Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter October 18, 2022

Molecular subclasses of preeclampsia characterized by a longitudinal maternal proteomics study: distinct biomarkers, disease pathways and options for prevention

  • Nándor Gábor Than EMAIL logo , Roberto Romero , Dániel Györffy , Máté Posta , Gaurav Bhatti , Bogdan Done , Piya Chaemsaithong , Eunjung Jung , Manaphat Suksai , Francesca Gotsch , Dahiana M. Gallo , Mariachiara Bosco , Bomi Kim , Yeon Mee Kim , Tinnakorn Chaiworapongsa , Simona W. Rossi , András Szilágyi , Offer Erez , Adi L. Tarca and Zoltán Papp EMAIL logo

Abstract

Objectives

The heterogeneous nature of preeclampsia is a major obstacle to early screening and prevention, and a molecular taxonomy of disease is needed. We have previously identified four subclasses of preeclampsia based on first-trimester plasma proteomic profiles. Herein, we expanded this approach by using a more comprehensive panel of proteins profiled in longitudinal samples.

Methods

Proteomic data collected longitudinally from plasma samples of women who developed preeclampsia (n=109) and of controls (n=90) were available from our previous report on 1,125 proteins. Consensus clustering was performed to identify subgroups of patients with preeclampsia based on data from five gestational-age intervals by using select interval-specific features. Demographic, clinical, and proteomic differences among clusters were determined. Differentially abundant proteins were used to identify cluster-specific perturbed KEGG pathways.

Results

Four molecular clusters with different clinical phenotypes were discovered by longitudinal proteomic profiling. Cluster 1 involves metabolic and prothrombotic changes with high rates of early-onset preeclampsia and small-for-gestational-age neonates; Cluster 2 includes maternal anti-fetal rejection mechanisms and recurrent preeclampsia cases; Cluster 3 is associated with extracellular matrix regulation and comprises cases of mostly mild, late-onset preeclampsia; and Cluster 4 is characterized by angiogenic imbalance and a high prevalence of early-onset disease.

Conclusions

This study is an independent validation and further refining of molecular subclasses of preeclampsia identified by a different proteomic platform and study population. The results lay the groundwork for novel diagnostic and personalized tools of prevention.


Corresponding authors: Nándor Gábor Than, MD, PhD, Systems Biology of Reproduction Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary; Maternity Private Clinic of Obstetrics and Gynecology, Budapest, Hungary; Genesis Theranostix Group, Budapest, Hungary; First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary; Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA; and Genesis Theranostix Group, Budapest, Hungary; E-mail: ; and Prof. Zoltán Papp, MD, DSci, Maternity Private Clinic of Obstetrics and Gynecology, Budapest, Hungary; Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary, E-mail:

Award Identifier / Grant number: Contract No. HHSN275201300006C

Award Identifier / Grant number: Momentum Grant LP2014-7/2014

Acknowledgments

We thank Maureen McGerty (Wayne State University) for her critical reading of the manuscript.

  1. Research funding: The study was funded, in part, by the Perinatology Research Branch, Division of Obstetrics and Maternal Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services (NICHD/NIH/DHHS), and partly with Federal funds from NICHD/NIH/DHHS under contract No. HHSN275201300006C. ALT was supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health. Data analysis and manuscript writing was also funded by the Hungarian Academy of Sciences Momentum Grant LP2014-7/2014 and the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the FIEK_16-1-2016-0005, K124862, K128262, 2020-1.1.2-PIACI-KFI-2021-00273 and 2020-1.1.5-GYORSÍTÓSÁV-2021-00012 funding schemes.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: No potential conflict of interest was reported by the authors. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results. RR has contributed to this work as part of his official duties as an employee of the United States Federal Government.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: Research involving human subjects complied with all relevant national regulations and institutional policies; is in accordance with the tenets of the Helsinki Declaration (as revised in 2013); data and specimens were collected under the protocol “Biological Markers of Disease in the Prediction of Preterm Delivery, Preeclampsia and Intra-Uterine Growth Restriction: A Longitudinal Study.” The study was approved by the Institutional Review Boards of NICHD (OH97-CH-N067) and Wayne State University (WSU IRB#110605MP2F). All patients provided written informed consent prior to sample collection.

References

1. Erez, O, Romero, R, Jung, E, Chaemsaithong, P, Bosco, M, Suksai, M, et al.. Preeclampsia and eclampsia: the conceptual evolution of a syndrome. Am J Obstet Gynecol 2022;226:S786–803. https://doi.org/10.1016/j.ajog.2021.12.001.Search in Google Scholar PubMed PubMed Central

2. Jung, E, Romero, R, Yeo, L, Gomez-Lopez, N, Chaemsaithong, P, Jaovisidha, A, et al.. The etiology of preeclampsia. Am J Obstet Gynecol 2022;226:S844–66. https://doi.org/10.1016/j.ajog.2021.11.1356.Search in Google Scholar PubMed PubMed Central

3. Ness, RB, Roberts, JM. Heterogeneous causes constituting the single syndrome of preeclampsia: a hypothesis and its implications. Am J Obstet Gynecol 1996;175:1365–70. https://doi.org/10.1016/s0002-9378(96)70056-x.Search in Google Scholar PubMed

4. von Dadelszen, P, Magee, LA, Roberts, JM. Subclassification of preeclampsia. Hypertens Pregnancy 2003;22:143–8. https://doi.org/10.1081/prg-120021060.Search in Google Scholar PubMed

5. Chaiworapongsa, T, Chaemsaithong, P, Yeo, L, Romero, R. Pre-eclampsia part 1: current understanding of its pathophysiology. Nat Rev Nephrol 2014;10:466–80. https://doi.org/10.1038/nrneph.2014.102.Search in Google Scholar PubMed PubMed Central

