Skip to main content Accessibility help
  • Print publication year: 2012
  • Online publication date: February 2013

Chapter 18.1 - Intrauterine growth restriction

from Section 2 - Fetal disease


Advances in obstetrical ultrasound, combined with ancillary magnetic resonance imaging and rapid molecular testing of amniotic fluid, have greatly improved the diagnostic capabilities when assessing the fetus with suspected intrauterine growth restriction (IUGR). Placental villi are covered by the fetally derived epithelial layer termed villous trophoblast; this is a distinct lineage under separate transcriptional control from the extravillous trophoblast (EVT) in mammalian placentae. The maternal-fetal interface, or decidua, is rich in cell lineages of the maternal immune system, in particular large granular lymphocytes and uterine natural killer (NK) cells. The net effect of abnormal maternal perfusion of the placental villi is one or more of the following: spiral artery thrombosis and unstable perfusion. The developmentally abnormal placenta, characterized by decidual bed pathology, structurally abnormal villi with defective or damaged areas of syncytiotrophoblast is prone to thrombosis.

Related content

Powered by UNSILO
Boers, KE, Vijgen, SM, Bijlenga, D, et al. Induction versus expectant monitoring for intrauterine growth restriction at term: randomised equivalence trial (DIGITAT). BMJ 2010;341:c7087.
Kaufmann, P, Scheffen, I. Placental development. In: Polin, R, Fox, W, eds. Neonatal and Fetal Medicine:Physiology and Pathology, Vol. 1. Orlando, Saunders. 1992; 47–55.
Jackson, MR, Walsh, AJ, Morrow, RJ, et al. Reduced placental villous tree elaboration in small-for-gestational-age pregnancies: relationship with umbilical artery Doppler waveforms. Am J Obstet Gynecol 1995;172(2 Pt 1):518–25.
Robson, SC, Simpson, H, Ball, E, Lyall, F, Bulmer, JN. Punch biopsy of the human placental bed. Am J Obstet Gynecol 2002;187(5):1349–55.
Burton, GJ. Oxygen, the Janus gas; its effects on human placental development and function. J Anat 2009;215(1):27–35.
Burton, GJ, Watson, AL, Hempstock, J, Skepper, JN, Jauniaux, E. Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy. J Clin Endocrinol Metab 2002;87(6):2954–9.
Burton, GJ, Jauniaux, E, Watson, AL. Maternal arterial connections to the placental intervillous space during the first trimester of human pregnancy: the Boyd collection revisited. Am J Obstet Gynecol 1999;181(3):718–24.
Burton, GJ, Hempstock, J, Jauniaux, E. Oxygen, early embryonic metabolism and free radical-mediated embryopathies. Reprod Biomed Online 2003;6(1):84–96.
Jauniaux, E, Cindrora-Davies, T, Johns, J, et al. Distribution and transfer pathways of antioxidant molecules inside the first trimester human gestation sac. J Clin Endocrinol Metab 2004;89(3):1452–9.
Jauniaux, E, Hempstock, J, Greenwold, N, Burton, GJ. Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancies. Am J Pathol 2003;162(1):115–25.
Kaufmann, P, Black, S, Huppertz, B. Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol Reprod 2003;69(1):1–7.
Burton, GJ, Jauniaux, E, Charnock-Jones, DS. The influence of the intrauterine environment on human placental development. Int J Dev Biol 2010;54(2–3):303–12.
Proctor, LK, Toal, M, Keating, S, et al. Placental size and the prediction of severe early-onset intrauterine growth restriction in women with low pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol 2009;34(3):274–82.
Nordenvall, M, Ullberg, U, Laurin, J, et al. Placental morphology in relation to umbilical artery blood velocity waveforms. Eur J Obstet Gynecol Reprod Biol 1991;40(3):179–90.
Dunk, C, Smith, S, Hazan, A, Whittle, W, Jones, RL. Promotion of angiogenesis by human endometrial lymphocytes. Immunol Invest 2008;37(5):583–610.
Kadyrov, M, Kingdom, JC, Huppertz, B. Divergent trophoblast invasion and apoptosis in placental bed spiral arteries from pregnancies complicated by maternal anemia and early-onset preeclampsia/intrauterine growth restriction. Am J Obstet Gynecol 2006;194(2):557–63.
Burton, GJ, Woods, AW, Jauniaux, E, Kingdom, JC. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta 2009;30(6):473–82.
