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.

Advertisement

Hypertension Research
  • View all journals
  • Search
  • Log in
  • Content Explore content
  • About the journal
  • Publish with us
  • Sign up for alerts
  • RSS feed
  1. nature
  2. hypertension research
  3. original article
  4. article
Alterations in Placental Growth Factor Levels before and after the Onset of Preeclampsia Are More Pronounced in Women with Early Onset Severe Preeclampsia
Download PDF
Download PDF
  • Original Article
  • Published: 01 February 2007

Alterations in Placental Growth Factor Levels before and after the Onset of Preeclampsia Are More Pronounced in Women with Early Onset Severe Preeclampsia

  • Akihide Ohkuchi1,
  • Chikako Hirashima1,
  • Shigeki Matsubara1,
  • Hirotada Suzuki1,
  • Kayo Takahashi1,
  • Fujimi Arai1,
  • Takashi Watanabe1,
  • Kazuomi Kario2 &
  • …
  • Mitsuaki Suzuki1 

Hypertension Research volume 30, pages 151–159 (2007)Cite this article

  • 2308 Accesses

  • 3 Altmetric

  • Metrics details

Abstract

It has been established that the serum placental growth factor (PlGF) decreases and the soluble fms-like tyrosine kinase-1 (sFlt-1) increases in women with preeclampsia. However, there have been no studies on the relation between preeclampsia onset time and the changes in PlGF and sFlt-1. Furthermore, the PlGF and sFlt-1 levels have not been evaluated using their reference values specific to each gestational age. In this study we reevaluated the serum PlGF and sFlt-1 levels before and after the clinical manifestation of early and late onset severe preeclampsia using the new reference values developed in our recent longitudinal study. Blood specimens were obtained immediately after the clinical manifestation of severe preeclampsia in 34 referred women, and both before and after the clinical manifestation in 8 women receiving a routine checkup at our institute. Both women with early and those with late preeclampsia showed decreased PlGF and increased sFlt-1 levels compared to normotensive controls at 28 and 37 weeks (n=68). However, those with early onset preeclampsia had a higher incidence of low PlGF (<5th percentile on the reference values) and high sFlt-1 (≥95th percentile) than those with late onset (low PlGF: 93% vs. 55%; high sFlt-1: 100% vs. 60%). log10PlGF (r=0.574, p<0.001) and log10(sFlt-1/PlGF) (r=−0.556, p<0.001) were correlated with the week of onset of preeclampsia. Before the onset of preeclampsia, the incidence rate of low PlGF in the women with early onset preeclampsia was 100% (5/5), whereas that in the women with late onset preeclampsia was 0% (0/2) (p=0.048). Therefore, alterations in the PlGF levels both before and after the onset of preeclampsia may be more pronounced in women with early onset than those with late onset severe preeclampsia.

Similar content being viewed by others

Maternal angiogenic factor disruptions prior to clinical diagnosis of preeclampsia: insights from the REVAMP study

Article 04 July 2024

Elevated sFlt-1/PlGF ratio in women with suspected or confirmed early-onset preeclampsia and super-imposed preeclampsia complicated by HELLP syndrome as well as abnormal umbilical artery Doppler findings and non-reassuring fetal status requiring immediate delivery: a prospective cohort study

Article 20 October 2025

Automated electrochemiluminescence immunoassay for serum PlGF levels in women with singleton pregnancy at 9–13 weeks of gestation predicts preterm preeclampsia: a retrospective cohort study

Article 22 December 2023

Article PDF

References

  1. Nagaya K, Fetters MD, Ishikawa M, et al: Causes of maternal mortality in Japan. JAMA 2000; 283: 2661–2667.

    Article  CAS  Google Scholar 

  2. Hecher K, Campbell S, Doyle P, Harrington K, Nicolaides K : Assessment of fetal compromise by Doppler ultrasound investigation of the fetal circulation. Arterial, intracardiac, and venous blood flow velocity studies. Circulation 1995; 91: 129–138.

    Article  CAS  Google Scholar 

  3. Sato K : A proposal for a new definition and classification of “Pregnancy Induced Hypertension (PIH)” (2004), in Japan Society for the Study of Toxemia of Pregnancy (ed): Historical Perspective of Study of Pregnancy-Induced Hypertension in Japan. Tokyo, Medical View Co, 2005, pp 54–87.

