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Chapter 18.1 - Intrauterine growth restriction

placental basis and implications for clinical practice

from Section 2 - Fetal disease

Published online by Cambridge University Press:  05 February 2013

By
John Kingdom ,
Melissa Walker ,
Sascha Drewlo  and
Sarah Keating
Edited by
Mark D. Kilby ,
Anthony Johnson  and
Dick Oepkes
Mark D. Kilby
Affiliation:
Department of Fetal Medicine, University of Birmingham
Anthony Johnson
Affiliation:
Baylor College of Medicine, Texas
Dick Oepkes
Affiliation:
Department of Obstetrics, Leiden University Medical Center
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Summary

Introduction

Advances in obstetrical ultrasound, combined with ancillary magnetic resonance imaging and rapid molecular testing of amniotic fluid, have greatly improved our diagnostic capabilities when assessing the fetus with suspected intrauterine growth restriction (IUGR). Despite these advances, several frustrating issues confront clinicians when managing suspected IUGR as follows. First, an unacceptably high false-positive rate for the diagnosis of IUGR in later gestation increases unnecessary interventions (induction of labor and/or Cesarean delivery) and iatrogenic morbidity in small-for-gestational-age newborns. As an example, 33.4% of 650 women recruited to the recently published DIGITAT (Disproportionate Intrauterine Growth Intervention Trial at Term) trial had no postnatal evidence of IUGR (birth weight <10th percentile) [1]. Second, clinician uncertainty regarding cause or prognosis for suspected IUGR may trigger frequent short-term tests of fetal well-being (biophysical profile ultrasounds and non-stress tests) even via hospital admission, in the absence of any objective diagnosis. Third, in the absence of a perinatal and placental pathology service, clinicians have only proxy markers of disease, reflected by performance in labor and short-term neonatal morbidity, to audit their decision-making. A common solution to improving clinical practice in IUGR management may therefore be found in a reappraisal of the value of placental pathology to guide maternal-fetal medicine and obstetric practice. This chapter will review the pathological basis of placental IUGR that is meaningful to everyday practice, so that “placentology” can be integrated into obstetric and postpartum care.

Keywords

placental villiintrauterine growth restrictionmaternal immune systemplacental pathologyinterstitial extravillous trophoblastclinical practicedevelopmental pathology
Type
Chapter
Information
Fetal Therapy
Scientific Basis and Critical Appraisal of Clinical Benefits
 , pp. 341 - 354
Publisher: Cambridge University Press
Print publication year: 2012

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References

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.Google Scholar
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.Google Scholar
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.Google Scholar
Burton, GJ. Oxygen, the Janus gas; its effects on human placental development and function. J Anat 2009;215(1):27–35.Google Scholar
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.Google Scholar
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.Google Scholar
Burton, GJ, Hempstock, J, Jauniaux, E. Oxygen, early embryonic metabolism and free radical-mediated embryopathies. Reprod Biomed Online 2003;6(1):84–96.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
Dunk, C, Smith, S, Hazan, A, Whittle, W, Jones, RL. Promotion of angiogenesis by human endometrial lymphocytes. Immunol Invest 2008;37(5):583–610.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
Kingdom, JC, Drewlo, S. Is heparin a placental anticoagulant in high-risk pregnancies? Blood 2011;118(18):478–8.Google Scholar
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.Google Scholar
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.Google Scholar
Tanaka, S, Kunath, T, Hadjantonakis, AK, Nagy, A, Rossant J. Promotion of trophoblast stem cell proliferation by FGF4. Science 1998;282(5396):2072–5.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
Burton, GJ, Jones, CJ. Syncytial knots, sprouts, apoptosis, and trophoblast deportation from the human placenta. Taiwan J Obstet Gynecol 2009;48(1):28–37.Google Scholar
Parham, P, Guethlein, LA. Pregnancy immunogenetics: NK cell education in the womb? J Clin Invest 2010;120(11):3801–4.Google Scholar
Munn, DH, Zhou, M, Attwood, JT, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998;281(5380):1191–3.Google Scholar
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.Google Scholar
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.Google Scholar
Nicolaides, KH. Screening for fetal aneuploidies at 11 to 13 weeks. Prenat Diagn 2011;31(1):7–15.Google Scholar
Dugoff, L. First- and second-trimester maternal serum markers for aneuploidy and adverse obstetric outcomes. Obstet Gynecol 2010;115(5):1052–61.Google Scholar
Smith, GC, Crossley, JA, Aitken, DA, et al. First-trimester placentation and the risk of antepartum stillbirth. JAMA 2004;292(18):2249–54.Google Scholar
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.Google Scholar
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.Google Scholar
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).Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
Soleymanlou, N, Jurisica, I, Nevo, O, et al. Molecular evidence of placental hypoxia in preeclampsia. J Clin Endocrinol Metab 2005;90(7):4299–308.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
Franco, C, Walker, M, Robertson, J, et al. Placental infarction and thrombophilia. Obstet Gynecol 2011;117(4):929–34.Google Scholar
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.Google Scholar
Walker, M, Whittle, W, Keating, S, Kingdom, J. Sonographic diagnosis of chronic abruption. J Obstet Gynaecol Can 2010;32(11):1056–8.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
Redline, RW. Placental pathology: a systematic approach with clinical correlations. Placenta 2008;29 Suppl A:S86–91.Google Scholar
Cox, P, Marton, T. Pathological assessment of intrauterine growth restriction. Best Pract Res Clin Obstet Gynaecol 2009;23(6):751–64.Google Scholar
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.Google Scholar
Contro, E, deSouza, R, Bhide, A. Chronic intervillositis of the placenta: a systematic review. Placenta 2010;31(12):1106–10.Google Scholar
Boog, G. Chronic villitis of unknown etiology. Eur J Obstet Gynecol Reprod Biol 2008;136(1):9–15.Google Scholar
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.Google Scholar
Tang, Z, Abrahams, VM, Mor, G, Guller, S. Placental Hofbauer cells and complications of pregnancy. Ann N Y Acad Sci 2011;1221:103–8.Google Scholar
Feeley, L, Mooney, EE. Villitis of unknown aetiology: correlation of recurrence with clinical outcome. J Obstet Gynaecol 2010;30(5):476–9.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
Campbell, S. Is placental size a good predictor of obstetric complications? Ultrasound Obstet Gynecol 2009;34(3):247–8.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
Burke, CJ, Tannenberg, AE, Payton, DJ. Ischaemic cerebral injury, intrauterine growth retardation, and placental infarction. Dev Med Child Neurol 1997;39(11):726–30.Google Scholar
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.Google Scholar
Sobel, ML, Kingdom, J, Drewlo, S. Angiogenic response of placental villi to heparin. Obstet Gynecol 2011;117(6):1375–83.Google Scholar
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.Google Scholar
Preston, FE, Rosendaal, FR, Walker, ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996;348(9032):913–16.Google Scholar
Mousa, HA, Alfirevic, Z. Do placental lesions reflect thrombophilia state in women with adverse pregnancy outcome? Hum Reprod 2000;15(8):1830–3.Google Scholar
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.Google Scholar
Murji, A, Proctor, LK, Paterson, A, et al. Male sex bias in placental dysfunction. Am J Med Genet 2012;158A(4):779–83.Google Scholar
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.Google Scholar

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