Review
Defective implantation and placentation: laying the blueprint for pregnancy complications

https://doi.org/10.1016/S1472-6483(10)60649-9Get rights and content

Abstract

Normal implantation and placentation is critical for pregnancy success. Many pregnancy-related complications that present late in gestation (such as pre-eclampsia and preterm labour) appear to have their origins early in pregnancy with abnormalities in implantation and placental development. Implantation is characterized by invasion of the maternal tissues of the uterus by fetal trophoblast, and the degree to which trophoblast invades these tissues appears to be a major determinant of pregnancy outcome. Excessive invasion can lead to abnormally firm attachment of the placenta to the myometrium (placenta accreta) with increased maternal and perinatal morbidity. Inadequate invasion, specifically restricted endovascular invasion, has been implicated in the pathophysiology of such conditions as pre-eclampsia (gestational proteinuric hypertension), preterm premature rupture of membranes, preterm labour, and intrauterine growth restriction. The molecular and cellular mechanisms responsible for implantation remain enigmatic. This review will include an overview of implantation followed by a discussion of a number of molecular mechanisms implicated in defective implantation and placentation including the role of decidual prostaglandins and haemorrhage in regulating trophoblast invasion. An improved understanding of the molecular mechanisms responsible for abnormal implantation and placentation will likely improve clinicians’ abilities to treat disorders that occur along this continuum, including infertility, recurrent pregnancy loss, pre-eclampsia, and preterm birth.

Section snippets

Dr Errol Norwitz is Associate Professor of Obstetrics, Gynecology and Reproductive Sciences at Yale University School of Medicine, and Director of Perinatal Research and Co-Director of the Division of Maternal-Fetal Medicine at Yale-New Haven Hospital. His qualifications were obtained at University of Cape Town, South Africa, Oxford University, UK, and Harvard University, USA. His research has been supported by NIH/NICHD by way of the Reproductive Scientist Development Program and the Women's

References (106)

  • MH Abel et al.

    Suppression of concentration of endometrial prostaglandin in early intra-uterine and ectopic pregnancy in women

    Journal of Endocrinology

    (1980)
  • S Afonso et al.

    The expression and function of cystatin C and cathepsin B and cathepsin L during mouse embryo implantation and placentation

    Development

    (1997)
  • Z Alfirevic et al.

    How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review

    European Journal of Obstetrics, Gynecology and Reproductive Biology

    (2002)
  • DS Allan et al.

    Tetrameric complexes of human histocompatibility leukocyte antigen (HLA)-G bind to peripheral blood myelomonocytic cells

    Journal of Experimental Medicine

    (1999)
  • K Aoyama et al.

    Cardiac failure caused by severe pre-eclampsia with placental abruption, and its treatment with anti-hypertensive drugs

    Journal of Obstetrics and Gynaecology Research

    (2003)
  • A Athanassiades et al.

    Vascular endothelial growth factor stimulates proliferation but not migration or invasiveness in human extravillous trophoblast

    Biology of Reproduction

    (1998)
  • DR Bainbridge et al.

    Little evidence of HLA-G mRNA polymorphism in Caucasian or Afro-Caribbean populations

    Journal of Immunology

    (1999)
  • Y Barak et al.

    PPAR gamma is required for placental, cardiac, and adipose tissue development

    Molecular Cell

    (1999)
  • KE Bass et al.

    Tissue inhibitor of metalloproteinase-3 expression is upregulated during human cytotrophoblast invasion in vitro

    Developmental Genetics

    (1997)
  • K Benirschke et al.

    Early development of the human placenta

  • GV Benson et al.

    Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeostasis and loss of maternal Hoxa-10 expression

    Development

    (1996)
  • F Bladt et al.

    Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud

    Nature

    (1995)
  • DW Branch et al.

    Antiphospholipid antibodies in women at risk for preeclampsia

    American Journal of Obstetrics and Gynecology

    (2001)
  • IA Brosens

    Morphological changes in the utero–placental bed in pregnancy hypertension

    Clinical Obstetrics and Gynaecology

    (1977)
  • CS Buhimschi et al.

    Urinary angiogenic factors cluster hypertensive disorders and identify women with severe preeclampsia

    American Journal of Obstetrics and Gynecology

    (2005)
  • PH Burri et al.

    Intussusceptive angiogenesis: its emergence, its characteristics, and its significance

    Developmental Dynamics

    (2004)
  • G Chaouat et al.

    Immuno-endocrine interactions in early pregnancy

    Human Reproduction

    (1995)
  • DE Clark et al.

    A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation

    Biology of Reproduction

    (1998)
  • PE Cohen et al.

    Absence of colony stimulating factor-1 in osteopetrotic (csfmop/csfmop) mice disrupts estrous cycles and ovulation

    Biology of Reproduction

    (1997)
  • F Colotta et al.

    Expression of monocyte chemotactic protein-1 by monocytes and endothelial cells exposed to thrombin

    American Journal of Pathology

    (1994)
  • JC Cross

    Formation of the placenta and extraembryonic membranes

    Annals of the New York Academy of Science

    (1998)
  • AI Csapo et al.

    Indispensability of the human corpus luteum in the maintenance of early pregnancy. Lutectomy evidence

    Obstetrical and Gynecological Survey

    (1978)
  • EB Cullinan et al.

    Leukemia inhibitory factor (LIF) and LIF receptor expression in human endometrium suggests a potential autocrine/paracrine function in regulating embryo implantation

    Proceedings for the National Academy of Sciences of the USA

    (1996)
  • CH Damsky et al.