6. Myatt, L, Roberts, JM. Preeclampsia: syndrome or disease? Curr Hypertens Rep 2015;17:83. https://doi.org/10.1007/s11906-015-0595-4.Search in Google Scholar PubMed

7. Tsigas, EZ. The Preeclampsia Foundation: the voice and views of the patient and her family. Am J Obstet Gynecol 2022;226:S1254–64.e1. https://doi.org/10.1016/j.ajog.2020.10.053.Search in Google Scholar PubMed

8. Ngwenya, S, Jones, B, Mwembe, D, Nare, H, Heazell, AEP. The prevalence of and risk factors for stillbirths in women with severe preeclampsia in a high-burden setting at Mpilo Central Hospital, Bulawayo, Zimbabwe. J Perinat Med 2022;50:678–83. https://doi.org/10.1515/jpm-2022-0080.Search in Google Scholar PubMed

9. Roberts, JM, Taylor, RN, Musci, TJ, Rodgers, GM, Hubel, CA, McLaughlin, MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol 1989;161:1200–4. https://doi.org/10.1016/0002-9378(89)90665-0.Search in Google Scholar PubMed

10. Maynard, SE, Min, JY, Merchan, J, Lim, KH, Li, J, Mondal, S, 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;111:649–58. https://doi.org/10.1172/jci17189.Search in Google Scholar PubMed PubMed Central

11. Matthiesen, L, Berg, G, Ernerudh, J, Ekerfelt, C, Jonsson, Y, Sharma, S. Immunology of preeclampsia. Chem Immunol Allergy 2005;89:49–61. https://doi.org/10.1159/000087912.Search in Google Scholar PubMed

12. Venkatesha, S, Toporsian, M, Lam, C, Hanai, JI, Mammoto, T, Kim, YM, et al.. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 2006;12:642–9. https://doi.org/10.1038/nm1429.Search in Google Scholar PubMed

13. Vatten, LJ, Eskild, A, Nilsen, TIL, Jeansson, S, Jenum, PA, Staff, AC. Changes in circulating level of angiogenic factors from the first to second trimester as predictors of preeclampsia. Am J Obstet Gynecol 2007;196:239.e1–6. https://doi.org/10.1016/j.ajog.2006.10.909.Search in Google Scholar PubMed

14. Crispi, F, Llurba, E, Domínguez, C, Martín-Gallán, P, Cabero, L, Gratacós, E. Predictive value of angiogenic factors and uterine artery Doppler for early- versus late-onset pre-eclampsia and intrauterine growth restriction. Ultrasound Obstet Gynecol 2008;31:303–9. https://doi.org/10.1002/uog.5184.Search in Google Scholar PubMed

15. Romero, R, Nien, JK, Espinoza, J, Todem, D, Fu, W, Chung, H, et al.. A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. J Matern Fetal Neonatal Med 2008;21:9–23. https://doi.org/10.1080/14767050701830480.Search in Google Scholar PubMed PubMed Central

16. Cindrova-Davies, T. Gabor Than Award Lecture 2008: pre-eclampsia - from placental oxidative stress to maternal endothelial dysfunction. Placenta 2009;30:S55–65. https://doi.org/10.1016/j.placenta.2008.11.020.Search in Google Scholar PubMed

17. Hahn, S, Giaglis, S, Hoesli, I, Hasler, P. Neutrophil NETs in reproduction: from infertility to preeclampsia and the possibility of fetal loss. Front Immunol 2012;3:362.1–8. https://doi.org/10.3389/fimmu.2012.00362.Search in Google Scholar PubMed PubMed Central

18. Soto, E, Romero, R, Kusanovic, JP, Ogge, G, Hussein, Y, Yeo, L, et al.. Late-onset preeclampsia is associated with an imbalance of angiogenic and anti-angiogenic factors in patients with and without placental lesions consistent with maternal underperfusion. J Matern Fetal Neonatal Med 2012;25:498–507. https://doi.org/10.3109/14767058.2011.591461.Search in Google Scholar PubMed PubMed Central

19. Verlohren, S, Melchiorre, K, Khalil, A, Thilaganathan, B. Uterine artery doppler, birth weight and timing of onset of pre-eclampsia: providing insights into the dual etiology of late-onset pre-eclampsia: UtA Doppler, birth weight and pre-eclampsia. Ultrasound Obstet Gynecol 2014;44:293–8. https://doi.org/10.1002/uog.13310.Search in Google Scholar PubMed

20. Redman, CW, Sargent, IL, Staff, AC. IFPA senior award lecture: making sense of pre-eclampsia – two placental causes of preeclampsia? Placenta 2014;35:S20–5. https://doi.org/10.1016/j.placenta.2013.12.008.Search in Google Scholar PubMed

21. Hahn, S, Lapaire, O, Than, NG. Biomarker development for presymptomatic molecular diagnosis of preeclampsia: feasible, useful or even unnecessary? Expert Rev Mol Diagn 2015;15:617–29. https://doi.org/10.1586/14737159.2015.1025757.Search in Google Scholar PubMed PubMed Central

22. Scioscia, M, Karumanchi, SA, Goldman-Wohl, D, Robillard, PY. Endothelial dysfunction and metabolic syndrome in preeclampsia: an alternative viewpoint. J Reprod Immunol 2015;108:42–7. https://doi.org/10.1016/j.jri.2015.01.009.Search in Google Scholar PubMed

23. Blois, SM, Dechend, R, Barrientos, G, Staff, AC. A potential pathophysiological role for galectins and the renin-angiotensin system in preeclampsia. Cell Mol Life Sci 2015;72:39–50. https://doi.org/10.1007/s00018-014-1713-1.Search in Google Scholar PubMed

24. Hansson, SR, Nääv, Å, Erlandsson, L. Oxidative stress in preeclampsia and the role of free fetal hemoglobin. Front Physiol 2014;5:516. https://doi.org/10.3389/fphys.2014.00516.Search in Google Scholar PubMed PubMed Central