Nanaev, A, Chwalisz, K, Frank, HG, et al. Physiological dilation of uteroplacental arteries in the guinea pig depends on nitric oxide synthase activity of extravillous trophoblast. Cell Tissue Res 1995;282(3):407–21.
Lyall, F, Barber, A, Myatt, L, Bulmer, JN, Robson, SC. Hemeoxygenase expression in human placenta and placental bed implies a role in regulation of trophoblast invasion and placental function. FASEB J 2000;14(1):208–19.
Proctor, LK, Whittle, WL, Keating, S, Viero, S, Kingdom, JC. Pathologic basis of echogenic cystic lesions in the human placenta: role of ultrasound-guided wire localization. Placenta 2010;31(12):1111–15.
Yung, HW, Calabrese, S, Hynx, D, et al. Evidence of placental translation inhibition and endoplasmic reticulum stress in the etiology of human intrauterine growth restriction. Am J Pathol 2008;173(2):451–62.
Kaufmann, P, Mayhew, TM, Charnock-Jones, DS. Aspects of human fetoplacental vasculogenesis and angiogenesis. II. Changes during normal pregnancy. Placenta 2004;25(2–3):114–26.
Simmons, DG, Natale, DR, Begay, V, et al. Early patterning of the chorion leads to the trilaminar trophoblast cell structure in the placental labyrinth. Development 2008;135(12):2083–91.
Simpson, RA, Mayhew, TM, Barnes, PR. From 13 weeks to term, the trophoblast of human placenta grows by the continuous recruitment of new proliferative units: a study of nuclear number using the disector. Placenta 1992;13(5):501–12.
Kingdom, JC, Drewlo, S. Is heparin a placental anticoagulant in high-risk pregnancies? Blood 2011;118(18):478–8.
Baczyk, D, Drewlo, S, Proctor, L, et al. Glial cell missing-1 transcription factor is required for the differentiation of the human trophoblast. Cell Death Differ 2009;16(5):719–27.
Liang, CY, Wang, LJ, Chen, CP, et al. GCM1 regulation of the expression of syncytin 2 and its cognate receptor MFSD2A in human placenta. Biol Reprod 2010;83(3):387–95.
Tanaka, S, Kunath, T, Hadjantonakis, AK, Nagy, A, Rossant J. Promotion of trophoblast stem cell proliferation by FGF4. Science 1998;282(5396):2072–5.
Baczyk, D, Dunk, C, Huppertz, B, et al. Bi-potential behaviour of cytotrophoblasts in first trimester chorionic villi. Placenta 2006;27(4–5):367–74.
Hemberger, M, Udayashankar, R, Tesar, P, Moore, H, Burton, GJ. ELF5-enforced transcriptional networks define an epigenetically regulated trophoblast stem cell compartment in the human placenta. Hum Mol Genet 2010;19(12):2456–67.
Macara, L, Kingdom, JC, Kaufmann, P, et al. Structural analysis of placental terminal villi from growth-restricted pregnancies with abnormal umbilical artery Doppler waveforms. Placenta 1996;17(1):37–48.
Huppertz, B, Frank, HG, Kingdom, JC, Reister, F, Kaufmann, P. Villous cytotrophoblast regulation of the syncytial apoptotic cascade in the human placenta. Histochem Cell Biol 1998;110(5):495–508.
Ellery, PM, Cindrova-Davies, T, Jauniaux, E, Ferguson-Smith, AC, Burton, GJ. Evidence for transcriptional activity in the syncytiotrophoblast of the human placenta. Placenta 2009;30(4):329–34.
Fogarty, NM, Mayhew, TM, Ferguson-Smith AC, Burton GJ. A quantitative analysis of transcriptionally active syncytiotrophoblast nuclei across human gestation. J Anat 2011;219(5):601–10.
Burton, GJ, Jones, CJ. Syncytial knots, sprouts, apoptosis, and trophoblast deportation from the human placenta. Taiwan J Obstet Gynecol 2009;48(1):28–37.
Parham, P, Guethlein, LA. Pregnancy immunogenetics: NK cell education in the womb? J Clin Invest 2010;120(11):3801–4.
Munn, DH, Zhou, M, Attwood, JT, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998;281(5380):1191–3.
Walker, MG, Fitzgerald, B, Keating, S, et al. Sex-specific basis of severe placental dysfunction leading to extreme preterm delivery. Placenta 2012;33(7)568–71.
Saraswat, L, Bhattacharya, S, Maheshwari, A. Maternal and perinatal outcome in women with threatened miscarriage in the first trimester: a systematic review. BJOG 2010;117(3):245–57.