    Trophoblast pseudo-vasculogenesis: faking it with endothelial adhesion receptors

    Current Opinion in Cell Biology

    (1998)
  • SK Das et al.

    Expression of betacellulin and epiregulin genes in the mouse uterus temporally by the blastocyst solely at the site of its apposition is coincident with the ‘window’ of implantation

    Developmental Biology

    (1997)
  • SK Das et al.

    Heparin-binding EGF-like growth factor gene is induced in the mouse uterus temporally by the blastocyst solely at the site of its apposition: a possible ligand for interaction with blastocyst EGF-receptor in implantation

    Development

    (1994)
  • TE Dudding et al.

    The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta-analysis

    Thrombosis and Haemostatis

    (2004)
  • AC Enders et al.

    Implantation in the marmoset monkey: expansion of the early implantation site

    Anatomical Record

    (1999)
  • AT Fazleabas et al.

    Modulation of the baboon (Papio anubis) uterine endometrium by chorionic gonadotrophin during the period of uterine receptivity

    Proceedings of the National Academy of Sciences of the USA

    (1999)
  • O Genbacev et al.

    Regulation of human placental development by oxygen tension

    Science

    (1997)
  • LC Giudice et al.

    Roles of the insulin-like growth factor family in nonpregnant human endometrium and at the decidual: trophoblast interface

    Seminars in Reproductive Endocrinology

    (1999)
  • JD Godkin et al.

    Transforming growth factor beta and the endometrium

    Reviews of Reproduction

    (1998)
  • G Grandaliano et al.

    A novel biologic activity of thrombin: stimulation of monocyte chemotactic protein production

    Journal of Experimental Medicine

    (1994)
  • DA Hoozemans et al.

    Human embryo implantation: current knowledge and clinical implications in assisted reproductive technology

    Reproductive BioMedicine Online

    (2004)
  • JC Huang et al.

    Interleukin-1 beta induces cyclooxygenase-2 gene expression in cultured endometrial stromal cells

    Journal of Clinical Endocrinology and Metabolism

    (1998)
  • B Huppertz et al.

    Immunohistochemistry of matrix metalloproteinases (MMP), their substrates, and their inhibitors (TIMP) during trophoblast invasion in the human placenta

    Cell and Tissue Research

    (1998)
  • MJ Janatpour et al.

    Id-2 regulates critical aspects of human cytotrophoblast differentiation, invasion and migration

    Development

    (2000)
  • MJ Janatpour et al.

    A repertoire of differentially expressed transcription factors that offers insight into mechanisms of human cytotrophoblast differentiation

    Developmental Genetics

    (1999)
  • OE Jaschevatzky et al.

    Increased decidual prostaglandin E concentration in human abortion

    British Journal of Obstetrics and Gynaecology

    (1983)
  • E Jauniaux

    Design, beauty and differentiation: the human fetus during the first trimester of gestation

    Reproductive BioMedicine Online

    (2000)
  • S Kamimura et al.

    Localization and developmental change of indoleamine 2,3-dioxygenase activity in the human placenta

    Acta Medica Okayama

    (1991)
  • YM Kim et al.

    Failure of physiologic transformation of the spiral arteries in patients with preterm labor and intact membranes

    American Journal of Obstetrics and Gynecology

    (2003)
  • S Kovats et al.

    A class I antigen, HLA-G, expressed in human trophoblasts

    Science

    (1990)
  • S Kumar et al.

    Progesterone induces calcitonin gene expression in human endometrium within the putative window of implantation

    Journal of Clinical Endocrinology and Metabolism

    (1998)
  • E Lagow et al.

    Mammalian reproductive tract mucins

    Human Reproduction Update

    (1999)
  • LL Lanier

    Natural killer cells fertile with receptors for HLA-G?

    Proceedings of the National Academy of Sciences of the USA

    (1999)
  • BA Lessey

    Endometrial integrins and the establishment of uterine receptivity

    Human Reproduction

    (1998)
  • BA Lessey et al.

    Paracrine signaling in the endometrium: integrins and the establishment of uterine receptivity

    Journal of Reproductive Immunology

    (1998)
  • CL Librach et al.

    92-kD type IV collagenase mediates invasion of human cytotrophoblasts

    Journal of Cell Biology

    (1991)
  • H Lim et al.

    Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARdelta

    Genes and Development

    (1999)
  • Cited by (215)

    • Unveiling uterine aging: Much more to learn

      2023, Ageing Research Reviews
    View all citing articles on Scopus

    Dr Errol Norwitz is Associate Professor of Obstetrics, Gynecology and Reproductive Sciences at Yale University School of Medicine, and Director of Perinatal Research and Co-Director of the Division of Maternal-Fetal Medicine at Yale-New Haven Hospital. His qualifications were obtained at University of Cape Town, South Africa, Oxford University, UK, and Harvard University, USA. His research has been supported by NIH/NICHD by way of the Reproductive Scientist Development Program and the Women's Reproductive Health Research Scholarship and, most recently, by March of Dimes. His areas of research interest include the regulation of GnRH receptor gene expression and the molecular regulation of parturition, both term and preterm.

    Paper based on contribution presented at the International Serono Symposium ‘Human implantation: the new frontiers of human assisted reproductive technologies’ in Erice, Sicily, Italy, May 5–6, 2006.

    View full text