Preeclampsia pp 157-172 | Cite as

The Differences Between Early- and Late-Onset Pre-eclampsia

  • Anne Cathrine StaffEmail author
  • Christopher W. G. Redman
Part of the Comprehensive Gynecology and Obstetrics book series (CGO)


Early- and late-onset pre-eclampsia (PE) exhibit important clinical differences both regarding associations to foetal growth restriction as well as short- and long-term health consequences for the mother and offspring. There is no definition consensus, but dichotomizing into preterm or term delivery (i.e. before or from gestational week (GW) 37) or into a very premature delivery or not (i.e. before or from gestational week 34) is common. The early-onset type is linked to poor placentation and foetal growth restriction, whereas maternal factors were suggested to cause the late-onset disease, without a placental impact. As an alternative model, we have suggested that both forms represent placental dysfunction (stage 1) prior to development of its clinical signs (stage 2), but both the causes of the placental malperfusion and its timing differ. In early-onset pre-eclampsia, the placental dysfunction is ‘extrinsic’ to the placenta, with incomplete spiral artery remodelling (an early pregnancy event). The cause of late-onset pre-eclampsia is ‘intrinsic’ to the growing and ageing placenta, restricting intervillous perfusion. Both pathways lead to secondary syncytiotrophoblast stress and release of pro-inflammatory factors into the maternal circulation. Maternal factors may increase the risk on many levels for the two stages of pre-eclampsia and contribute to the risk for both early- and late-onset forms. Our revised two-stage model of pre-eclampsia is in line with the clinical and biomarker heterogeneity of early- and late-onset disease. In conclusion, we present evidence that placental malperfusion and dysfunction cause both early- and onset pre-eclampsia, albeit for different reasons and with a different timing.


Decidua Pre-eclampsia Placenta Hypertension Malperfusion Pathophysiology Pregnancy Spiral artery Two-stage 


  1. 1.
    Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122(5):1122–31.Google Scholar
  2. 2.
    Tranquilli AL, Dekker G, Magee L, Roberts J, Sibai BM, Steyn W, et al. The classification, diagnosis and management of the hypertensive disorders of pregnancy: a revised statement from the ISSHP. Pregnancy Hypertens. 2014;4(2):97–104.CrossRefPubMedGoogle Scholar
  3. 3.
    Abalos E, Cuesta C, Carroli G, Qureshi Z, Widmer M, Vogel JP, et al. Pre-eclampsia, eclampsia and adverse maternal and perinatal outcomes: a secondary analysis of the World Health Organization Multicountry Survey on Maternal and Newborn Health. BJOG. 2014;121(Suppl 1):14–24.CrossRefPubMedGoogle Scholar
  4. 4.
    Vogel JP, Souza JP, Mori R, Morisaki N, Lumbiganon P, Laopaiboon M, et al. Maternal complications and perinatal mortality: findings of the World Health Organization Multicountry Survey on Maternal and Newborn Health. BJOG. 2014;121(Suppl 1):76–88.CrossRefPubMedGoogle Scholar
  5. 5.
    Abalos E, Cuesta C, Grosso AL, Chou D, Say L. Global and regional estimates of preeclampsia and eclampsia: a systematic review. Eur J Obstet Gynecol Reprod Biol. 2013;170(1):1–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Lindheimer MD, Spargo BH, Katz AI. Eclampsia during the 16th gestational week. JAMA. 1974;230(7):1006–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Redman CW, Sargent IL, Staff AC. IFPA Senior Award Lecture: making sense of pre-eclampsia—two placental causes of preeclampsia? Placenta. 2014;35(Suppl):S20–S5.CrossRefPubMedGoogle Scholar
  8. 8.
    Ghulmiyyah L, Sibai B. Maternal mortality from preeclampsia/eclampsia. Semin Perinatol. 2012;36(1):56–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Duley L. Pre-eclampsia and the hypertensive disorders of pregnancy. Br Med Bull. 2003;67:161–76.CrossRefPubMedGoogle Scholar
  10. 10.