Nicolaides, KH. Screening for fetal aneuploidies at 11 to 13 weeks. Prenat Diagn 2011;31(1):7–15.
Dugoff, L. First- and second-trimester maternal serum markers for aneuploidy and adverse obstetric outcomes. Obstet Gynecol 2010;115(5):1052–61.
Smith, GC, Crossley, JA, Aitken, DA, et al. First-trimester placentation and the risk of antepartum stillbirth. JAMA 2004;292(18):2249–54.
Smith, GC, Shah, I, Crossley, JA, et al. Pregnancy-associated plasma protein A and alpha-fetoprotein and prediction of adverse perinatal outcome. Obstet Gynecol 2006;107(1):161–6.
Toal, M, Keating, S, Machin, G, et al. Determinants of adverse perinatal outcome in high-risk women with abnormal uterine artery Doppler images. Am J Obstet Gynecol 2008;198(3):330 e1–7.
Constantini, D, Walker, M, Miltyan, N, Keating, S, Kingdom, J. Pathologic basis of improving the screening utility of 2-dimensional placental morphology ultrasound. Placenta 2012; (in press).
Schwartz, N, Coletta, J, Pessel, C, et al. Novel 3-dimensional placental measurements in early pregnancy as predictors of adverse pregnancy outcomes. J Ultrasound Med 2010;29(8):1203–12.
Rizzo, G, Capponi, A, Pietrolucci, ME, Capece, A, Arduini, D. First-trimester placental volume and vascularization measured by 3-dimensional power Doppler sonography in pregnancies with low serum pregnancy-associated plasma protein a levels. J Ultrasound Med 2009;28(12):1615–22.
Yigiter, AB, Kavak, ZN, Durukan, B, et al. Placental volume and vascularization flow indices by 3D power Doppler US using VOCAL technique and correlation with IGF-1, free beta-hCG, PAPP-A, and uterine artery Doppler at 11–14 weeks of pregnancy. J Perinat Med 2011;39(2):137–41.
Pijenborg, R, Brosens, I, Romero, R. Placental Bed Disorders, 1st edn. Cambridge, UK, Cambridge University Press, 2010.
Reister, F, Frank, HG, Kingdom, JC, et al. Macrophage-induced apoptosis limits endovascular trophoblast invasion in the uterine wall of preeclamptic women. Lab Invest 2001;81(8):1143–52.
Fitzgerald, B, Shannon, P, Kingdom, J, Keating, S. Rounded intraplacental haematomas due to decidual vasculopathy have a distinctive morphology. J Clin Pathol 2011;64(8):729–32.
Ray, JE, Garcia, J, Jurisicova, A, Caniggia, I. Mtd/Bok takes a swing: proapoptotic Mtd/Bok regulates trophoblast cell proliferation during human placental development and in preeclampsia. Cell Death Differ 2010;17(5):846–59.
Fitzgerald, B, Levytska, K, Kingdom, J, et al. Villous trophoblast abnormalities in extremely preterm deliveries with elevated second trimester maternal serum hCG or inhibin-A. Placenta 2011;32(4):339–45.
Nevo, O, Soleymanlou, N, Wu, Y, et al. Increased expression of sFlt-1 in in vivo and in vitro models of human placental hypoxia is mediated by HIF-1. Am J Physiol Regul Integr Comp Physiol 2006;291(4):R1085–93.
Drewlo, S, Levytska, K, Sobel, M, et al. Heparin promotes soluble VEGF receptor expression in human placental villi to impair endothelial VEGF signaling. J Thromb Haemost 2011;8(12):2486–97.
Tache, V, LaCoursiere, DY, Saleemuddin, A, Parast, MM. Placental expression of vascular endothelial growth factor receptor-1/soluble vascular endothelial growth factor receptor-1 correlates with severity of clinical preeclampsia and villous hypermaturity. Hum Pathol 2011;42(9):1283–8.
Auer, J, Camoin, L, Guillonneau, F, et al. Serum profile in preeclampsia and intra-uterine growth restriction revealed by iTRAQ technology. J Proteomics 2010;73(5):1004–17.
Buhimschi, IA, Zhao, G, Funai, EF, et al. Proteomic profiling of urine identifies specific fragments of SERPINA1 and albumin as biomarkers of preeclampsia. Am J Obstet Gynecol 2008;199(5):551e1–16.
Krebs, C, Macara, LM, Leiser, R, et al. Intrauterine growth restriction with absent end-diastolic flow velocity in the umbilical artery is associated with maldevelopment of the placental terminal villous tree. Am J Obstet Gynecol 1996;175(6):1534–42.
