The Role of the Placenta in Intrauterine Growth Restriction (IUGR)

 

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Abstract

Intrauterine growth restriction (IUGR) represents a reduction from the physiological growth rate. Fetal growth depends from the maternal supply of nutrients through the placenta into the umbilical circulation. Consequently, fetal growth restriction is associated with a reduced nutritional placental supply and this can result from a decrease in utero-placental blood flows as well as a reduced placental transport capacity. In IUGR, the placental supply of amino acids is significantly reduced independently from the severity of growth restriction and from the presence of hypoxia. Moreover, maternal-fetal gradients of glucose are increased in severe IUGR fetuses, i. e. those with alterations of umbilical blood flows, and reduced conversion ratios of long chain-polyunsaturated fatty acids (LC-PUFA) from their parent fatty acids have been demonstrated. Mouse and human models suggest that epigenetic regulation of fetal growth may also play a significant role, through placental imprinted genes. This review summarizes the current knowledge about placental role in intrauterine growth restricion.

Zusammenfassung

Die intrauterine Wachstumsrestriktion ist definiert als eine Einschränkung der physiologischen Wachstumsrate. Das Wachstum des Feten hängt von der mütterlichen Versorgung mit Nahrungsstoffen über die Plazenta in den Nabelschnurkreislauf ab. Die Wachstumsbeeinträchtigung des Feten ist mit einer Retsriktion der plazentaren Zufuhr von Nahrungsstoffen assoziiert und dies kann Folge einer Abnahme des utero-plazentaren Blutflusses wie auch einer Verminderung der plazentaren Transportkapazität sein. Bei der IUGR ist die Versorgung mit Aminosäuren deutlich vermindert unabhängig von der Schwere der IUGR und davon, ob eine Hypoxie besteht. Darüber hinaus ist der materno-fetale Gradient für Glukose bei schwerer IUGR erhöht, d. h. bei solchen mit gestörtem Blutfluss im umbilikalen Kreislauf, und eine verminderte Konversion von langkettigen, ungesättigten Fettsäuren (LC-PUFA) von den entsprechenden Vorstufen wurde gezeigt. In Modellen der Maus sowie auch beim Menschen bestehen Hinweise darauf, dass auch eine epigenetische Regulation des Wachstums des Feten durch sog. imprinted Gene der Plazenta von Bedeutung ist. In dieser Übersicht sind die wichtigsten Erkenntnisse über die Rolle der Planzenta bei der IUGR zusammengefasst.