  4. Moore MP, Redman CW : Case-control study of severe pre-eclampsia of early onset. BMJ 1983; 287: 580–583.

    Article  CAS  Google Scholar 

  5. Long PA, Abell DA, Beischer NA : Fetal growth retardation and pre-eclampsia. Br J Obstet Gynaecol 1980; 87: 13–18.

    Article  CAS  Google Scholar 

  6. Odegard RA, Vatten LJ, Nilsen ST, Salvesen KA, Austgulen R : Preeclampsia and fetal growth. Obstet Gynecol 2000; 96: 950–955.

    CAS  PubMed  Google Scholar 

  7. Aucott SW, Donohue PK, Northington FJ : Increased morbidity in severe early intrauterine growth restriction. J Perinatol 2004; 24: 435–440.

    Article  Google Scholar 

  8. 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: 649–658.

    Article  CAS  Google Scholar 

  9. Livingston JC, Chin R, Haddad B, McKinney ET, Ahokas R, Sibai BM : Reductions of vascular endothelial growth factor and placental growth factor concentrations in severe preeclampsia. Am J Obstet Gynecol 2000; 183: 1554–1557.

    Article  CAS  Google Scholar 

  10. Tsatsaris V, Goffin F, Munaut C, et al: Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab 2003; 88: 5555–5563.

    Article  CAS  Google Scholar 

  11. Levine RJ, Maynard SE, Qian C, et al: Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350: 672–683.

    Article  CAS  Google Scholar 

  12. Staff AC, Braekke K, Harsem NK, Lyberg T, Holthe MR : Circulating concentrations of sFlt1 (soluble fms-like tyrosine kinase 1) in fetal and maternal serum during pre-eclampsia. Eur J Obstet Gynecol Reprod Biol 2005; 122: 33–39.

    Article  CAS  Google Scholar 

  13. Koga K, Osuga Y, Yoshino O, et al: Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. J Clin Endocrinol Metab 2003; 88: 2348–2351.

    Article  CAS  Google Scholar 

  14. Chaiworapongsa T, Romero R, Kim YM, et al: Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia. J Matern Fetal Neonatal Med 2005; 17: 3–18.

    Article  CAS  Google Scholar 

  15. Shibata E, Rajakumar A, Powers RW, et al: 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 2005; 90: 4895–4903.

    Article  CAS  Google Scholar 

  16. Powers RW, Roberts JM, Cooper KM, et al: Maternal serum soluble fms-like tyrosine kinase 1 concentrations are not increased in early pregnancy and decrease more slowly postpartum in women who develop preeclampsia. Am J Obstet Gynecol 2005; 193: 185–191.

    Article  CAS  Google Scholar 

  17. Miura S, Fujino M, Matsuo Y, Tanigawa H, Saku K : Nifedipine-induced vascular endothelial growth factor secretion from coronary smooth muscle cells promotes endothelial tube formation via the kinase insert domain-containing receptor/fetal liver kinase-1/NO pathway. Hypertens Res 2005; 28: 147–153.

    Article  CAS  Google Scholar 

  18. Uruno A, Sugawara A, Kanatsuka H, et al: Hepatocyte growth factor stimulates nitric oxide production through endothelial nitric oxide synthase activation by the phosphoinositide 3-kinase/Akt pathway and possibly by mitogen-activated protein kinase kinase in vascular endothelial cells. Hypertens Res 2004; 27: 887–895.

    Article  CAS  Google Scholar 

  19. Ikeda Y, Fukuda N, Wada M, et al: Development of angiogenic cell and gene therapy by transplantation of umbilical cord blood with vascular endothelial growth factor gene. Hypertens Res 2004; 27: 119–128.

    Article  CAS  Google Scholar 

  20. Imanishi T, Hano T, Nishio I : Angiotensin II potentiates vascular endothelial growth factor–induced proliferation and network formation of endothelial progenitor cells. Hypertens Res 2004; 27: 101–108.

    Article  CAS  Google Scholar 

  21. 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: 1R–7R.

    Article  Google Scholar 

  22. Hirashima C, Ohkuchi A, Arai F, et al: Establishing reference values for both total soluble fms-like tyrosine kinase 1 and free placental growth factor in pregnant women. Hypertens Res 2005; 28: 727–732.