Soleymanlou, N, Jurisica, I, Nevo, O, et al. Molecular evidence of placental hypoxia in preeclampsia. J Clin Endocrinol Metab 2005;90(7):4299–308.
Crocker, IP, Cooper, S, Ong, SC, Baker, PN. Differences in apoptotic susceptibility of cytotrophoblasts and syncytiotrophoblasts in normal pregnancy to those complicated with preeclampsia and intrauterine growth restriction. Am J Pathol 2003;162(2):637–43.
Langbein, M, Strick, R, Strissel, PL, et al. Impaired cytotrophoblast cell-cell fusion is associated with reduced Syncytin and increased apoptosis in patients with placental dysfunction. Mol Reprod Dev. 2008;75(1):175–83.
Ruebner, M, Strissel, PL, Langbein, M, et al. Impaired cell fusion and differentiation in placentae from patients with intrauterine growth restriction correlate with reduced levels of HERV envelope genes. J Mol Med (Berl) 2010;88(11): 1143–56.
Farina, A, Zucchini, C, De Sanctis, P, et al. Gene expression in chorionic villous samples at 11 weeks of gestation in women who develop pre-eclampsia later in pregnancy: implications for screening. Prenat Diagn 2011;31(2):181–5.
Franco, C, Walker, M, Robertson, J, et al. Placental infarction and thrombophilia. Obstet Gynecol 2011;117(4):929–34.
Viero, S, Chaddha, V, Alkazaleh, F, et al. Prognostic value of placental ultrasound in pregnancies complicated by absent end-diastolic flow velocity in the umbilical arteries. Placenta 2004;25(8–9):735–41.
Walker, M, Whittle, W, Keating, S, Kingdom, J. Sonographic diagnosis of chronic abruption. J Obstet Gynaecol Can 2010;32(11):1056–8.
Uxa, R, Baczyk, D, Kingdom, JC, et al. Genetic polymorphisms in the fibrinolytic system of placentas with massive perivillous fibrin deposition. Placenta 2010;31(6):499–505.
Saleemuddin, A, Tantbirojn, P, Sirois, K, et al. Obstetric and perinatal complications in placentas with fetal thrombotic vasculopathy. Pediatr Dev Pathol 2010;13(6):459–64.
Salafia, CM, Pezzullo, JC, Minior, VK, Divon, MY. Placental pathology of absent and reversed end-diastolic flow in growth-restricted fetuses. Obstet Gynecol 1997;90(5):830–6.
Pardi, G, Cetin, I, Marconi, AM, et al. Diagnostic value of blood sampling in fetuses with growth retardation. N Engl J Med 1993;328(10):692–6.
Redline, RW. Placental pathology: a systematic approach with clinical correlations. Placenta 2008;29 Suppl A:S86–91.
Cox, P, Marton, T. Pathological assessment of intrauterine growth restriction. Best Pract Res Clin Obstet Gynaecol 2009;23(6):751–64.
Klaritsch, P, Haeusler, M, Karpf, E, Schlembach, D, Lang, U. Spontaneous intrauterine umbilical artery thrombosis leading to severe fetal growth restriction. Placenta 2008;29(4):374–7.
Contro, E, deSouza, R, Bhide, A. Chronic intervillositis of the placenta: a systematic review. Placenta 2010;31(12):1106–10.
Boog, G. Chronic villitis of unknown etiology. Eur J Obstet Gynecol Reprod Biol 2008;136(1):9–15.
Katzman, PJ, Murphy, SP, Oble, DA. Immunohistochemical analysis reveals an influx of regulatory T cells and focal trophoblastic STAT-1 phosphorylation in chronic villitis of unknown etiology. Pediatr Dev Pathol 2011;14(4):284–93.
Tang, Z, Abrahams, VM, Mor, G, Guller, S. Placental Hofbauer cells and complications of pregnancy. Ann N Y Acad Sci 2011;1221:103–8.
Feeley, L, Mooney, EE. Villitis of unknown aetiology: correlation of recurrence with clinical outcome. J Obstet Gynaecol 2010;30(5):476–9.
Walker, MG, Hindmarsh, PC, Geary, M, Kingdom, JC. Sonographic maturation of the placenta at 30 to 34 weeks is not associated with second trimester markers of placental insufficiency in low-risk pregnancies. J Obstet Gynaecol Can 2010;32(12):1134–9.
Cooley, SM, Donnelly, JC, Walsh, T, et al. The impact of ultrasonographic placental architecture on antenatal course, labor and delivery in a low-risk primigravid population. J Matern Fetal Neonatal Med 2011;24(3):493–7.