25. Palmer, KR, Tong, S, Kaitu’u-Lino, TJ. Placental-specific sFLT-1: role in pre-eclamptic pathophysiology and its translational possibilities for clinical prediction and diagnosis. Mol Hum Reprod 2017;23:69–78. https://doi.org/10.1093/molehr/gaw077.Search in Google Scholar PubMed

26. Tamás, P. Early and late preeclampsia are characterized by high cardiac output, but in the presence of fetal growth restriction, cardiac output is low: insights from a prospective study. Am J Obstet Gynecol 2018;219:627. https://doi.org/10.1016/j.ajog.2018.07.029.Search in Google Scholar PubMed

27. Hürter, H, Vontelin van Breda, S, Vokalova, L, Brandl, M, Baumann, M, Hösli, I, et al.. Prevention of pre-eclampsia after infertility treatment: preconceptional minimalisation of risk factors. Best Pract Res Clin Endocrinol Metabol 2019;33:127–32. https://doi.org/10.1016/j.beem.2019.05.001.Search in Google Scholar PubMed

28. Robillard, PY, Dekker, G, Scioscia, M, Bonsante, F, Iacobelli, S, Boukerrou, M, et al.. Increased BMI has a linear association with late-onset preeclampsia: a population-based study. PLoS One 2019;14:e0223888. https://doi.org/10.1371/journal.pone.0223888.Search in Google Scholar PubMed PubMed Central

29. Umapathy, A, Chamley, LW, James, JL. Reconciling the distinct roles of angiogenic/anti-angiogenic factors in the placenta and maternal circulation of normal and pathological pregnancies. Angiogenesis 2020;23:105–17. https://doi.org/10.1007/s10456-019-09694-w.Search in Google Scholar PubMed

30. Staff, AC, Fjeldstad, HE, Fosheim, IK, Moe, K, Turowski, G, Johnsen, GM, et al.. Failure of physiological transformation and spiral artery atherosis: their roles in preeclampsia. Am J Obstet Gynecol 2022;226:S895–906. https://doi.org/10.1016/j.ajog.2020.09.026.Search in Google Scholar PubMed

31. Tamás, P, Betlehem, J, Szekeres-Barthó, J, Kovács, K, Wami, GA, Vértes, V, et al.. A praeeclampsia két arca. Orv Hetil 2022;163:663–9.10.1556/650.2022.32427Search in Google Scholar PubMed

32. Robillard, PY, Dekker, G, Scioscia, M, Saito, S. Progress in the understanding of the pathophysiology of immunologic maladaptation related to early-onset preeclampsia and metabolic syndrome related to late-onset preeclampsia. Am J Obstet Gynecol 2022;226:S867–75. https://doi.org/10.1016/j.ajog.2021.11.019.Search in Google Scholar PubMed

33. Redman, CWG, Staff, AC, Roberts, JM. Syncytiotrophoblast stress in preeclampsia: the convergence point for multiple pathways. Am J Obstet Gynecol 2022;226:S907–27. https://doi.org/10.1016/j.ajog.2020.09.047.Search in Google Scholar PubMed

34. Rana, S, Burke, SD, Karumanchi, SA. Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders. Am J Obstet Gynecol 2022;226:S1019–34. https://doi.org/10.1016/j.ajog.2020.10.022.Search in Google Scholar PubMed PubMed Central

35. Medjedovic, E, Stanojevic, M, Kurjak, A, Begic, E, Iglica, A, Jonuzovic-Prosic, S. Association between maternal thyroid function and risk of gestational hypertension and preeclampsia. J Perinat Med 2022;50:904–9.10.1515/jpm-2022-0121Search in Google Scholar PubMed

36. Hanson, E, Rull, K, Ratnik, K, Vaas, P, Teesalu, P, Laan, M. Value of soluble fms-like tyrosine kinase-1/placental growth factor test in third trimester of pregnancy for predicting preeclampsia in asymptomatic women. J Perinat Med 2022;50:939–46.10.1515/jpm-2022-0127Search in Google Scholar PubMed

37. Moldenhauer, JS, Stanek, J, Warshak, C, Khoury, J, Sibai, B. The frequency and severity of placental findings in women with preeclampsia are gestational age dependent. Am J Obstet Gynecol 2003;189:1173–7. https://doi.org/10.1067/s0002-9378(03)00576-3.Search in Google Scholar PubMed

38. Brosens, I, Pijnenborg, R, Vercruysse, L, Romero, R. The ‘Great Obstetrical Syndromes’ are associated with disorders of deep placentation. Am J Obstet Gynecol 2011;204:193–201. https://doi.org/10.1016/j.ajog.2010.08.009.Search in Google Scholar PubMed PubMed Central

39. Ogge, G, Chaiworapongsa, T, Romero, R, Hussein, Y, Kusanovic, JP, Yeo, L, et al.. Placental lesions associated with maternal underperfusion are more frequent in early-onset than in late-onset preeclampsia. J Perinat Med 2011;39:641–52.10.1515/jpm.2011.098Search in Google Scholar PubMed PubMed Central

40. Erez, O, Romero, R, Maymon, E, Chaemsaithong, P, Done, B, Pacora, P, et al.. The prediction of late-onset preeclampsia: results from a longitudinal proteomics study. PLoS One 2017;12:e0181468. https://doi.org/10.1371/journal.pone.0181468.Search in Google Scholar PubMed PubMed Central

41. Chuah, TT, Tey, WS, Ng, MJ, Tan, ETH, Chern, B, Tan, KH. Serum sFlt-1/PlGF ratio has better diagnostic ability in early- compared to late-onset pre-eclampsia. J Perinat Med 2018;47:35–40. https://doi.org/10.1515/jpm-2017-0288.Search in Google Scholar PubMed

