Abstract
Objective
To predict the occurrence of fetal growth restriction (FGR) by analyzing messenger RNA (mRNA) expression levels of vascular endothelial growth factor receptor 1 (fms-like tyrosine kinase 1 [Flt-1]) in maternal blood.
Study Design
Eleven women with FGR were matched with 88 controls. Plasma samples were obtained during each trimester. The Flt-1 mRNA expression levels were compared between groups. Predicted probabilities were calculated, and sensitivity-specificity (receiver-operating characteristic [ROC]) curves were assessed based on regression models for each trimester measurement and possible combinations of measurements.
Results
The mRNA levels of the FGR group during all trimesters were significantly higher than those of the control group. The ROC curve of combined first and second trimester data yielded a detection rate of 60% at a 10% false-positive rate, with an area under curve of 0.79.
Conclusion
The Flt-1 mRNA expression in maternal blood can be used as a marker to predict the development of FGR, long before a clinical diagnosis is made.
Similar content being viewed by others
References
Valsamakis G, Kanaka-Gantenbein C, Malamitsi-Puchner A, Mastorakos G. Causes of intrauterine growth restriction and the postnatal development of the metabolic syndrome. Ann N Y Acad Sci. 2006;1092:138–147.
Neerhof MG, Thaete LG. The fetal response to chronic placental insufficiency. Semin Perinatol. 2008;32(3):201–205.
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(5):649–658.
Mutter WP, Karumanchi SA. Molecular mechanisms of preeclampsia. Microvasc Res. 2008;75(1):1–8.
Crispi F, Domínguez C, Llurba E, Martín-Gallán P, Cabero L, Gratacós 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(1):201–207.
Wallner W, Sengenberger R, Strick R, et al. Angiogenic growth factors in maternal and fetal serum in pregnancies complicated by intrauterine growth restriction. Clin Sci (Lond). 2007;112(1): 51–57.
Savvidou MD, Yu CK, Harland LC, Hingorani AD, Nicolaides KH. Maternal serum concentration of soluble fms-like tyrosine kinase 1 and vascular endothelial growth factor in women with abnormal uterine artery Doppler and in those with fetal growth restriction. Am J Obstet Gynecol. 2006;195(6):1668–1673.
Stepan H, Krämer T, Faber R. Maternal plasma concentrations of soluble endoglin in pregnancies with intrauterine growth restriction. J Clin Endocrinol Metab. 2007;92(7):2831–2834.
Nevo O, Many A, Xu J, et al. Placental expression of soluble fms-like tyrosine kinase 1 is increased in singletons and twin pregnancies with intrauterine growth restriction. J Clin Endocrinol Metab. 2008;93(1):285–292.
Smith GC, Crossley JA, Aitken DA, et al. Circulating angiogenic factors in early pregnancy and the risk of preeclampsia, intrauterine growth restriction, spontaneous preterm birth, and stillbirth. Obstet Gynecol. 2007;109(6):1316–1324.
Åsvold BO, Vatten LJ, Romundstad PR, Jenum PA, Karumanchi SA, Eskild A. Angiogenic factors in maternal circulation and the risk of severe fetal growth restriction. Am J Epidemiol. 2011; 173(6):630–639.
Wathén KA, Tuutti E, Stenman UH, et al. Maternal serum-soluble vascular endothelial growth factor receptor-1 in early pregnancy ending in preeclampsia or intrauterine growth retardation. J Clin Endocrinol Metab. 2006;91(1):180–184.
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(8):4895–4903.
Poon LL, Leung TN, Lau TK, Lo YM. Presence of fetal RNA in maternal plasma. Clin Chem. 2000;46(11):1832–1834.
Ng EK, Tsui NB, Lau TK, et al. mRNA of placental origin is readily detectable in maternal plasma. Proc Natl Acad Sci USA. 2003; 100(8):4748–4753.
Purwosunu Y, Sekizawa A, Okazaki S, et al. Prediction of preeclampsia by analysis of cell-free messenger RNA in maternal plasma. Am J Obstet Gynecol. 2009;200(4):386.e381–387.
Farina A, Zucchini C, Sekizawa A, et al. Performance of messenger RNAs circulating in maternal blood in the prediction of preeclampsia at 10–14 weeks. Am J Obstet Gynecol. 2010; 203(6):575.e571–e577.
Sekizawa A, Purwosunu Y, Farina A, et al. Prediction of preeclampsia by an analysis of placenta-derived cellular mRNA in the blood of pregnant women at 15–20 weeks of gestation. BJOG. 2010;117(5):557–564.
Pang WW, Tsui MH, Sahota D, et al. A strategy for identifying circulating placental RNA markers for fetal growth assessment. Prenat Diagn. 2009;29(5):495–504.
Whitehead CL, Walker SP, Mendis S, Lappas M, Tong S. Quantifying mRNA coding growth genes in the maternal circulation to detect fetal growth restriction. Am J Obstet Gynecol. 2013;209(2): 133. e131–e139.
Okazaki S, Sekizawa A, Purwosunu Y, Iwasaki M, Farina A, Okai T. Measurement of mRNA of trophoblast-specific genes in cellular and plasma components of maternal blood. J Med Genet. 2006;43(9):e47.
Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350(7): 672–683.
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(2): 770–775.
Romero R, Nien JK, Espinoza J, et al. A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. J Matern Fetal Neonatal Med. 2008;21(1):9–23.
Erez O, Romero R, Espinoza J, et al. The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age. J Matern Fetal Neonatal Med. 2008; 21(5):279–287.
Pilalis A, Souka AP, Antsaklis P, et al. Screening for preeclampsia and fetal growth restriction by uterine artery Doppler and PAPP-A at 11–14 weeks’ gestation. Ultrasound Obstet Gynecol. 2007;29(2): 135–140.
North RA, Ferrier C, Long D, Townend K, Kincaid-Smith P. Uterine artery Doppler flow velocity waveforms in the second trimester for the prediction of preeclampsia and fetal growth retardation. Obstet Gynecol. 1994;83(3):378–386.
Wibowo N, Purwosunu Y, Sekizawa A, Farina A, Idriansyah L, Fitriana I. Antioxidant supplementation in pregnant women with low antioxidant status. J Obstet Gynaecol Res. 2012;38(9): 1152–1161.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Takenaka, S., Ventura, W., Sterrantino, A.F. et al. Prediction of Fetal Growth Restriction by Analyzing the Messenger RNAs of Angiogenic Factor in the Plasma of Pregnant Women. Reprod. Sci. 22, 743–749 (2015). https://doi.org/10.1177/1933719114557895
Published:
Issue Date:
DOI: https://doi.org/10.1177/1933719114557895