Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

How should women with pre-eclampsia be followed up? New insights from mechanistic studies

Nature Clinical Practice Nephrology volume 4, pages 503–509 (2008)Cite this article

Abstract

Understanding of the maternal syndrome of pre-eclampsia has greatly improved over the past 5 years. Specifically, the notion has emerged that the placenta is a source of antiangiogenic factors, such as soluble fms-like tyrosine kinase 1, that can progressively impair the mother's vascular and glomerular function throughout pregnancy. This impairment can be harmless during normal pregnancy, but in cases of defective placentation, concentrations of antiangiogenic factors increase to a level that compromises vital vascular functions in the short term and jeopardizes long-term maternal and fetal outcomes. In both pre-eclamptic and healthy pregnancies, the transient imbalance between angiogenic and antiangiogenic factors elicited by pregnancy acts as a 'stress test' for the endothelium, particularly in the glomerular capillary bed. Women who do not pass this test (i.e. those who develop pre-eclampsia or gestational hypertension) should be screened for glomerular disease, and their cardiovascular risk should be carefully monitored throughout life.

Key Points

  • During the final weeks of pregnancy, secretion by the placenta of soluble fms-like tyrosine kinase 1, an inhibitor of vascular endothelial growth factor, increases, and circulating levels of vascular endothelial growth factor decrease

  • Since vascular endothelial growth factor is critical for maintenance of the glomerular environment, the third trimester acts as a 'stress test' for the glomeruli, and glomerular endotheliosis is common at this stage

  • Pregnancy-induced hypertension and pre-eclampsia are linked to early, excessive secretion of soluble fms-like tyrosine kinase 1 and endoglin, another antiangiogenic factor

  • Women with complicated pregnancies should be routinely screened for chronic hypertension and/or glomerulopathy (i.e. albuminuria) 8 weeks after giving birth

  • Follow-up of women with pre-eclampsia should continue for the long term and aim to minimize cardiovascular risk factors (e.g. with lifestyle advice)

  • In cases of severe pre-eclampsia, screening for thrombophilia and antinuclear antibodies might be advisable

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Recommended follow-up after delivery for women with pregnancy-induced hypertension or pre-eclampsia.

Similar content being viewed by others

References

  1. Sibai B et al. (2005) Pre-eclampsia. Lancet 365: 785–799

    Article  Google Scholar 

  2. Maynard SE et al. (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111: 649–658

    Article  CAS  Google Scholar 

  3. Mignini LE (2006) Mapping the theories of preeclampsia: the need for systematic reviews of mechanisms of the disease. Am J Obstet Gynecol 194: 317–321

    Article  Google Scholar 

  4. Luttun A and Carmeliet P (2003) Soluble VEGF receptor Flt1: the elusive preeclampsia factor discovered? J Clin Invest 111: 600–602

    Article  CAS  Google Scholar 

  5. Schaffer NK et al. (1943) Uric acid clearance in normal pregnancy and pre-eclampsia. J Clin Invest 22: 201–206

    Article  CAS  Google Scholar 

  6. Groopman J (online 24 June 2006) The preeclampsia puzzle: making sense of a mysterious pregnancy disorder. The New Yorker [http://www.newyorker.com/archive/2006/07/24/060724fa_fact] (accessed 6 June 2008)

    Google Scholar 

  7. Chaiworapongsa T et al. (2004) Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Young Investigator Award. Am J Obstet Gynecol 190: 1541–1547

    Article  CAS  Google Scholar 

  8. Hertig A et al. (2004) Maternal serum sFlt1 concentration is an early and reliable predictive marker of preeclampsia. Clin Chem 50: 1702–1703

    Article  CAS  Google Scholar 

  9. McKeeman GC et al. (2004) Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation in patients who have preeclampsia develop. Am J Obstet Gynecol 191: 1240–1246

    Article  CAS  Google Scholar 

  10. Shibata E et al. (2005) Soluble fms-like tyrosine kinase 1 is increased in preeclampsia but not in normotensive pregnancies with small-for-gestational-age neonates: relationship to circulating placental growth factor. J Clin Endocrinol Metab 90: 4895–4903

    Article  CAS  Google Scholar 

  11. Tsatsaris V et al. (2003) Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab 88: 5555–5563

    Article  CAS  Google Scholar 

  12. Wathen KA et al. (2006) Maternal serum-soluble vascular endothelial growth factor receptor-1 in early pregnancy ending in preeclampsia or intrauterine growth retardation. J Clin Endocrinol Metab 91: 180–184