42. Tarca, AL, Romero, R, Benshalom-Tirosh, N, Than, NG, Gudicha, DW, Done, B, et al.. The prediction of early preeclampsia: results from a longitudinal proteomics study. PLoS One 2019;14:e0217273. https://doi.org/10.1371/journal.pone.0217273.Search in Google Scholar PubMed PubMed Central

43. Romero, R, Jung, E, Chaiworapongsa, T, Erez, O, Gudicha, DW, Kim, YM, et al.. Toward a new taxonomy of obstetrical disease: improved performance of maternal blood biomarkers for the great obstetrical syndromes when classified according to placental pathology. Am J Obstet Gynecol 2022. https://doi.org/10.1016/j.ajog.2022.04.015 [Epub ahead of print].Search in Google Scholar PubMed PubMed Central

44. Chaiworapongsa, T, Romero, R, Tarca, A, Kusanovic, JP, Mittal, P, Kim, SK, et al.. A subset of patients destined to develop spontaneous preterm labor has an abnormal angiogenic/anti-angiogenic profile in maternal plasma: evidence in support of pathophysiologic heterogeneity of preterm labor derived from a longitudinal study. J Matern Fetal Neonatal Med 2009;22:1122–39. https://doi.org/10.3109/14767050902994838.Search in Google Scholar PubMed PubMed Central

45. Whitten, AE, Romero, R, Korzeniewski, SJ, Tarca, AL, Schwartz, AG, Yeo, L, et al.. Evidence of an imbalance of angiogenic/antiangiogenic factors in massive perivillous fibrin deposition (maternal floor infarction): a placental lesion associated with recurrent miscarriage and fetal death. Am J Obstet Gynecol 2013;208:310.e1–11. https://doi.org/10.1016/j.ajog.2013.01.017.Search in Google Scholar PubMed PubMed Central

46. Leavey, K, Bainbridge, SA, Cox, BJ. Large scale aggregate microarray analysis reveals three distinct molecular subclasses of human preeclampsia. Plos One 2015;10:e0116508. https://doi.org/10.1371/journal.pone.0116508.Search in Google Scholar PubMed PubMed Central

47. Leavey, K, Benton, SJ, Grynspan, D, Kingdom, JC, Bainbridge, SA, Cox, BJ. Unsupervised placental gene expression profiling identifies clinically relevant subclasses of human preeclampsia. Hypertension 2016;68:137–47. https://doi.org/10.1161/hypertensionaha.116.07293.Search in Google Scholar PubMed

48. Than, NG, Posta, M, Györffy, D, Orosz, L, Orosz, G, Rossi, SW, et al.. Early pathways, biomarkers, and four distinct molecular subclasses of preeclampsia: the intersection of clinical, pathological, and high-dimensional biology studies. Placenta 2022;125:10–9. https://doi.org/10.1016/j.placenta.2022.03.009.Search in Google Scholar PubMed PubMed Central

49. ACOG Committee on Practice Bulletins--Obstetrics. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet Gynecol 2002;99:159–67. https://doi.org/10.1016/s0029-7844(01)01747-1.Search in Google Scholar PubMed

50. Tranquilli, AL, Brown, MA, Zeeman, GG, Dekker, G, Sibai, BM. 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. https://doi.org/10.1016/j.preghy.2012.11.001.Search in Google Scholar PubMed

51. Gold, L, Ayers, D, Bertino, J, Bock, C, Bock, A, Brody, EN, et al.. Aptamer-based multiplexed proteomic technology for biomarker discovery. PLoS One 2010;5:e15004. https://doi.org/10.1371/journal.pone.0015004.Search in Google Scholar PubMed PubMed Central

52. Langston, C, Kaplan, C, Macpherson, T, Manci, E, Peevy, K, Clark, B, et al.. Practice guideline for examination of the placenta: developed by the placental pathology practice guideline development task force of the college of American pathologists. Arch Pathol Lab Med 1997;121:449–76.Search in Google Scholar

53. Romero, R, Kim, YM, Pacora, P, Kim, CJ, Benshalom-Tirosh, N, Jaiman, S, et al.. The frequency and type of placental histologic lesions in term pregnancies with normal outcome. J Perinat Med 2018;46:613–30. https://doi.org/10.1515/jpm-2018-0055.Search in Google Scholar PubMed PubMed Central

54. Redline, RW, Heller, D, Keating, S, Kingdom, J. Placental diagnostic criteria and clinical correlation--a workshop report. Placenta 2005;26:S114–117. https://doi.org/10.1016/j.placenta.2005.02.009.Search in Google Scholar PubMed

55. Khong, TY, Mooney, EE, Ariel, I, Balmus, NCM, Boyd, TK, Brundler, MA, et al.. Sampling and definitions of placental lesions: Amsterdam placental workshop group consensus statement. Arch Pathol Lab Med 2016;140:698–713. https://doi.org/10.5858/arpa.2015-0225-cc.Search in Google Scholar

56. Tarca, AL, Taran, A, Romero, R, Jung, E, Paredes, C, Bhatti, G, et al.. Prediction of preeclampsia throughout gestation with maternal characteristics and biophysical and biochemical markers: a longitudinal study. Am J Obstet Gynecol 2022;226:126.e1–22. https://doi.org/10.1016/j.ajog.2021.01.020.Search in Google Scholar PubMed PubMed Central

57. Dash, M, Ong, YS. RELIEF-C: efficient feature selection for clustering over noisy data. In: 2011 IEEE 23rd international conference on tools with artificial intelligence. Boca Raton, FL, USA: IEEE; 2011:869–72 pp.10.1109/ICTAI.2011.135Search in Google Scholar

58. Kira, K, Rendell, LA. The feature selection problem: traditional methods and a new algorithm. Proc Tenth Natl Conf Artif Intell 1992:129–34.Search in Google Scholar