    Backes CH, Markham K, Moorehead P, Cordero L, Nankervis CA, Giannone PJ. Maternal preeclampsia and neonatal outcomes. J Pregnancy. 2011;2011:214365.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Klungsoyr K, Morken NH, Irgens L, Vollset SE, Skjaerven R. Secular trends in the epidemiology of pre-eclampsia throughout 40 years in Norway: prevalence, risk factors and perinatal survival. Paediatr Perinat Epidemiol. 2012;26(3):190–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Bilano VL, Ota E, Ganchimeg T, Mori R, Souza JP. Risk factors of pre-eclampsia/eclampsia and its adverse outcomes in low- and middle-income countries: a WHO secondary analysis. PLoS One. 2014;9(3):e91198.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Firoz T, Sanghvi H, Merialdi M, von Dadelszen P. Pre-eclampsia in low and middle income countries. Best Pract Res Clin Obstet Gynaecol. 2011;25(4):537–48.CrossRefPubMedGoogle Scholar
  14. 14.
    von Dadelszen P, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertens Pregnancy. 2003;22(2):143–8.CrossRefGoogle Scholar
  15. 15.
    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(1):44–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Douglas KA, Redman CW. Eclampsia in the United Kingdom. BMJ. 1994;309(6966):1395–400.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Broekhuijsen K, van Baaren GJ, van Pampus MG, Ganzevoort W, Sikkema JM, Woiski MD, et al. Immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy between 34 and 37 weeks of gestation (HYPITAT-II): an open-label, randomised controlled trial. Lancet. 2015;385(9986):2492–501.CrossRefPubMedGoogle Scholar
  18. 18.
    Raymond D, Peterson E. A critical review of early-onset and late-onset preeclampsia. Obstet Gynecol Surv. 2011;66(8):497–506.CrossRefPubMedGoogle Scholar
  19. 19.
    Xiong X, Demianczuk NN, Saunders LD, Wang FL, Fraser WD. Impact of preeclampsia and gestational hypertension on birth weight by gestational age. Am J Epidemiol. 2002;155(3):203–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Vatten LJ, Skjaerven R. Is pre-eclampsia more than one disease? BJOG. 2004;111(4):298–302.CrossRefPubMedGoogle Scholar
  21. 21.
    Caughey AB, Stotland NE, Escobar GJ. What is the best measure of maternal complications of term pregnancy: ongoing pregnancies or pregnancies delivered? Am J Obstet Gynecol. 2003;189(4):1047–52.CrossRefPubMedGoogle Scholar
  22. 22.
    Sibai BM, Ramadan MK, Usta I, Salama M, Mercer BM, Friedman SA. Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Am J Obstet Gynecol. 1993;169(4):1000–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Moore MP, Redman CW. Case-control study of severe pre-eclampsia of early onset. Br Med J (Clin Res Ed). 1983;287(6392):580–3.CrossRefGoogle Scholar
  24. 24.
    Verlohren S, Melchiorre K, Khalil A, Thilaganathan B. Uterine artery Doppler, birthweight and timing of preeclampsia onset: providing insights into the dual etiology of late-onset preeclampsia. Ultrasound Obstet Gynecol. 2014;44:293–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Murphy DJ, Stirrat GM. Mortality and morbidity associated with early-onset preeclampsia. Hypertens Pregnancy. 2010;19:221–31.CrossRefGoogle Scholar
  26. 26.
    Sebire NJ, Goldin RD, Regan L. Term preeclampsia is associated with minimal histopathological placental features regardless of clinical severity. J Obstet Gynaecol. 2005;25(2):117–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Mifsud W, Sebire NJ. Placental pathology in early-onset and late-onset fetal growth restriction. Fetal Diagn Ther. 2014;36(2):117–28.CrossRefPubMedGoogle Scholar
  28. 28.