    Article  CAS  Google Scholar 

  13. Levine RJ et al. (2004) Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350: 672–683

    Article  CAS  Google Scholar 

  14. Berkane N et al. (2008) Hypertensive disorders of pregnancy: future perspectives. A French point of view. Curr Opin Obstet Gynecol 20: 107–109

    Article  Google Scholar 

  15. Sugimoto H et al. (2003) Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J Biol Chem 278: 12605–12608

    Article  CAS  Google Scholar 

  16. Eremina V et al. (2003) Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 111: 707–716

    Article  CAS  Google Scholar 

  17. Ostendorf T et al. (1999) VEGF(165) mediates glomerular endothelial repair. J Clin Invest 104: 913–923

    Article  CAS  Google Scholar 

  18. Berkane N et al. (2007) Angiogenic factors in preeclampsia: so complex, so simple? Nephrol Dial Transplant 22: 2753–2756

    Article  Google Scholar 

  19. Shimizu A et al. (2004) Vascular endothelial growth factor165 resolves glomerular inflammation and accelerates glomerular capillary repair in rat anti-glomerular basement membrane glomerulonephritis. J Am Soc Nephrol 15: 2655–2665

    Article  CAS  Google Scholar 

  20. Kabbinavar F et al. (2003) Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21: 60–65

    Article  CAS  Google Scholar 

  21. Eremina V et al. (2008) VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 358: 1129–1136

    Article  CAS  Google Scholar 

  22. Ferrara N and Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438: 967–974

    Article  CAS  Google Scholar 

  23. Yoshimatsu J et al. (2006) Relationship between urinary albumin and serum soluble fms-like tyrosine kinase 1 (sFlt-1) in normal pregnancy. Eur J Obstet Gynecol Reprod Biol 128: 204–208

    Article  CAS  Google Scholar 

  24. Strevens H et al. (2003) Glomerular endotheliosis in normal pregnancy and pre-eclampsia. BJOG 110: 831–836

    Article  CAS  Google Scholar 

  25. Murakami S et al. (2000) Renal disease in women with severe preeclampsia or gestational proteinuria. Obstet Gynecol 96: 945–949

    CAS  PubMed  Google Scholar 

  26. Levine RJ et al. (2006) Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 355: 992–1005

    Article  CAS  Google Scholar 

  27. Lopez-Espinoza I et al. (1986) Urinary albumin excretion in pregnancy. BJOG 93: 176–181

    Article  CAS  Google Scholar 

  28. Misiani R et al. (1991) Urinary albumin excretion in normal pregnancy and pregnancy-induced hypertension. Nephron 59: 416–422

    Article  CAS  Google Scholar 

  29. Hladunewich MA et al. (2008) Course of preeclamptic glomerular injury after delivery. Am J Physiol Renal Physiol 294: F614–F620

    Article  CAS  Google Scholar 

  30. Bar J et al. (1999) Microalbuminuria after pregnancy complicated by pre-eclampsia. Nephrol Dial Transplant 14: 1129–1132

    Article  CAS  Google Scholar 

  31. Nisell H et al. (1995) Blood pressure and renal function seven years after pregnancy complicated by hypertension. BJOG 102: 876–881

    Article  CAS  Google Scholar 

  32. Vikse BE et al. (2006) Adverse perinatal outcome and later kidney biopsy in the mother. J Am Soc Nephrol 17: 837–845

    Article  Google Scholar 

  33. Sibai BM et al. (1986) Severe preeclampsia-eclampsia in young primigravid women: subsequent pregnancy outcome and remote prognosis. Am J Obstet Gynecol 155: 1011–1016

    Article  CAS  Google Scholar 

  34. Pouta A et al. (2004) Manifestations of metabolic syndrome after hypertensive pregnancy. Hypertension 43: 825–831

    Article  CAS  Google Scholar 

  35. Irgens HU et al. (2001) Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ 323: 1213–1217

    Article  CAS  Google Scholar 

  36. Ray JG et al. (2005) Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet 366: 1797–1803

    Article  Google Scholar 

  37. Wilson BJ et al. (2003) Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study. BMJ 326: 845

    Article  Google Scholar 

  38. Smith GC et al. (2001) Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet 357: 2002–2006

    Article  CAS  Google Scholar 

  39. Lawlor DA et al. (2005) Birth weight is inversely associated with incident coronary heart disease and stroke among individuals born in the 1950s: findings from the Aberdeen Children of the 1950s prospective cohort study. Circulation 112: 1414–1418

    Article  Google Scholar 

  40. Sibai BM (1996) Treatment of hypertension in pregnant women. N Engl J Med 335: 257–265

    Article  CAS  Google Scholar 

  41. Higgins JR and de Swiet M (2001) Blood-pressure measurement and classification in pregnancy. Lancet 357: 131–135

    Article  CAS  Google Scholar 

  42. Salahuddin S et al. (2007) Diagnostic utility of soluble fms-like tyrosine kinase 1 and soluble endoglin in hypertensive diseases of pregnancy. Am J Obstet Gynecol 197: 28.e1–28.e6