Literatur

• 1 Allan WC, Riviello JJ. Perinatal cerebrovascular disease in the neonate.  Ped Clin N Amer. 1992;  39 621
  PubMedGoogle Scholar
• 2 Barker DJ. The fetal and infant origins of adult disease.  BMJ. 1990;  301 ((6761)) 1111
  CrossrefPubMedGoogle Scholar
• 3 Barker DJ. The intrauterine origins of cardiovascular disease.  Acta Pediatr Suppl. 1993;  82 ((Suppl 391)) 93-99
  PubMedGoogle Scholar
• 4 Pijnenborg R, Bland JM, Robertson WB. et al . Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy.  Placenta. 1983;  4 397-414
  CrossrefPubMedGoogle Scholar
• 5 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
  PubMedGoogle Scholar
• 6 Pardi G, Marconi AM, Cetin I. Placental-fetal interrelationship in IUGR fetuses-a review.  lacenta. 2002;  23 ((Suppl A)) S136-S141
  CrossrefPubMedGoogle Scholar
• 7 Sibley CP, Turner MA, Cetin I. et al . Placental phenotypes of intrauterine growth.  Pediatr Res. 2005;  58 ((5)) 827-832
  CrossrefPubMedGoogle Scholar
• 8 Resnik R. Intrauterine growth restriction.  Obest Gynecol. 2002;  99 490-496
  PubMedGoogle Scholar
• 9 Pardi G. et al . Placental-fetal interrelationship in IUGR fetuses – a Review.  Trophoblast Research. 2002;  23 S136-S141
  CrossrefPubMedGoogle Scholar
• 10 Sparks JW, Hay WW, Meschia G. et al . Partition of maternal nutrients to the placenta and fetus in the sheep.  Europ J Obstet Gynec Reprod Biol. 1983;  14 331-340
  PubMedGoogle Scholar
• 11 Heinonen S, Taipale P, Saarikoski S. Weights of placentae from small-for gestational age infants revisited.  Placenta. 2001;  22 399-404
  CrossrefPubMedGoogle Scholar
• 12 Carter AM. Placental oxygen consumption. Part I: in vivo studies – a review.  Placenta. 2000;  21 ((Suppl A)) S31-S37
  CrossrefPubMedGoogle Scholar
• 13 Kaufmann P, Scheffen I. Placental development. In Polin RA, Fox WW, Eds. Fetal and neonatal physiology. Philadelphia, Pa., USA: WB Saunders Company 1998: p
  Google Scholar
• 14 Lattuada D, Colleoni F, Martinelli A. et al . Higher Mitochondrial DNA Content in Human IUGR Placenta.  Placenta. 2008;  , (in press).
  PubMedGoogle Scholar
• 15 Radaelli T, Boito S, Cozzi V. et al . Fetal oxygen consumption in term normal pregnancies.  Society for Gynecologic Investigations, Los Angeles, CA, USA, March 23–26, 2005. J Soc Gynecol Invest Abstract. 2005;  175 12
  PubMedGoogle Scholar
• 16 Sibley CP, Birdsey TJ, Brownbill P. et al . Mechanisms of maternofetal exchange across the human placenta.  Biochem Soc Trans. 1998;  26 86-90
  PubMedGoogle Scholar
• 17 Pardi G, Cetin I, Marconi AM. et al . Diagnostic value of blood sampling in fetuses with growth retardation.  N Engl J Med. 1993;  328 692-696
  CrossrefPubMedGoogle Scholar
• 18 Cetin I, Ronzoni S, Marconi AM. et al . Maternal concentrations and fetal-maternal concentration differences of plasma amino acids in normal and intrauterine growth retarded (IUGR) pregnancies.  Am J Obstet Gynecol. 1996;  174 1575-1583
  CrossrefPubMedGoogle Scholar
• 19 Cetin I, Marconi AM, Bozetti P. et al . Umbilical amino acid concentrations in appropriate and small for gestational age infants: a biochemical difference present in utero.  Am J Obstet Gynecol. 1988;  158 120-126
  PubMedGoogle Scholar
• 20 Cetin I, Corbetta C, Piceni Sereni L. et al . Umbilical amino acid concentrations in normal and growth retarded fetuses sampled in utero by cordocentesis.  Am J Obstet Gynecol. 1990;  162 253-261
  PubMedGoogle Scholar
• 21 Glazier JD, Cetin I, Perugino G. et al . Association between the activity of the system A amino acid transporter in the microvillous plasma membrane of the human placenta and severity of fetal compromise in intrauterine growth restriction.  Pediatr Res. 1997;  42 514-519
  CrossrefPubMedGoogle Scholar
• 22 Mahendran D, Donnai P, Glazier JD. et al . Amino acid (system A) transporter activity in microvillous membrane vesicles from the placentas of appropriate and small for gestational age babies.  Pediatr Res. 1993;  34 661-665
  PubMedGoogle Scholar
• 23 Jansson T, Scholtbach V, Powell TL. Placental transport of leucine and lysine is reduced in intrauterine growth restriction.  Pediatr Res. 1998;  44 532-537
  CrossrefPubMedGoogle Scholar
• 24 Jansson T, Ylvén K, Wennergren M. et al . Glucose transport and system A activity in syncytiotrophoblast microvillous and basal plasma membranes in intrauterine growth restriction.  Placenta. 2002;  23 392-399
  CrossrefPubMedGoogle Scholar
• 25 Marconi AM, Paolini CL, Stramare L. et al . The steady state maternal-fetal leucine enrichments in normal and fetal growth restricted pregnancies.  Pediatr Res. 1999;  46 114-119
  CrossrefPubMedGoogle Scholar
• 26 Roos S, Jansson N, Palmberg I. et al . Mammalian target of rapamycin in the human placenta regulates leucine transport and is down-regulated in restricted foetal growth.  J Physiol. 2007;  582 449-459
  CrossrefPubMedGoogle Scholar
• 27 Marconi AM, Paolini C, Buscaglia M. et al . The impact of gestational age and fetal growth on the maternal-fetal glucose concentration difference.  Obstet Gynecol. 1996;  87 937-942
  CrossrefPubMedGoogle Scholar
• 28 Marconi AM, Cetin I, Davoli E. et al . Pardi An evaluation of fetal glucogenesis in intrauterine growth-retarded pregnancies.  Metabolism. 1993;  42 860-864
  CrossrefPubMedGoogle Scholar
• 29 Cetin I, Giovannini N, Alvino G. et al . Intrauterine growth restriction is associated with changes in polyunsaturated fatty acid fetal-maternal relationships.  Pediatr Res. 2002;  52 750-755
  PubMedGoogle Scholar
• 30 Magnusson AL, Waterman IJ, Wennergren M. et al . Triglyceride hydrolase activities and expression of fatty acid binding proteins in the human placenta in pregnancies complicated by intrauterine growth restriction and diabetes.  J Clin Endocrinol Metab. 2004;  89 4607-4614
  CrossrefPubMedGoogle Scholar
• 31 Tabano S, Alvino G, Antonazzo P. et al . Placental LPL gene expression is increased in severe intrauterine growth restricted pregnancies.  Pediatr Res. 2006;  59 250-253
  CrossrefPubMedGoogle Scholar
• 32 Wadsack C, Tabano S, Maier A. et al . Intrauterine growth restriction (IUGR) is associated with alterations in placental lipoprotein receptors and maternal lipoprotein composition.  Am J Physiol Endocrinol Metab. 2007;  292 476-484
  PubMedGoogle Scholar
• 33 Gauster M, Hiden U, Blaschitz A. et al . Dysregulation of placental endothelial lipase and lipoprotein lipase in intrauterine growth-restricted pregnancies.  J Clin Endocr Metab. 2007;  92 2256-2263
  CrossrefPubMedGoogle Scholar
• 34 Rossant J, Cross JC. Placental development: lessons from mouse mutants.  Nat Rev Genet. 2001;  2 ((7)) 538-548
  PubMedGoogle Scholar
• 35 Miozzo M, Simoni G. The role of imprinted genes in fetal growth.  Biol Neonate. 2002;  81 ((4)) 217-228
  CrossrefPubMedGoogle Scholar
• 36 McMinn J, Wei M, Schupf N. et al . Unbalanced placental expression of imprinted genes in human intrauterine growth restriction.  Placenta. 2006;  27 ((6–7)) 540-549
  CrossrefPubMedGoogle Scholar
• 37 Miozzo M, Grati FR, Bulfamante G. et al . Post-zygotic origin of complete maternal chromosome 7 isodisomy and consequent loss of placental PEG1/MEST expression.  Placenta. 2001;  22 ((10)) 813-821
  CrossrefPubMedGoogle Scholar
• 38 Cetin I, Foidart JM, Miozzo M. et al . Fetal growth restriction: a workshop report.  Placenta. 2004;  25 ((8–9)) 753-757
  CrossrefPubMedGoogle Scholar
• 39 Grati FR, Miozzo M, Cassani B. et al . Fetal and placental chromosomal mosaicism revealed by QF-PCR in severe IUGR pregnancies.  Placenta. 2005;  26 ((1)) 10-18
  CrossrefPubMedGoogle Scholar
• 40 Tilghman SM. The sins of the fathers and mothers: genomic imprintingin mammalian development.  Cell. 1999;  96 185-193
  CrossrefPubMedGoogle Scholar
• 41 Constancia M, Dean W, Lopes S. et al . Deletion of a silencer element in Igf2 results in loss of imprinting independent of H19.  Nat Genet. 2000;  26 ((2)) 203-206
  PubMedGoogle Scholar
• 42 DeChiara TM, Efstratiadis A, Robertson EJ. A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting.  Nature. 1990;  345 ((6270)) 78-80
  CrossrefPubMedGoogle Scholar
• 43 DeChiara TM, Robertson EJ, Efstratiadis A. Parental imprinting of the mouse insulin-like growth factor II gene.  Cell. 1991;  64 ((4)) 849-859
  CrossrefPubMedGoogle Scholar
• 44 Leighton PA, Saam JR, Ingram RS. et al . An enhancer deletion affects both H19 and Igf2 expression.  Genes Dev. 1995;  9 2079-2089
  CrossrefPubMedGoogle Scholar
• 45 Leighton PA, Ingram RS, Eggenschwiler J. et al . Disruption of imprinting caused by deletion of the H19 region in mice.  Nature. 1995;  375 34-39
  CrossrefPubMedGoogle Scholar
• 46 Reik W, Constancia M, Fowden A. et al . Regulation of supply and demand for maternal nutrients in mammals by imprinted genes.  J Physiol. 2003;  547 ((Pt 1)) 35-44
  CrossrefPubMedGoogle Scholar
• 47 Sibley CP, Coan PM, Ferguson-Smith AC. et al . Placental-specific insulin-like growth factor 2 (Igf2) regulates the diffusional exchange characteristics of the mouse placenta.  Proc Natl Acad Sci USA. 2004;  101 ((21)) 8204-8208
  CrossrefPubMedGoogle Scholar
• 48 Constancia M, Hemberger M, Hughes J. et al . Placental-specific IGF-II is a major modulator of placental and fetal growth.  Nature. 2002;  417 ((6892)) 945-948
  CrossrefPubMedGoogle Scholar
• 49 Constancia M, Angiolini E, Sandovici I. et al . Adaptation of nutrient supply to fetal demand in the mouse involves interaction between the Igf2 gene and placental transporter systems.  Proc Natl Acad Sci USA. 2005;  102 ((52)) 19219-19224
  CrossrefPubMedGoogle Scholar
• 50 Antonazzo P, Alvino G, Cozzi V. et al . Placental IGF2 expression in normal and intrauterine growth restricted (IUGR) pregnancies.  Placenta. 2008;  29 ((1)) 99-101
  CrossrefPubMedGoogle Scholar
• 51 Killian JK, Nolan CM, Wylie AA. et al . Divergent evolution in M6P/IGF2R imprinting from the Jurassic to the Quaternary.  Hum Mol Genet. 2001;  10 ((17)) 1721-1728
  CrossrefPubMedGoogle Scholar
• 52 Grati FR, Sirchia SM, Gentilin B. et al . Biparental expression of ESX1L gene in placentas from normal and intrauterine growth-restricted pregnancies.  Eur J Hum Genet. 2004;  12 ((4)) 272-278
  PubMedGoogle Scholar

Correspondence

Prof. Irene Cetin

Unit of Obstetrics and Gynecology

Department of Clinical Sciences “L. Sacco”

University of Milan

Via G. B. Grassi 74

20151 Milano

Phone: +3902/50/31 98 04

Fax: +3902/50/31 98 06

Email: irene.cetin@unimi.it