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
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Smith GC, Fretts RC . Stillbirth. Lancet 2007; 370 (9600): 1715–1725.
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.
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.
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.
Sharp AN, Heazell AE, Crocker IP, Mor G . Placental apoptosis in health and disease. Am J Reprod Immunol 2010; 64 (3): 159–169.
Marsal K . Obstetric management of intrauterine growth restriction. Best Pract Res Clin Obstet Gynaecol 2009; 23 (6): 857–870.
Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R . Pre-eclampsia. Lancet 2010; 376 (9741): 631–644.
Backe B, Nakling J . Effectiveness of antenatal care: a population based study. Br J Obstet Gynaecol 1993; 100 (8): 727–732.
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.
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.
Poon LL, Leung TN, Lau TK, Lo YM . Presence of fetal RNA in maternal plasma. Clin Chem 2000; 46 (11): 1832–1834.
Redman CW, Sargent IL . Circulating microparticles in normal pregnancy and pre-eclampsia. Placenta 2008; 29 (Suppl A): S73–S77.
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.
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.
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.
ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet Gynecol 2002; 99 (1): 159–167.
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.
Baschat AA . Fetal growth restriction - from observation to intervention. J Perinat Med 2010; 38 (3): 239–246.
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.
Smith SC, Baker PN, Symonds EM . Placental apoptosis in normal human pregnancy. Am J Obstet Gynecol 1997; 177 (1): 57–65.
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.
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.
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.
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.
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.
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.
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.
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
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights 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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/jp.2013.16
Keywords
This article is cited by
-
Sexually dimorphic patterns in maternal circulating microRNAs in pregnancies complicated by fetal growth restriction
Biology of Sex Differences (2021)