59. Bouman, CA. CLUSTER: an unsupervised algorithm for modeling gaussian mixtures; 1997. Available from: https://engineering.purdue.edu/∼bouman/software/cluster/manual.pdf.Search in Google Scholar

60. Monti, S. Consensus Clustering: a resampling-based method for class discovery and visualization of gene expression microarray data. Mach Learn 2003;52:91–118.10.1023/A:1023949509487Search in Google Scholar

61. Șenbabaoğlu, Y, Michailidis, G, Li, JZ. Critical limitations of consensus clustering in class discovery. Sci Rep 2014;4:6207. https://doi.org/10.1038/srep06207.Search in Google Scholar PubMed PubMed Central

62. Khatri, P, Sirota, M, Butte, AJ. Ten years of pathway analysis: current approaches and outstanding challenges. PLoS Comput Biol 2012;8:e1002375. https://doi.org/10.1371/journal.pcbi.1002375.Search in Google Scholar PubMed PubMed Central

63. Draghici, S, Khatri, P, Tarca, AL, Amin, K, Done, A, Voichita, C, et al.. A systems biology approach for pathway level analysis. Genome Res 2007;17:1537–45. https://doi.org/10.1101/gr.6202607.Search in Google Scholar PubMed PubMed Central

64. Khatri, P, Draghici, S, Tarca, AL, Hassan, SS, Romero, R. A system biology approach for the steady-state analysis of gene signaling networks. In: Rueda, L, Mery, D, Kittler, J, editors. Progress in Pattern Recognition, Image Analysis and Applications. Berlin, Heidelberg: Springer; 2007:32–41 pp.10.1007/978-3-540-76725-1_4Search in Google Scholar

65. Tarca, AL, Draghici, S, Khatri, P, Hassan, SS, Mittal, P, Kim, JS, et al.. A novel signaling pathway impact analysis. Bioinformatics 2009;25:75–82. https://doi.org/10.1093/bioinformatics/btn577.Search in Google Scholar PubMed PubMed Central

66. Kanehisa, M, Goto, S, Sato, Y, Furumichi, M, Tanabe, M. KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res 2012;40:D109–114. https://doi.org/10.1093/nar/gkr988.Search in Google Scholar PubMed PubMed Central

67. Than, NG, Romero, R, Tarca, AL, Kekesi, KA, Xu, Y, Xu, Z, et al.. Integrated systems biology approach identifies novel maternal and placental pathways of preeclampsia. Front Immunol 2018;9:1661. https://doi.org/10.3389/fimmu.2018.01661.Search in Google Scholar PubMed PubMed Central

68. Tarca, AL, Romero, R, Draghici, S. Analysis of microarray experiments of gene expression profiling. Am J Obstet Gynecol 2006;195:373–88. https://doi.org/10.1016/j.ajog.2006.07.001.Search in Google Scholar PubMed PubMed Central

69. Bellos, I, Fitrou, G, Pergialiotis, V, Papantoniou, N, Daskalakis, G. Mean platelet volume values in preeclampsia: a systematic review and meta-analysis. Pregnancy Hypertens 2018;13:174–80. https://doi.org/10.1016/j.preghy.2018.06.016.Search in Google Scholar PubMed

70. Monteith, C, Egan, K, O’Connor, H, Maguire, P, Kevane, B, Szklanna, PB, et al.. Early onset preeclampsia is associated with an elevated mean platelet volume (MPV) and a greater rise in MPV from time of booking compared with pregnant controls: results of the CAPE study. J Perinat Med 2018;46:1010–5. https://doi.org/10.1515/jpm-2017-0188.Search in Google Scholar PubMed

71. Jakobsen, C, Larsen, JB, Fuglsang, J, Hvas, AM. Platelet function in preeclampsia - a systematic review and meta-analysis. Platelets 2019;30:549–62. https://doi.org/10.1080/09537104.2019.1595561.Search in Google Scholar PubMed

72. Forstner, D, Guettler, J, Gauster, M. Changes in maternal platelet physiology during gestation and their interaction with trophoblasts. Int J Mol Sci 2021;22:10732. https://doi.org/10.3390/ijms221910732.Search in Google Scholar PubMed PubMed Central

73. Ghasemzadeh, M, Hosseini, E. Platelet-leukocyte crosstalk: linking proinflammatory responses to procoagulant state. Thromb Res 2013;131:191–7. https://doi.org/10.1016/j.thromres.2012.11.028.Search in Google Scholar PubMed

74. Robillard, PY, Dekker, G, Scioscia, M, Bonsante, F, Iacobelli, S, Boukerrou, M, et al.. The blurring boundaries between placental and maternal preeclampsia: a critical appraisal of 1800 consecutive preeclamptic cases. J Matern Fetal Neonatal Med 2020;35:1–7.10.1080/14767058.2020.1786516Search in Google Scholar PubMed

75. Burton, GJ, Woods, AW, Jauniaux, E, Kingdom, JCP. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta 2009;30:473–82. https://doi.org/10.1016/j.placenta.2009.02.009.Search in Google Scholar PubMed PubMed Central

76. Szabo, S, Mody, M, Romero, R, Xu, Y, Karaszi, K, Mihalik, N, et al.. Activation of villous trophoblastic p38 and ERK1/2 signaling pathways in preterm preeclampsia and HELLP syndrome. Pathol Oncol Res 2015;21:659–68. https://doi.org/10.1007/s12253-014-9872-9.Search in Google Scholar PubMed PubMed Central

77. Szilagyi, A, Gelencser, Z, Romero, R, Xu, Y, Kiraly, P, Demeter, A, et al.. Placenta-specific genes, their regulation during villous trophoblast differentiation and dysregulation in preterm preeclampsia. Int J Mol Sci 2020;21:E628. https://doi.org/10.3390/ijms21020628.Search in Google Scholar PubMed PubMed Central

