitken DA, Cameron AD, Connor JM. Early pregnancy levels of pregnancy-associated plasma protein A and the risk of intrauterine growth restriction, premature birth, preeclampsia, and stillbirth. J Clin Endocrinol Metab. 2002;87(4):1762–7. https://doi.org/10.1210/jcem.87.4.8430.

    Article  CAS  PubMed  Google Scholar 

  31. Zhong Y, Zhu F, Ding Y. Serum screening in first trimester to predict pre-eclampsia, small for gestational age and preterm delivery: systematic review and meta-analysis. BMC Pregnancy Childbirth. 2015;15(1):191. https://doi.org/10.1186/s12884-015-0608-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sammar M, Drobnjak T, Mandala M, Gizurarson S, Huppertz B, Meiri H. Galectin 13 (PP13) facilitates remodeling and structural stabilization of maternal vessels during pregnancy. Int J Mol Sci. 2019;20(13). https://doi.org/10.3390/ijms20133192.

  33. Huppertz B, Meiri H, Gizurarson S, Osol G, Sammar M. Placental protein 13 (PP13): a new biological target shifting individualized risk assessment to personalized drug design combating pre-eclampsia. Hum Reprod Update. 2013;19(4):391–405. https://doi.org/10.1093/humupd/dmt003.

    Article  CAS  PubMed  Google Scholar 

  34. Eastabrook G, Aksoy T, Bedell S, Penava D, de Vrijer B. Preeclampsia biomarkers: an assessment of maternal cardiometabolic health. Pregnancy Hypertens. 2018;13:204–213. https://doi.org/10.1016/j.preghy.2018.06.005

  35. Parretti E, Lapolla A, Dalfrà MG, et al. Preeclampsia in lean normotensive normotolerant pregnant women can be predicted by simple insulin sensitivity indexes. Hypertension. 2006;47(3):449–53. https://doi.org/10.1161/01.HYP.0000205122.47333.7f.

    Article  CAS  PubMed  Google Scholar 

  36. Hauth JC, Clifton RG, Roberts JM, et al. Maternal insulin resistance and preeclampsia. Am J Obstet Gynecol. 2011;204(4):327.e1–327.e6. https://doi.org/10.1016/j.ajog.2011.02.024.

    Article  CAS  PubMed Central  Google Scholar 

  37. Kwon H, Pessin JE. Adipokines mediate inflammation and insulin resistance. Front Endocrinol (Lausanne). 2013;4(JUN). https://doi.org/10.3389/fendo.2013.00071.

  38. Daskalakis G, Bellos I, Nikolakea M, Pergialiotis V, Papapanagiotou A, Loutradis D. The role of serum adipokine levels in preeclampsia: a systematic review. Metabolism. 2020;106. https://doi.org/10.1016/j.metabol.2020.154172.

  39. Masuzaki H, Ogawa Y, Sagawa N, et al. Nonadipose tissue production of leptin: leptin as a novel placenta- derived hormone in humans. Nat Med. 1997;3(9):1029–33. https://doi.org/10.1038/nm0997-1029.

    Article  CAS  PubMed  Google Scholar 

  40. Samolis S, Papastefanou I, Panagopoulos P, Galazios G, Kouskoukis A, Maroulis G. Relation between first trimester maternal serum leptin levels and body mass index in normotensive and pre-eclamptic pregnancies Role of leptin as a marker of pre-eclampsia: a prospective casecontrol study. Gynecol Endocrinol. 2010;26(5):338–43. https://doi.org/10.3109/09513590903511463.

    Article  CAS  PubMed  Google Scholar 

  41. Bawah AT, Yeboah FA, Nanga S, Alidu H, Ngala RA. Serum adipocytokines and adiposity as predictive indices of preeclampsia. Clin Hypertens. 2020;26(1):19. https://doi.org/10.1186/s40885-020-00152-0.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Cnossen JS, Morris RK, Ter Riet G, et al. Use of uterine artery Doppler ultrasonography to predict pre-eclampsia and intrauterine growth restriction: a systematic review and bivariable meta-analysis. CMAJ. 2008;178(6):701–11. https://doi.org/10.1503/cmaj.070430.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Maynard SE, Karumanchi SA. Angiogenic factors and preeclampsia. Semin Nephrol. 2011;31(1):33–46. https://doi.org/10.1016/j.semnephrol.2010.10.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ras RT, Streppel MT, Draijer R, Zock PL. Flow-mediated dilation and cardiovascular risk prediction: a systematic review with meta-analysis. Int J Cardiol. 2013;168(1):344–51. https://doi.org/10.1016/j.ijcard.2012.09.047.

    Article  PubMed  Google Scholar 

  45. • Kirollos S, Skilton M, Patel S, Arnott C. A systematic review of vascular structure and function in pre-eclampsia: non-invasive assessment and mechanistic links. Front Cardiovasc Med. 2019;6:166. https://doi.org/10.3389/fcvm.2019.00166 Kirollos 2019 FCM – Systematic review of vascular structure and function in preeclampsia.

  46. Brodszki J, Länne T, Laurini R, Strevens H, Wide-Swensson D, Maršál K. Vascular mechanical properties and endothelial function in pre-eclampsia with special reference to bilateral uterine artery notch. Acta Obstet Gynecol Scand. 2008;87(2):154–62. https://doi.org/10.1080/00016340701733646.