    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(4):1173–7.CrossRefPubMedGoogle Scholar
  29. 29.
    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(6):641–52.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Funai EF, Friedlander Y, Paltiel O, Tiram E, Xue X, Deutsch L, et al. Long-term mortality after preeclampsia. Epidemiology. 2005;16(2):206–15.CrossRefPubMedGoogle Scholar
  31. 31.
    Mongraw-Chaffin ML, Cirillo PM, Cohn BA. Preeclampsia and cardiovascular disease death: prospective evidence from the child health and development studies cohort. Hypertension. 2010;56(1):166–71.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from preeclampsia and eclampsia. Obstet Gynecol. 2001;97(4):533–8.PubMedGoogle Scholar
  33. 33.
    Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH. First-trimester prediction of hypertensive disorders in pregnancy. Hypertension. 2009;53(5):812–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Redman CW, Staff AC. Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity. Am J Obstet Gynecol. 2015;213(4 Suppl):S9–4.PubMedGoogle Scholar
  35. 35.
    Burke O, Benton S, Szafranski P, von Dadelszen P, Buhimschi SC, Cetin I, et al. Extending the scope of pooled analyses of individual patient biomarker data from heterogeneous laboratory platforms and cohorts using merging algorithms. Pregnancy Hypertens. 2016;6(1):53–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Hnat MD, Sibai BM, Caritis S, Hauth J, Lindheimer MD, MacPherson C, et al. Perinatal outcome in women with recurrent preeclampsia compared with women who develop preeclampsia as nulliparas. Am J Obstet Gynecol. 2002;186(3):422–6.CrossRefPubMedGoogle Scholar
  37. 37.
    Ebbing C, Rasmussen S, Skjaerven R, Irgens LM. Risk factors for recurrence of hypertensive disorders of pregnancy, a population based cohort study. Acta Obstet Gynecol Scand. 2017;96(2):243–50.CrossRefPubMedGoogle Scholar
  38. 38.
    Staff AC, Redman CW, Williams D, Leeson P, Moe K, Thilaganathan B, et al. Pregnancy and long-term maternal cardiovascular health: progress through harmonization of research cohorts and biobanks. Hypertension. 2016;67(2):251–60.PubMedGoogle Scholar
  39. 39.
    Wikstrom AK, Haglund B, Olovsson M, Lindeberg SN. The risk of maternal ischaemic heart disease after gestational hypertensive disease. BJOG. 2005;112(11):1486–91.CrossRefPubMedGoogle Scholar
  40. 40.
    Ness RB, Hubel CA. Risk for coronary artery disease and morbid preeclampsia: a commentary. Ann Epidemiol. 2005;15(9):726–33.CrossRefPubMedGoogle Scholar
  41. 41.
    Skjaerven R, Wilcox AJ, Klungsoyr K, Irgens LM, Vikse BE, Vatten LJ, et al. Cardiovascular mortality after pre-eclampsia in one child mothers: prospective, population based cohort study. BMJ. 2012;345:e7677.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ. 2001;323(7323):1213–7.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Newstead J, von Dadelszen DP, Magee LA. Preeclampsia and future cardiovascular risk. Expert Rev Cardiovasc Ther. 2007;5(2):283–94.CrossRefPubMedGoogle Scholar
  44. 44.
    Stekkinger E, Zandstra M, Peeters LL, Spaanderman ME. Early-onset preeclampsia and the prevalence of postpartum metabolic syndrome. Obstet Gynecol. 2009;114(5):1076–84.CrossRefPubMedGoogle Scholar
  45. 45.
    Ihle BU, Long P, Oats J. Early onset pre-eclampsia: recognition of underlying renal disease. Br Med J (Clin Res Ed). 1987;294(6564):79–81.CrossRefGoogle Scholar
  46. 46.
    Vikse BE, Irgens LM, Leivestad T, Skjaerven R, Iversen BM. Preeclampsia and the risk of end-stage renal disease. N Engl J Med. 2008;359(8):800–9.CrossRefPubMedGoogle Scholar
  47. 47.
    Auger N, Fraser WD, Paradis G, Healy-Profitos J, Hsieh A, Rheaume MA. Preeclampsia and long-term risk of maternal retinal disorders. Obstet Gynecol. 2017;129(1):42–9.CrossRefPubMedGoogle Scholar
  48. 48.
    Davis EF, Newton L, Lewandowski AJ, Lazdam M, Kelly BA, Kyriakou T, et al. Pre-eclampsia and offspring cardiovascular health: mechanistic insights from experimental studies. Clin Sci (Lond). 2012;123(2):53–72.CrossRefGoogle Scholar
  49. 49.
    Davis EF, Lazdam M, Lewandowski AJ, Worton SA, Kelly B, Kenworthy Y, et al. Cardiovascular risk factors in children and young adults born to preeclamptic pregnancies: a systematic review. Pediatrics. 2012;129(6):e1552–e61.CrossRefPubMedGoogle Scholar
  50. 50.
    Fugelseth D, Ramstad HB, Kvehaugen AS, Nestaas E, Stoylen A, Staff AC. Myocardial function in offspring 5-8years after pregnancy complicated by preeclampsia. Early Hum Dev. 2011;87(8):531–5.CrossRefPubMedGoogle Scholar
  51. 51.
    Lazdam M, de la Horra A, Pitcher A, Mannie Z, Diesch J, Trevitt C, et al. Elevated blood pressure in offspring born premature to hypertensive pregnancy: is endothelial dysfunction the underlying vascular mechanism? Hypertension. 2010;56(1):159–65.CrossRefPubMedGoogle Scholar
  52. 52.
    Aksornphusitaphong A, Phupong V. Risk factors of early and late onset pre-eclampsia. J Obstet Gynaecol Res. 2013;39(3):627–31.CrossRefPubMedGoogle Scholar
  53. 53.
    Iacobelli S, Bonsante F, Robillard PY. Pre-eclampsia and preterm birth in Reunion Island: a 13 years cohort-based study. Comparison with international data. J Matern Fetal Neonatal Med. 2016;29(18):3035–40.PubMedGoogle Scholar
  54. 54.
    Lisonkova S, Joseph KS. Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease. Am J Obstet Gynecol. 2013;209(6):544.e1–e12.CrossRefGoogle Scholar
  55. 55.
    Roberts CL, Ford JB, Algert CS, Antonsen S, Chalmers J, Cnattingius S, et al. Population-based trends in pregnancy hypertension and pre-eclampsia: an international comparative study. BMJ Open. 2011;1(1):e000101.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Redman CW. Current topic pre-eclampsia and the placenta. Placenta. 1991;12(4):301–8.CrossRefPubMedGoogle Scholar
  57. 57.
    Robertson WB, Brosens I, Dixon HG. The pathological response of the vessels of the placental bed to hypertensive pregnancy. J Pathol Bacteriol. 1967;93:581–92.CrossRefPubMedGoogle Scholar
  58. 58.
    Staff AC, Benton SJ, von Dadelszen P, Roberts JM, Taylor RN, Powers RW, et al. Redefining preeclampsia using placenta-derived biomarkers. Hypertension. 2013;61(5):932–42.CrossRefPubMedGoogle Scholar
  59. 59.
    Redman CW. Platelets and the beginnings of preeclampsia. N Engl J Med. 1990;323(7):478–80.CrossRefPubMedGoogle Scholar
  60. 60.
    Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol. 1989;161(5):1200–4.CrossRefPubMedGoogle Scholar
  61. 61.
    Ness RB, Roberts JM. Heterogeneous causes constituting the single syndrome of preeclampsia: a hypothesis and its implications. Am J Obstet Gynecol. 1996;175(5):1365–70.CrossRefPubMedGoogle Scholar
  62. 62.