78. Wright, D, Wright, A, Nicolaides, KH. The competing risk approach for prediction of preeclampsia. Am J Obstet Gynecol 2020;223:12–23.e7. https://doi.org/10.1016/j.ajog.2019.11.1247.Search in Google Scholar PubMed

79. Poon, LC, Shennan, A, Hyett, JA, Kapur, A, Hadar, E, Divakar, H, et al.. The International Federation of Gynecology and Obstetrics (FIGO) initiative on pre-eclampsia: a pragmatic guide for first-trimester screening and prevention. Int J Gynaecol Obstet 2019;145:1–33. https://doi.org/10.1002/ijgo.12802.Search in Google Scholar PubMed PubMed Central

80. Chaemsaithong, P, Sahota, DS, Poon, LC. First trimester preeclampsia screening and prediction. Am J Obstet Gynecol 2022;226:S1071–97.e2. https://doi.org/10.1016/j.ajog.2020.07.020.Search in Google Scholar PubMed

81. Roberge, S, Villa, P, Nicolaides, K, Giguère, Y, Vainio, M, Bakthi, A, et al.. Early administration of low-dose aspirin for the prevention of preterm and term preeclampsia: a systematic review and meta-analysis. Fetal Diagn Ther 2012;31:141–6. https://doi.org/10.1159/000336662.Search in Google Scholar PubMed

82. Rolnik, DL, Wright, D, Poon, LC, O’Gorman, N, Syngelaki, A, de Paco Matallana, C, et al.. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017;377:613–22. https://doi.org/10.1056/nejmoa1704559.Search in Google Scholar

83. Stefanovic, V. International Academy of Perinatal Medicine (IAPM) guidelines for screening, prediction, prevention and management of pre-eclampsia to reduce maternal mortality in developing countries. J Perinat Med 2021. https://doi.org/10.1515/jpm-2021-0636 [Epub ahead of print].Search in Google Scholar PubMed

84. Rolnik, DL, Nicolaides, KH, Poon, LC. Prevention of preeclampsia with aspirin. Am J Obstet Gynecol 2022;226:S1108–19. https://doi.org/10.1016/j.ajog.2020.08.045.Search in Google Scholar PubMed

85. Foisy, M, Marchant, I, Lessard, L, Caron, L, Bujold, E. Aspirin for the prevention of preeclampsia. J Perinat Med 2022 [Epub ahead of print].10.1515/jpm-2022-0301Search in Google Scholar PubMed

86. Shamshirsaz, AA, Paidas, M, Krikun, G. Preeclampsia, hypoxia, thrombosis, and inflammation. J Pregnancy 2012;2012:374047. https://doi.org/10.1155/2012/374047.Search in Google Scholar PubMed PubMed Central

87. Chaiworapongsa, T, Yoshimatsu, J, Espinoza, J, Kim, YM, Berman, S, Edwin, S, et al.. Evidence of in vivo generation of thrombin in patients with small-for-gestational-age fetuses and pre-eclampsia. J Matern Fetal Neonatal Med 2002;11:362–7. https://doi.org/10.1080/jmf.11.6.362.367.Search in Google Scholar PubMed

88. Mastrolia, SA, Mazor, M, Loverro, G, Klaitman, V, Erez, O. Placental vascular pathology and increased thrombin generation as mechanisms of disease in obstetrical syndromes. PeerJ 2014;2:e653. https://doi.org/10.7717/peerj.653.Search in Google Scholar PubMed PubMed Central

89. Erez, O, Romero, R, Vaisbuch, E, Kusanovic, JP, Mazaki-Tovi, S, Chaiworapongsa, T, et al.. The pattern and magnitude of ‘in vivo thrombin generation’ differ in women with preeclampsia and in those with SGA fetuses without preeclampsia. J Matern Fetal Neonatal Med 2018;31:1671–80. https://doi.org/10.1080/14767058.2017.1323327.Search in Google Scholar PubMed PubMed Central

90. Huntington, JA. Thrombin inhibition by the serpins. J Thromb Haemost 2013;11(1 Suppl):254–64. https://doi.org/10.1111/jth.12252.Search in Google Scholar PubMed

91. España, F, Gilabert, J, Aznar, J, Estellés, A, Kobayashi, T, Griffin, JH. Complexes of activated protein C with alpha 1-antitrypsin in normal pregnancy and in severe preeclampsia. Am J Obstet Gynecol 1991;164:1310–6. https://doi.org/10.1016/0002-9378(91)90706-w.Search in Google Scholar PubMed

92. Aye, ILMH, Aiken, CE, Charnock-Jones, DS, Smith, GCS. Placental energy metabolism in health and disease—significance of development and implications for preeclampsia. Am J Obstet Gynecol 2022;226:S928–44. https://doi.org/10.1016/j.ajog.2020.11.005.Search in Google Scholar PubMed

93. Villalobos-Labra, R, Silva, L, Subiabre, M, Araos, J, Salsoso, R, Fuenzalida, B, et al.. Akt/mTOR Role in human foetoplacental vascular insulin resistance in diseases of pregnancy. J Diabetes Res 2017;2017:5947859. https://doi.org/10.1155/2017/5947859.Search in Google Scholar PubMed PubMed Central

94. McElwain, CJ, Tuboly, E, McCarthy, FP, McCarthy, CM. Mechanisms of endothelial dysfunction in pre-eclampsia and gestational diabetes mellitus: windows into future cardiometabolic health? Front Endocrinol 2020;11:655. https://doi.org/10.3389/fendo.2020.00655.Search in Google Scholar PubMed PubMed Central

95. Ho, L, van Dijk, M, Chye, STJ, Messerschmidt, DM, Chng, SC, Ong, S, et al.. ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice. Science 2017;357:707–13. https://doi.org/10.1126/science.aam6607.Search in Google Scholar PubMed