    Article  Google Scholar 

  43. He H et al. (1999) Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src. J Biol Chem 274: 25130–25135

    Article  CAS  Google Scholar 

  44. Venkatesha S et al. (2006) Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 12: 642–649

    Article  CAS  Google Scholar 

  45. Hertig A et al. (2007) Soluble endoglin levels during normotensive and hypertensive pregnancies. Eur J Obstet Gynecol Reprod Biol [10.1016/j.ejogrb.2007.09.007]

  46. Villar J et al. (2006) Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions? Am J Obstet Gynecol 194: 921–931

    Article  Google Scholar 

  47. Fisher KA et al. (1981) Hypertension in pregnancy: clinical-pathological correlations and remote prognosis. Medicine (Baltimore) 60: 267–276

    Article  CAS  Google Scholar 

  48. Alfirevic Z et al. (2002) How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review. Eur J Obstet Gynecol Reprod Biol 101: 6–14

    Article  Google Scholar 

  49. Kupferminc MJ (2003) Thrombophilia and pregnancy. Reprod Biol Endocrinol 1: 111

    Article  Google Scholar 

  50. Johansen M et al. (1999) Trophoblast deportation in human pregnancy—its relevance for pre-eclampsia. Placenta 20: 531–539

    Article  CAS  Google Scholar 

  51. Germain SJ et al. (2007) Systemic inflammatory priming in normal pregnancy and preeclampsia: the role of circulating syncytiotrophoblast microparticles. J Immunol 178: 5949–5956

    Article  CAS  Google Scholar 

  52. Lin J and August P (2005) Genetic thrombophilias and preeclampsia: a meta-analysis. Obstet Gynecol 105: 182–192

    Article  Google Scholar 

  53. Zhou CC et al. (2008) Autoantibody from women with preeclampsia induces soluble Fms-like tyrosine kinase-1 production via angiotensin type 1 receptor and calcineurin/nuclear factor of activated T-cells signaling. Hypertension 51: 1010–1019

    Article  CAS  Google Scholar 

  54. Wallukat G et al. (1999) Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest 103: 945–952

    Article  CAS  Google Scholar 

  55. Karumanchi SA and Lindheimer MD (2008) Preeclampsia pathogenesis: “triple a rating”-autoantibodies and antiangiogenic factors. Hypertension 51: 991–992

    Article  CAS  Google Scholar 

  56. Subramanya A et al. (2005) Steroid-responsive idiopathic glomerular capillary endotheliosis: case report and literature review. Am J Kidney Dis 45: 1090–1095

    Article  Google Scholar 

  57. Matthiesen LS et al. (1999) A prospective study on the occurrence of autoantibodies in low-risk pregnancies. Eur J Obstet Gynecol Reprod Biol 83: 21–26

    Article  CAS  Google Scholar 

  58. Kanasaki K et al. (2008) Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia. Nature [10.1038/nature06951]

  59. Qazi U et al. (2008) Soluble fms-like tyrosine kinase associated with preeclampsia in pregnancy in systemic lupus erythematosus. J Rheumatol 35: 631–634

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. A Hertig is a Nephrologist in the Department of Nephrology and Renal Transplantation at the Hôpital Tenon, Paris, France,

    Alexandre Hertig

  2. S Watnick is a Nephrologist at Portland VA Medical Center, Portland, OR, USA,

    Suzanne Watnick

  3. H Strevens is a Gynecologist in the Department of Obstetrics and Gynecology at the University of Lund, Lund, Sweden,

    Helena Strevens

  4. H Boulanger is a Nephrologist in the Department of Nephrology and Dialysis at the Clinique de l'Estrée, Stains, France,

    Henri Boulanger

  5. N Berkane is a Gynecologist in the Department of Obstetric Gynecology at the Hôpital Tenon, Paris, France,

    Nadia Berkane

  6. E Rondeau is Chief of the Department of Nephrology and Renal Transplantation at the Hôpital Tenon, Paris, France.,

    Eric Rondeau

Authors
  1. Alexandre Hertig
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Suzanne Watnick
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Helena Strevens
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Henri Boulanger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nadia Berkane
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eric Rondeau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexandre Hertig.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hertig, A., Watnick, S., Strevens, H. et al. How should women with pre-eclampsia be followed up? New insights from mechanistic studies. Nat Rev Nephrol 4, 503–509 (2008). https://doi.org/10.1038/ncpneph0880

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpneph0880

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing