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.

  • Original Article
  • Published:

Circulating RNA coding genes regulating apoptosis in maternal blood in severe early onset fetal growth restriction and pre-eclampsia

Abstract

Objective:

To determine whether the intrinsic apoptosis pathway is differentially expressed in placenta and maternal blood in severe preterm fetal growth restriction (FGR) and pre-eclampsia (PE), and to examine whether circulating RNA in maternal blood may be potential biomarkers.

Study design:

Maternal blood samples and placental biopsies were collected from women with preterm: FGR (n=20), PE without FGR (n=8) and controls (n=20). Real-time PCR examined the expression of genes in the intrinsic apoptosis pathway in FGR and PE, stratified according to the severity of placental insufficiency.

Result:

Severe preterm FGR, with or without PE, was associated with increased expression of BCL2, BCL-XL, BIM, BAD and Survivin in both the placenta and maternal blood (1.6 to 3.3-fold, P<0.05). In preterm PE, but not FGR, there was increased placental expression of BCL-XL and BCL2 (1.6 to 2.5-fold, P<0.05), but only BCL2 was significantly increased in the maternal blood (1.8-fold, P<0.05). Increased expression of genes of the intrinsic apoptosis pathway reflected the severity of FGR as determined by deteriorations in umbilical artery Doppler velocimetry.

Conclusion:

In severe early onset FGR there was increased expression of genes regulating intrinsic apoptosis in both the placenta and maternal blood. Circulating RNA regulating placenta apoptosis may be used to develop noninvasive novel biomarkers for FGR.

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

Access options

Buy this article

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

Evdokia Dimitriadis, Daniel L. Rolnik, … Ellen Menkhorst

References

  1. Smith GC, Fretts RC . Stillbirth. Lancet 2007; 370 (9600): 1715–1725.

    Article  Google Scholar 

  2. Froen JF, Gardosi JO, Thurmann A, Francis A, Stray-Pedersen B . Restricted fetal growth in sudden intrauterine unexplained death. Acta Obstet Gynecol Scand 2004; 83 (9): 801–807.

    Article  Google Scholar 

  3. Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF . WHO analysis of causes of maternal death: a systematic review. Lancet 2006; 367 (9516): 1066–1074.

    Article  Google Scholar 

  4. 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 (3): 193–201.

    Article  Google Scholar 

  5. Sharp AN, Heazell AE, Crocker IP, Mor G . Placental apoptosis in health and disease. Am J Reprod Immunol 2010; 64 (3): 159–169.

    Article  CAS  Google Scholar 

  6. Marsal K . Obstetric management of intrauterine growth restriction. Best Pract Res Clin Obstet Gynaecol 2009; 23 (6): 857–870.

    Article  Google Scholar 

  7. Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R . Pre-eclampsia. Lancet 2010; 376 (9741): 631–644.

    Article  Google Scholar 

  8. Backe B, Nakling J . Effectiveness of antenatal care: a population based study. Br J Obstet Gynaecol 1993; 100 (8): 727–732.

    Article  CAS  Google Scholar 

  9. Flenady V, Middleton P, Smith GC, Duke W, Erwich JJ, Khong TY et al. Stillbirths: the way forward in high-income countries. Lancet 2011; 377 (9778): 1703–1717.

    Article  Google Scholar 

  10. Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CW et al. Presence of fetal DNA in maternal plasma and serum. Lancet 1997; 350 (9076): 485–487.

    Article  CAS  Google Scholar 

  11. Poon LL, Leung TN, Lau TK, Lo YM . Presence of fetal RNA in maternal plasma. Clin Chem 2000; 46 (11): 1832–1834.

    CAS  PubMed  Google Scholar 

  12. Redman CW, Sargent IL . Circulating microparticles in normal pregnancy and pre-eclampsia. Placenta 2008; 29 (Suppl A): S73–S77.

    Article  Google Scholar 

  13. Hahn S, Huppertz B, Holgreve W . Fetal cells and cell free fetal nucleic acids in maternal blood: new tools to study abnormal placentation? Placenta 2005; 26 (7): 515–526.

    Article  CAS  Google Scholar 

  14. Ishihara N, Matsuo H, Murakoshi H, Laoag-Fernandez JB, Samoto T, Maruo T . Increased apoptosis in the syncytiotrophoblast in human term placentas complicated by either preeclampsia or intrauterine growth retardation. Am J Obstet Gynecol 2002; 186 (1): 158–166.