96. Para, R, Romero, R, Gomez-Lopez, N, Tarca, AL, Panaitescu, B, Done, B, et al.. Maternal circulating concentrations of soluble Fas and Elabela in early- and late-onset preeclampsia. J Matern Fetal Neonatal Med 2022;35:316–29. https://doi.org/10.1080/14767058.2020.1716720.Search in Google Scholar PubMed PubMed Central

97. Wang, C, Liu, X, Kong, D, Qin, X, Li, Y, Teng, X, et al.. Apelin as a novel drug for treating preeclampsia. Exp Ther Med 2017;14:5917–23. https://doi.org/10.3892/etm.2017.5304.Search in Google Scholar PubMed PubMed Central

98. Feferkorn, I, Badeghiesh, A, Baghlaf, H, Dahan, MH. The relation between cigarette smoking with delivery outcomes. An evaluation of a database of more than nine million deliveries. J Perinat Med 2022;50:56–62. https://doi.org/10.1515/jpm-2021-0053.Search in Google Scholar PubMed

99. Ambrose, JA, Barua, RS. The pathophysiology of cigarette smoking and cardiovascular disease: an update. J Am Coll Cardiol 2004;43:1731–7. https://doi.org/10.1016/j.jacc.2003.12.047.Search in Google Scholar PubMed

100. Dekker, GA, de Vries, JI, Doelitzsch, PM, Huijgens, PC, von Blomberg, BM, Jakobs, C, et al.. Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol 1995;173:1042–8. https://doi.org/10.1016/0002-9378(95)91324-6.Search in Google Scholar PubMed

101. Roberts, LN, Patel, RK, Chitongo, P, Bonner, L, Arya, R. African-Caribbean ethnicity is associated with a hypercoagulable state as measured by thrombin generation. Blood Coagul Fibrinolysis 2013;24:40–9. https://doi.org/10.1097/mbc.0b013e32835a07fa.Search in Google Scholar

102. Erez, O, Jung, E, Chaiworapongsa, T, Gudicha, DW, Gallo, D, Romero, R. An abnormal thrombin generation profile in early pregnancy identifies patients at risk for preeclampsia. Am J Obstet Gynecol 2022;226:S706–7. https://doi.org/10.1016/j.ajog.2021.11.1165.Search in Google Scholar

103. Cruz-Lemini, M, Vázquez, JC, Ullmo, J, Llurba, E. Low-molecular-weight heparin for prevention of preeclampsia and other placenta-mediated complications: a systematic review and meta-analysis. Am J Obstet Gynecol 2022;226:S1126–44.e17. https://doi.org/10.1016/j.ajog.2020.11.006.Search in Google Scholar PubMed

104. Mastrolia, SA, Novack, L, Thachil, J, Rabinovich, A, Pikovsky, O, Klaitman, V, et al.. LMWH in the prevention of preeclampsia and fetal growth restriction in women without thrombophilia. A systematic review and meta-analysis. Thromb Haemostasis 2016;116:868–78. https://doi.org/10.1160/TH16-02-0169.Search in Google Scholar PubMed

105. Kim, CJ, Romero, R, Chaemsaithong, P, Kim, JS. Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance. Am J Obstet Gynecol 2015;213(4 Suppl):S53–69. https://doi.org/10.1016/j.ajog.2015.08.041.Search in Google Scholar PubMed PubMed Central

106. Zhang, P, Haymar, T, Al-Sayyed, F, Dygulski, S, Dygulska, B, Devi, A, et al.. Placental pathology associated with maternal age and maternal obesity in singleton pregnancy. J Matern Fetal Neonatal Med 2022:1–10. https://doi.org/10.1080/14767058.2022.2044777 [Epub ahead of print].Search in Google Scholar PubMed

107. Gill, N, Leng, Y, Romero, R, Xu, Y, Panaitescu, B, Miller, D, et al.. The immunophenotype of decidual macrophages in acute atherosis. Am J Reprod Immunol 2019;81:e13098. https://doi.org/10.1111/aji.13098.Search in Google Scholar PubMed PubMed Central

108. Johnsen, GM, Fjeldstad, HES, Drabbels, JJM, Haasnoot, GW, Eikmans, M, Størvold, GL, et al.. A possible role for HLA-G in development of uteroplacental acute atherosis in preeclampsia. J Reprod Immunol 2021;144:103284. https://doi.org/10.1016/j.jri.2021.103284.Search in Google Scholar PubMed

109. Lee, J, Romero, R, Chaiworapongsa, T, Dong, Z, Tarca, AL, Xu, Y, et al.. Characterization of the fetal blood transcriptome and proteome in maternal anti-fetal rejection: evidence of a distinct and novel type of human fetal systemic inflammatory response. Am J Reprod Immunol 2013;70:265–84. https://doi.org/10.1111/aji.12142.Search in Google Scholar PubMed PubMed Central

110. Gotsch, F, Romero, R, Friel, L, Kusanovic, JP, Espinoza, J, Erez, O, et al.. CXCL10/IP-10: a missing link between inflammation and anti-angiogenesis in preeclampsia? J Matern-Fetal Neonatal Med 2007;20:777–92. https://doi.org/10.1080/14767050701483298.Search in Google Scholar PubMed PubMed Central

111. Gessner, A, Schröppel, K, Will, A, Enssle, KH, Lauffer, L, Röllinghoff, M. Recombinant soluble interleukin-4 (IL-4) receptor acts as an antagonist of IL-4 in murine cutaneous Leishmaniasis. Infect Immun 1994;62:4112–7. https://doi.org/10.1128/iai.62.10.4112-4117.1994.Search in Google Scholar PubMed PubMed Central

112. Andrews, AL, Holloway, JW, Holgate, ST, Davies, DE. IL-4 receptor alpha is an important modulator of IL-4 and IL-13 receptor binding: implications for the development of therapeutic targets. J Immunol 2006;176:7456–61. https://doi.org/10.4049/jimmunol.176.12.7456.Search in Google Scholar PubMed