    Article  CAS  PubMed  Google Scholar 

  47. Vaught AJ, Kovell LC, Szymanski LM, et al. Acute cardiac effects of severe pre-eclampsia. J Am Coll Cardiol. 2018;72(1):1–11. https://doi.org/10.1016/j.jacc.2018.04.048.

    Article  PubMed  Google Scholar 

  48. Melchiorre K, Sharma R, Thilaganathan B. Cardiovascular implications in preeclampsia: an overview. Circulation. 2014;130(8):703–14. https://doi.org/10.1161/CIRCULATIONAHA.113.003664.

    Article  PubMed  Google Scholar 

  49. • Castleman JS, Ganapathy R, Taki F, Lip GYH, Steeds RP, Kotecha D. Echocardiographic structure and function in hypertensive disorders of pregnancy: a systematic review. Circ Cardiovasc Imaging. 2016;9(9). https://doi.org/10.1161/CIRCIMAGING.116.004888 Castleman 2016 CCI, Systematic review of echocardiographic findings in preeclampsia and other hypertensive disorders in pregnancy.

  50. Melchiorre K, Sutherland GR, Watt-Coote I, Liberati M, Thilaganathan B. Hypertension in pregnancy severe myocardial impairment and chamber dysfunction in preterm preeclampsia. 2012. https://doi.org/10.3109/10641955.2012.697951.

  51. Kyung Choi S, Chul Shin J, Gyu Park Y, et al. The efficacy of peripartum transthoracic echocardiography in women with preeclampsia. Pregnancy Hypertens. 2017;10:187–91. https://doi.org/10.1016/j.preghy.2017.05.002.

    Article  PubMed  Google Scholar 

  52. Valensise H, Lo Presti D, Gagliardi G, et al. Persistent maternal cardiac dysfunction after preeclampsia identifies patients at risk for recurrent preeclampsia. Hypertension. 2016;67(4):748–53. https://doi.org/10.1161/HYPERTENSIONAHA.115.06674.

    Article  CAS  PubMed  Google Scholar 

  53. Reddy M, Wright L, Rolnik DL, et al. Evaluation of cardiac function in women with a history of preeclampsia: a systematic review and meta-analysis. J Am Heart Assoc. 2019;8(22). https://doi.org/10.1161/JAHA.119.013545.

  54. Arad Y, Goodman KJ, Roth M, Newstein D, Guerci AD. Coronary calcification, coronary disease risk factors, C-reactive protein, and atherosclerotic cardiovascular disease events: The St. Francis heart study. J Am Coll Cardiol. 2005;46(1):158–65. https://doi.org/10.1016/j.jacc.2005.02.088.

    Article  CAS  PubMed  Google Scholar 

  55. Valenti V, Ó Hartaigh B, Heo R, et al. A 15-year warranty period for asymptomatic individuals without coronary artery calcium: a prospective follow-up of 9715 individuals. JACC Cardiovasc Imaging. 2015;8(8):900–9. https://doi.org/10.1016/j.jcmg.2015.01.025.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Zoet GA, Benschop L, Boersma E, et al. Prevalence of subclinical coronary artery disease assessed by coronary computed tomography angiography in 45- to 55-year- old women with a history of preeclampsia. Circulation. 2018;137(8):877–9. https://doi.org/10.1161/CIRCULATIONAHA.117.032695.

    Article  PubMed  Google Scholar 

  57. Den Ruijter HM, Peters SAE, Anderson TJ, et al. Common carotid intima-media thickness measurements incardiovascular risk prediction: a meta-analysis. JAMA - J Am Med Assoc. 2012;308(8):796–803. https://doi.org/10.1001/jama.2012.9630.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medstar Heart and Vascular Institute, Baltimore, MD, USA

    Bethel Woldu MD, MPH

  2. Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 600 N Wolfe Street, Carnegie 565C, Baltimore, MD, 21287, USA

    Bethel Woldu MD, MPH, Lochan M. Shah MD, Erin Goerlich MD, Sammy Zakaria MD, MPH, Allison G. Hays MD, Roger S. Blumenthal MD & Garima Sharma MD FACC

  3. Division of Maternal and Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Angela K. Shaddeau MD & Arthur J. Vaught MD

  4. Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Andreea A. Creanga MD, PhD

Authors
  1. Bethel Woldu MD, MPH
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lochan M. Shah MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angela K. Shaddeau MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Erin Goerlich MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sammy Zakaria MD, MPH
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Allison G. Hays MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Arthur J. Vaught MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andreea A. Creanga MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Roger S. Blumenthal MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Garima Sharma MD FACC
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Garima Sharma MD FACC.

Ethics declarations

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Conflict of Interest

Bethel Woldu, Lochan M. Shah, Angela K. Shaddeau, Erin Goerlich, Sammy Zakaria, Allison G. Hays, Arthur J. Vaught, Andreea A. Creanga, Roger S. Blumenthal and Garima Sharma declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Reproductive Health and Cardiovascular Disease

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Woldu, B., Shah, L.M., Shaddeau, A.K. et al. The Role of Biomarkers and Imaging to Predict Preeclampsia and Subsequent Cardiovascular Dysfunction. Curr Treat Options Cardio Med 23, 42 (2021). https://doi.org/10.1007/s11936-021-00913-6

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11936-021-00913-6

Keywords

Search

Navigation