    Article  CAS  Google Scholar 

  23. Torry DS, Wang HS, Wang TH, Caudle MR, Torry RJ : Preeclampsia is associated with reduced serum levels of placenta growth factor. Am J Obstet Gynecol 1998; 179: 1539–1544.

    Article  CAS  Google Scholar 

  24. Ogawa Y, Iwamura T, Kuriya N, et al: Birth size standards by gestational age for Japanese neonates. Acta Neonatol Jpn 1998; 34: 624–632.

    Google Scholar 

  25. Crispi F, Dominguez C, Llurba E, Martin-Gallan P, Cabero L, Gratacos E : Placental angiogenic growth factors and uterine artery Doppler findings for characterization of different subsets in preeclampsia and in isolated intrauterine growth restriction. Am J Obstet Gynecol 2006; 195: 201–207.

    Article  CAS  Google Scholar 

  26. Tidwell SC, Ho HN, Chiu WH, Torry RJ, Torry DS : Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia. Am J Obstet Gynecol 2001; 184: 1267–1272.

    Article  CAS  Google Scholar 

  27. Taylor RN, Grimwood J, Taylor RS, McMaster MT, Fisher SJ, North RA : Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies. Am J Obstet Gynecol 2003; 188: 177–182.

    Article  CAS  Google Scholar 

  28. Thadhani R, Mutter WP, Wolf M, et al: First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. J Clin Endocrinol Metab 2004; 89: 770–775.

    Article  CAS  Google Scholar 

  29. Hertig A, Berkane N, Lefevre G, et al: Maternal serum sFlt1 concentration is an early and reliable predictive marker of preeclampsia. Clin Chem 2004; 50: 1702–1703.

    Article  CAS  Google Scholar 

  30. Stepan H, Geide A, Faber R : Soluble fms-like tyrosine kinase 1. N Engl J Med 2004; 351: 2241–2242.

    Article  CAS  Google Scholar 

  31. Park CW, Park JS, Shim SS, Jun JK, Yoon BH, Romero R : An elevated maternal plasma, but not amniotic fluid, soluble fms-like tyrosine kinase-1 (sFlt-1) at the time of mid-trimester genetic amniocentesis is a risk factor for preeclampsia. Am J Obstet Gynecol 2005; 193: 984–989.

    Article  CAS  Google Scholar 

  32. Levine RJ, Thadhani R, Qian C, et al: Urinary placental growth factor and risk of preeclampsia. JAMA 2005; 293: 77–85.

    Article  CAS  Google Scholar 

  33. Khong TY, De Wolf F, Robertson WB, Brosens I : Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol 1986; 93: 1049–1059.

    Article  CAS  Google Scholar 

  34. Lin S, Shimizu I, Suehara N, Nakayama M, Aono T : Uterine artery Doppler velocimetry in relation to trophoblast migration into the myometrium of the placental bed. Obstet Gynecol 1995; 85: 760–765.

    Article  CAS  Google Scholar 

  35. Li H, Gu B, Zhang Y, Lewis DF, Wang Y : Hypoxia-induced increase in soluble Flt-1 production correlates with enhanced oxidative stress in trophoblast cells from the human placenta. Placenta 2005; 26: 210–217.

    Article  CAS  Google Scholar 

  36. Lash GE, Taylor CM, Trew AJ, et al: Vascular endothelial growth factor and placental growth factor release in cultured trophoblast cells under different oxygen tensions. Growth Factors 2002; 20: 189–196.

    Article  CAS  Google Scholar 

  37. Papageorghiou AT, Yu CK, Bindra R, et al: Multicenter screening for pre-eclampsia and fetal growth restriction by transvaginal uterine artery Doppler at 23 weeks of gestation. Ultrasound Obstet Gynecol 2001; 18: 441–449.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Jichi Medical University School of Medicine, Shimotsuke, Japan

    Akihide Ohkuchi, Chikako Hirashima, Shigeki Matsubara, Hirotada Suzuki, Kayo Takahashi, Fujimi Arai, Takashi Watanabe & Mitsuaki Suzuki