113. Jonsson, Y, Rubèr, M, Matthiesen, L, Berg, G, Nieminen, K, Sharma, S, et al.. Cytokine mapping of sera from women with preeclampsia and normal pregnancies. J Reprod Immunol 2006;70:83–91. https://doi.org/10.1016/j.jri.2005.10.007.Search in Google Scholar PubMed

114. Kim, CJ, Romero, R, Kusanovic, JP, Yoo, W, Dong, Z, Topping, V, et al.. The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth. Mod Pathol 2010;23:1000–11. https://doi.org/10.1038/modpathol.2010.73.Search in Google Scholar PubMed PubMed Central

115. Moffett, A, Colucci, F. Co-evolution of NK receptors and HLA ligands in humans is driven by reproduction. Immunol Rev 2015;267:283–97. https://doi.org/10.1111/imr.12323.Search in Google Scholar PubMed

116. Lakatos, K, Elias, KM, Berkowitz, RS, Hasselblatt, K, Végh, G, Fülöp, V. A természetes ölősejtek szerepe az anyai-magzati immunhomeostasis fenntartásában. Orv Hetil 2022;163:734–42.10.1556/650.2022.32458Search in Google Scholar PubMed

117. Fink, NR, Chawes, B, Bønnelykke, K, Thorsen, J, Stokholm, J, Rasmussen, MA, et al.. Levels of systemic low-grade inflammation in pregnant mothers and their offspring are correlated. Sci Rep 2019;9:3043. https://doi.org/10.1038/s41598-019-39620-5.Search in Google Scholar PubMed PubMed Central

118. Priest, C, Tontonoz, P. Inter-organ cross-talk in metabolic syndrome. Nat Metab 2019;1:1177–88. https://doi.org/10.1038/s42255-019-0145-5.Search in Google Scholar PubMed

119. Gammill, HS, Chettier, R, Brewer, A, Roberts, JM, Shree, R, Tsigas, E, et al.. Cardiomyopathy and preeclampsia. Circulation 2018;138:2359–66. https://doi.org/10.1161/circulationaha.117.031527.Search in Google Scholar PubMed

120. Adu-Gyamfi, EA, Czika, A, Gorleku, PN, Ullah, A, Panhwar, Z, Ruan, LL, et al.. The involvement of cell adhesion molecules, tight junctions, and gap junctions in human placentation. Reprod Sci 2021;28:305–20. https://doi.org/10.1007/s43032-020-00364-7.Search in Google Scholar PubMed

121. Parameshwar, PK, Sagrillo-Fagundes, L, Fournier, C, Girard, S, Vaillancourt, C, Moraes, C. Disease-specific extracellular matrix composition regulates placental trophoblast fusion efficiency. Biomater Sci 2021;9:7247–56. https://doi.org/10.1039/d1bm00799h.Search in Google Scholar PubMed

122. Kagami, S, Kondo, S, Löster, K, Reutter, W, Kuhara, T, Yasutomo, K, et al.. Alpha1beta1 integrin-mediated collagen matrix remodeling by rat mesangial cells is differentially regulated by transforming growth factor-beta and platelet-derived growth factor-BB. J Am Soc Nephrol 1999;10:779–89. https://doi.org/10.1681/asn.v104779.Search in Google Scholar PubMed

123. Nugent, WH, Mishra, N, Strauss, JF, Walsh, SW. Matrix metalloproteinase 1 causes vasoconstriction and enhances vessel reactivity to angiotensin II via protease-activated receptor 1. Reprod Sci 2016;23:542–8. https://doi.org/10.1177/1933719115607998.Search in Google Scholar PubMed PubMed Central

124. Walsh, SW, Strauss, JF. Pregnancy-specific expression of protease-activated receptor 1: a therapeutic target for prevention and treatment of preeclampsia? Am J Obstet Gynecol 2022;226:S945–53. https://doi.org/10.1016/j.ajog.2021.11.1367.Search in Google Scholar PubMed PubMed Central

125. Romero, R, Erez, O, Hüttemann, M, Maymon, E, Panaitescu, B, Conde-Agudelo, A, et al.. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am J Obstet Gynecol 2017;217:282–302. https://doi.org/10.1016/j.ajog.2017.06.003.Search in Google Scholar PubMed PubMed Central

126. Tong, S, Kaitu’u-Lino, TJ, Hastie, R, Brownfoot, F, Cluver, C, Hannan, N. Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia. Am J Obstet Gynecol 2022;226:S1157–70. https://doi.org/10.1016/j.ajog.2020.09.014.Search in Google Scholar PubMed

127. Smith, DD, Costantine, MM. The role of statins in the prevention of preeclampsia. Am J Obstet Gynecol 2022;226:S1171–81. https://doi.org/10.1016/j.ajog.2020.08.040.Search in Google Scholar PubMed PubMed Central

128. Tarca, AL, Than, NG, Romero, R. Methodological approach from the best overall team in the sbv IMPROVER diagnostic signature challenge. Syst Biomed 2013;1:217–27. https://doi.org/10.4161/sysb.25980.Search in Google Scholar

129. Tarca, AL, Pataki, BÁ, Romero, R, Sirota, M, Guan, Y, Kutum, R, et al.. Crowdsourcing assessment of maternal blood multi-omics for predicting gestational age and preterm birth. Cell Rep Med 2021;2:100323. https://doi.org/10.1016/j.xcrm.2021.100323.Search in Google Scholar PubMed PubMed Central


Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/jpm-2022-0433).


Received: 2022-09-05
Accepted: 2022-09-09
Published Online: 2022-10-18
Published in Print: 2023-01-27

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 23.2.2024 from https://www.degruyter.com/document/doi/10.1515/jpm-2022-0433/html
Scroll to top button