Bujold, E, Roberge, S, Lacasse, Y, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol 2010;116(2 Pt 1):402–14.
Laskin, CA, Bombardier, C, Hannah, ME, et al. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med 1997;337(3):148–53.
Bewley, S, Cooper, D, Campbell, S. Doppler investigation of uteroplacental blood flow resistance in the second trimester: a screening study for pre-eclampsia and intrauterine growth retardation. Br J Obstet Gynaecol 1991;98(9):871–9.
Yu, CK, Smith, GC, Papageorghiou, AT, Cacho, AM, Nicolaides, KH. An integrated model for the prediction of preeclampsia using maternal factors and uterine artery Doppler velocimetry in unselected low-risk women. Am J Obstet Gynecol 2005;193(2):429–36.
Pardi, G, Cetin, I, Marconi, AM, et al. Venous drainage of the human uterus: respiratory gas studies in normal and fetal growth-retarded pregnancies. Am J Obstet Gynecol 1992;166(2):699–706.
Alkazaleh, F, Chaddha, V, Viero, S, et al. Second-trimester prediction of severe placental complications in women with combined elevations in alpha-fetoprotein and human chorionic gonadotrophin. Am J Obstet Gynecol 2006;194(3):821–7.
Huang, T, Hoffman, B, Meschino, W, Kingdom, J, Okun, N. Prediction of adverse pregnancy outcomes by combinations of first and second trimester biochemistry markers used in the routine prenatal screening of Down syndrome. Prenat Diagn 2010;30(5):471–7.
Toal, M, Chan, C, Fallah, S, et al. Usefulness of a placental profile in high-risk pregnancies. Am J Obstet Gynecol 2007;196(4):363e1–7.
Campbell, S. Is placental size a good predictor of obstetric complications? Ultrasound Obstet Gynecol 2009;34(3):247–8.
Sepulveda, W, Aviles, G, Carstens, E, Corral, E, Perez, N. Prenatal diagnosis of solid placental masses: the value of color flow imaging. Ultrasound Obstet Gynecol 2000;16(6):554–8.
Jauniaux, E, Moscoso, G, Campbell, S, et al. Correlation of ultrasound and pathologic findings of placental anomalies in pregnancies with elevated maternal serum alpha-fetoprotein. Eur J Obstet Gynecol Reprod Biol 1990;37(3):219–30.
Messerschmidt, A, Baschat, A, Linduska, N, et al. Magnetic resonance imaging of the placenta identifies placental vascular abnormalities independently of Doppler ultrasound. Ultrasound Obstet Gynecol 2011;37(6):717–22.
Bonel, HM, Stolz, B, Diedrichsen, L, et al. Diffusion-weighted MR imaging of the placenta in fetuses with placental insufficiency. Radiology 2010;257(3):810–19.
Burke, CJ, Tannenberg, AE, Payton, DJ. Ischaemic cerebral injury, intrauterine growth retardation, and placental infarction. Dev Med Child Neurol 1997;39(11):726–30.
Kingdom, JC, Walker, M, Proctor, LK, et al. Unfractionated heparin for second trimester placental insufficiency: a pilot randomized trial. J Thromb Haemost 2011;9(8):1483–92.
Sobel, ML, Kingdom, J, Drewlo, S. Angiogenic response of placental villi to heparin. Obstet Gynecol 2011;117(6):1375–83.
Sela, S, Natanson-Yaron, S, Zcharia, E, et al. Local retention versus systemic release of soluble VEGF receptor-1 are mediated by heparin-binding and regulated by heparanase. Circ Res 2011;108(9):1063–70.
Preston, FE, Rosendaal, FR, Walker, ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996;348(9032):913–16.
Mousa, HA, Alfirevic, Z. Do placental lesions reflect thrombophilia state in women with adverse pregnancy outcome? Hum Reprod 2000;15(8):1830–3.
Farine, D, Ryan, G, Kelly, EN, et al. Absent end-diastolic flow velocity waveforms in the umbilical artery – the subsequent pregnancy. Am J Obstet Gynecol 1993;168(2):637–40.
Murji, A, Proctor, LK, Paterson, A, et al. Male sex bias in placental dysfunction. Am J Med Genet 2012;158A(4):779–83.
Staff, AC, Dechend, R, Pijnenborg, R. Learning from the placenta: acute atherosis and vascular remodeling in preeclampsia – novel aspects for atherosclerosis and future cardiovascular health. Hypertension 2010;56(6):1026–34.