    Article  Google Scholar 

  15. Levy R, Smith SD, Yusuf K, Huettner PC, Kraus FT, Sadovsky Y et al. Trophoblast apoptosis from pregnancies complicated by fetal growth restriction is associated with enhanced p53 expression. Am J Obstet Gynecol 2002; 186 (5): 1056–1061.

    Article  CAS  Google Scholar 

  16. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet Gynecol 2002; 99 (1): 159–167.

    Google Scholar 

  17. Paiva P, Whitehead C, Saglam B, Palmer K, Tong S . Measurement of mRNA transcripts of very high placental expression in maternal blood as biomarkers of preeclampsia. J Clin Endocrinol Metab 2011; 96 (11): E1807–E1815.

    Article  CAS  Google Scholar 

  18. Baschat AA . Fetal growth restriction - from observation to intervention. J Perinat Med 2010; 38 (3): 239–246.

    Article  Google Scholar 

  19. Brosens I, Dixon HG, Robertson WB . Fetal growth retardation and the arteries of the placental bed. Br J Obstet Gynaecol 1977; 84 (9): 656–663.

    Article  CAS  Google Scholar 

  20. Smith SC, Baker PN, Symonds EM . Placental apoptosis in normal human pregnancy. Am J Obstet Gynecol 1997; 177 (1): 57–65.

    Article  CAS  Google Scholar 

  21. Kumpel B, King MJ, Sooranna S, Jackson D, Eastlake J, Cheng R et al. Phenotype and mRNA expression of syncytiotrophoblast microparticles isolated from human placenta. Ann N Y Acad Sci 2008; 1137: 144–147.

    Article  CAS  Google Scholar 

  22. Rajakumar A, Cerdeira AS, Rana S, Zsengeller Z, Edmunds L, Jeyabalan A et al. Transcriptionally active syncytial aggregates in the maternal circulation may contribute to circulating soluble fms-like tyrosine kinase 1 in preeclampsia. Hypertension 2012; 59 (2): 256–264.

    Article  CAS  Google Scholar 

  23. Goswami D, Tannetta DS, Magee LA, Fuchisawa A, Redman CW, Sargent IL et al. Excess syncytiotrophoblast microparticle shedding is a feature of early-onset pre-eclampsia, but not normotensive intrauterine growth restriction. Placenta 2006; 27 (1): 56–61.

    Article  CAS  Google Scholar 

  24. Kingdom J, Huppertz B, Seaward G, Kaufmann P . Development of the placental villous tree and its consequences for fetal growth. Eur J Obstet Gynecol Reprod Biol 2000; 92 (1): 35–43.

    Article  CAS  Google Scholar 

  25. Abumaree MH, Stone PR, Chamley LW . Changes in the expression of apoptosis-related proteins in the life cycle of human villous trophoblast. Reprod Sci 2012; 19 (6): 597–606.

    Article  CAS  Google Scholar 

  26. Rajakumar A, Chu T, Handley DE, Bunce KD, Burke B, Hubel CA et al. Maternal gene expression profiling during pregnancy and preeclampsia in human peripheral blood mononuclear cells. Placenta 2011; 32 (1): 70–78.

    Article  CAS  Google Scholar 

  27. Chen B, Longtine MS, Sadovsky Y, Nelson DM . Hypoxia downregulates p53 but induces apoptosis and enhances expression of BAD in cultures of human syncytiotrophoblasts. Am J Physiol Cell Physiol 2010; 299 (5): C968–C976.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful for funding from the Royal Australian and New Zealand College of Obstetricians and Gynecologists Arthur Wilson Scholarship, a William Buckland Foundation Grant, a Medical Research Foundation For Women and Babies Grant and a NHMRC Project Grant (no.1028521). ML and ST are supported by NHMRC Career Development Fellowships (MLno.454777) (STno.490870). We thank Gillian Barker for her assistance in sample processing. This project was funded by a Royal Australian and New Zealand College of Obstetricians and Gynecologists Arthur Wilson Scholarship, a William Buckland Foundation Grant, a Medical Research Foundation For Women and Babies Grant and a NHMRC Project Grant (no.1028521). ML and ST are supported by NHMRC Career Development Fellowships (STno.490970)

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C L Whitehead.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Whitehead, C., Walker, S., Lappas, M. et al. Circulating RNA coding genes regulating apoptosis in maternal blood in severe early onset fetal growth restriction and pre-eclampsia. J Perinatol 33, 600–604 (2013). https://doi.org/10.1038/jp.2013.16

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jp.2013.16

Keywords

This article is cited by

Search

Quick links