    Roberts JM, Redman CWG. Preeclampsia—more than pregnancy-induced hypertension. Lancet. 1993;341(8858):1447–51.CrossRefPubMedGoogle Scholar
  63. 63.
    Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350(7):672–83.CrossRefPubMedGoogle Scholar
  64. 64.
    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(5):649–58.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Sunderji S, Gaziano E, Wothe D, Rogers LC, Sibai B, Karumanchi SA, et al. Automated assays for sVEGF R1 and PlGF as an aid in the diagnosis of preterm preeclampsia: a prospective clinical study. Am J Obstet Gynecol. 2010;202(1):40–7.CrossRefPubMedGoogle Scholar
  66. 66.
    Benton SJ, McCowan LM, Heazell AE, Grynspan D, Hutcheon JA, Senger C, et al. Placental growth factor as a marker of fetal growth restriction caused by placental dysfunction. Placenta. 2016;42:1–8.CrossRefPubMedGoogle Scholar
  67. 67.
    Herraiz I, Droge LA, Gomez-Montes E, Henrich W, Galindo A, Verlohren S. Characterization of the soluble fms-like tyrosine kinase-1 to placental growth factor ratio in pregnancies complicated by fetal growth restriction. Obstet Gynecol. 2014;124(2 Pt 1):265–73.CrossRefPubMedGoogle Scholar
  68. 68.
    Molvarec A, Gullai N, Stenczer B, Fugedi G, Nagy B, Rigo J Jr. Comparison of placental growth factor and fetal flow Doppler ultrasonography to identify fetal adverse outcomes in women with hypertensive disorders of pregnancy: an observational study. BMC Pregnancy Childbirth. 2013;13:161.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Triunfo S, Lobmaier S, Parra-Saavedra M, Crovetto F, Peguero A, Nadal A, et al. Angiogenic factors at diagnosis of late-onset small-for-gestational age and histological placental underperfusion. Placenta. 2014;35(6):398–403.CrossRefPubMedGoogle Scholar
  70. 70.
    Ghosh SK, Raheja S, Tuli A, Raghunandan C, Agarwal S. 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(5):881–90.CrossRefPubMedGoogle Scholar
  71. 71.
    Schoofs K, Grittner U, Engels T, Pape J, Denk B, Henrich W, et al. The importance of repeated measurements of the sFlt-1/PlGF ratio for the prediction of preeclampsia and intrauterine growth restriction. J Perinat Med. 2014;42(1):61–8.CrossRefPubMedGoogle Scholar
  72. 72.
    Yung HW, Atkinson D, Campion-Smith T, Olovsson M, Charnock-Jones DS, Burton GJ. Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early- and late-onset pre-eclampsia. J Pathol. 2014;234(2):262–76.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Yung HW, Calabrese S, Hynx D, Hemmings BA, Cetin I, Charnock-Jones DS, et al. Evidence of placental translation inhibition and endoplasmic reticulum stress in the etiology of human intrauterine growth restriction. Am J Pathol. 2008;173(2):451–62.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Jones CJ, Fox H. Ultrastructure of the placenta in prolonged pregnancy. J Pathol. 1978;126(3):173–9.CrossRefPubMedGoogle Scholar
  75. 75.
    Lyall F, Robson SC, Bulmer JN. Spiral artery remodeling and trophoblast invasion in preeclampsia and fetal growth restriction: relationship to clinical outcome. Hypertension. 2013;62(6):1046–54.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Anne Cathrine Staff
    • 1
    • 2
    Email author
  • Christopher W. G. Redman
    • 3
  1. 1.Division of Obstetrics and GynaecologyOslo University HospitalOsloNorway
  2. 2.Faculty of MedicineUniversity of OsloOsloNorway
  3. 3.University of OxfordOxfordUK

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