  2. Division of Cardiovascular Medicine, Jichi Medical University School of Medicine, Shimotsuke, Japan

    Kazuomi Kario

Authors
  1. Akihide Ohkuchi
    View author publications

    Search author on:PubMed Google Scholar

  2. Chikako Hirashima
    View author publications

    Search author on:PubMed Google Scholar

  3. Shigeki Matsubara
    View author publications

    Search author on:PubMed Google Scholar

  4. Hirotada Suzuki
    View author publications

    Search author on:PubMed Google Scholar

  5. Kayo Takahashi
    View author publications

    Search author on:PubMed Google Scholar

  6. Fujimi Arai
    View author publications

    Search author on:PubMed Google Scholar

  7. Takashi Watanabe
    View author publications

    Search author on:PubMed Google Scholar

  8. Kazuomi Kario
    View author publications

    Search author on:PubMed Google Scholar

  9. Mitsuaki Suzuki
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Akihide Ohkuchi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ohkuchi, A., Hirashima, C., Matsubara, S. et al. Alterations in Placental Growth Factor Levels before and after the Onset of Preeclampsia Are More Pronounced in Women with Early Onset Severe Preeclampsia. Hypertens Res 30, 151–159 (2007). https://doi.org/10.1291/hypres.30.151

Download citation

  • Received: 05 July 2006

  • Accepted: 26 September 2006

  • Issue date: 01 February 2007

  • DOI: https://doi.org/10.1291/hypres.30.151

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Keywords

  • early onset preeclampsia
  • late onset preeclampsia
  • placental growth factor
  • soluble fms-like tyrosine kinase-1
  • severe preeclampsia

This article is cited by

  • Association of maternal angiotensin II type 1 and type 2 receptor combination genotypes with susceptibility to early-onset preeclampsia

    • M. Satra
    • M. Samara
    • S. Sotiriou

    Journal of Human Hypertension (2022)

  • Clinical usefulness of serum levels of soluble fms-like tyrosine kinase 1/placental growth factor ratio to rule out preeclampsia in women with new-onset lupus nephritis during pregnancy

    • Chikako Hirashima
    • Manabu Ogoyama
    • Akihide Ohkuchi

    CEN Case Reports (2019)

  • Prediction and prevention of hypertensive disorders of pregnancy

    • Akihide Ohkuchi
    • Chikako Hirashima
    • Shigeki Matsubara

    Hypertension Research (2017)

  • Anti-angiogenesis and Preeclampsia in 2016

    • Susanne Schrey-Petersen
    • Holger Stepan

    Current Hypertension Reports (2017)

  • Ambulatory BP monitoring and clinic BP in predicting small-for-gestational-age infants during pregnancy

    • K Eguchi
    • T Ohmaru
    • Mitsuaki Suzuki

    Journal of Human Hypertension (2016)

Download PDF

Advertisement

Explore content

  • Research articles
  • Reviews & Analysis
  • News & Comment
  • Current issue
  • Collections
  • Sign up for alerts
  • RSS feed

About the journal

  • Journal Information
  • Open Access Fees and Funding
  • Guide to Authors
  • About the Editors
  • Message from Editors
  • Call for Paper
  • Contact
  • About the Partner
  • For Advertisers
  • Subscribe
  • Showcase of Graphical Abstracts on Hypertension Research

Publish with us

  • For Authors & Referees
  • Language editing services
  • Open access funding
  • Submit manuscript

Search

Advanced search

Quick links

  • Explore articles by subject
  • Find a job
  • Guide to authors
  • Editorial policies

Hypertension Research (Hypertens Res)

ISSN 1348-4214 (online)

ISSN 0916-9636 (print)

nature.com footer links

About Nature Portfolio

  • About us
  • Press releases
  • Press office
  • Contact us

Discover content

  • Journals A-Z
  • Articles by subject
  • protocols.io
  • Nature Index

Publishing policies

  • Nature portfolio policies
  • Open access

Author & Researcher services

  • Reprints & permissions
  • Research data
  • Language editing
  • Scientific editing
  • Nature Masterclasses
  • Research Solutions

Libraries & institutions

  • Librarian service & tools
  • Librarian portal
  • Open research
  • Recommend to library

Advertising & partnerships

  • Advertising
  • Partnerships & Services
  • Media kits
  • Branded content

Professional development

  • Nature Awards
  • Nature Careers
  • Nature Conferences

Regional websites

  • Nature Africa
  • Nature China
  • Nature India
  • Nature Japan
  • Nature Middle East
  • Privacy Policy
  • Use of cookies
  • Legal notice
  • Accessibility statement
  • Terms & Conditions
  • Your US state privacy rights
Springer Nature

© 2026 Springer Nature Limited