Contents
Contents
To Brian, Emily and Allison for their unwavering support
To Peggy, my childhood sweetheart and wife
To the memory of my grandmother, Fengtong Zhao
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Library of Congress Cataloging-in-Publication Data
The placenta : from development to disease / edited by Helen H. Kay, D.
Michael Nelson, Yuping Wang.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-4443-3366-4 (hardcover : alk. paper)
1. Placenta–Diseases. 2. Placenta. I. Kay, Helen H. II. Nelson, D.
Michael. III. Wang, Yuping
[DNLM: 1. Placenta. 2. Placenta Diseases. WQ 212]
RG591.P56 2011
618.3′4–dc22
2010036448
A catalogue record for this book is available from the British Library.
This book is published in the following electronic formats: ePDF 9781444393903; Wiley Online Library 9781444393927; ePub 9781444393910
List of Contributors
Jacques S. Abramowicz, MD
The Francis T. and Lester B. Knight Professor
Director, Obstetrics and Gynecology Ultrasound
Department of Obstetrics and Gynecology
Co-Director, Rush Fetal and Neonatal Medicine Center
Rush University
Chicago, IL, USA
William E. Ackerman IV, MD
Assistant Professor
Department of Obstetrics and Gynecology
Ohio State University
Columbus, OH, USA
Mahmoud S. Ahmed, MD
Professor
Director of Maternal-Fetal Pharmacology & Biodevelopment Laboratories
Departments of Obstetrics & Gynecology, Biochemistry & Molecular Biology, and Pharmacology & Toxicology
University of Texas Medical Branch
Galveston, TX, USA
Ray Bahado-Singh, MD
Professor of Obstetrics and Gynecology
Director, Division of Fetal Imaging and Therapeutics,
Department of Obstetrics and Gynecology,
Wayne State University,
Detroit, MI, USA
Marie H. Beall, MD
Professor and Vice Chair
Department of Obstetrics and Gynecology
Harbor-UCLA Medical Center
Torrance CA, USA
and
David Geffen School of Medicine at UCLA
Los Angeles, CA, USA
Louiza Belkacemi, PhD
Assistant Professor
Department of Obstetrics and Gynecology
Los Angeles Biomedical Research Institute at
Harbor-UCLA Medical Center
Torrance, CA, USA
and
David Geffen School of Medicine at UCLA
Los Angeles, CA, USA
Mila Cervar-Zivkovic, MD, PhD
Professor
Department of Obstetrics and Gynecology
Medical University of Graz
Graz, Austria
Irene Cetin, MD
Professor of Obstetrics and Gynecology
Department of Clinical Sciences, Hospital
Luigi Sacco and Centre for Fetal Research
Giorgio Pardi
University of Milan
Grassi, Milan, Italy
Christine H. Comstock, MD
Clinical Professor
Department of Obstetrics and Gynecology
Oakland University William Beaumont School of Medicine
MI, USA
and
Director
Division of Fetal Imaging
William Beaumont Hospital
Royal Oak, MI, USA
Ian P. Crocker, PhD
Senior Scientist
Maternal and Fetal Health Research Centre
School of Biomedicine
University of Manchester
St. Mary’s Hospital
Manchester, UK
Mina Desai, PhD
Associate Professor
Department of Obstetrics and Gynecology
Los Angeles Biomedical Research Institute at
Harbor-UCLA Medical Center
Torrance, CA, USA
and
David Geffen School of Medicine at UCLA
Los Angeles, CA, USA
Gernot Desoye, PhD
Professor
Department of Obstetrics and Gynecology
Medical University of Graz
Graz, Austria
Dan Diego-Alvarez, PhD
Research Associate
Department of Medical Genetics
University of British Columbia
and
Child and Family Research Institute
Vancouver, BC, Canada
and
Professor
School of Biology
IE University
Segovia, Spain
Julia Froehlich, MSc
PhD Student
Department of Obstetrics and Gynecology
and
Institute of Histology, Embryology and Cell Biology
Medical University of Graz
Graz, Austria
Hilary S. Gammill, MD
Assistant Professor
Maternal-Fetal Medicine
Department of Obstetrics and Gynecology
University of Washington School of Medicine
Seattle, WA, USA
and
Research Associate
Fred Hutchinson Cancer Research Center
University of Washington School of Medicine
Seattle, WA, USA
Thaddeus G. Golos, PhD
Professor
Departments of Comparative Biosciences, Obstetrics, and Gynecology
The Wisconsin National Primate Research Center
University of Wisconsin-Madison
Madison, WI, USA
Ian A. Greer, MD, FRCP, FRCOG, FMedSci
Professor
Department of Health and Life Sciences
University of Liverpool
Liverpool, UK
Gilad A. Gross, MD
Professor
Department of Obstetrics, Gynecology and Women’s Health,
Division of Maternal-Fetal Medicine and Ultrasound-Genetics
St. Louis University School of Medicine
Assistant Director, MFM Fellowship Program
Medical Director, Labor and Delivery and Antepartum Service, St. Mary’s Health Center
St. Louis, MO, USA
Katja Gwin, MD, PhD
Assistant Professor
Department of Pathology
University of Chicago
Chicago, IL, USA
Christina S. Han, MD
Clinical instructor
Department of Obstetrics, Gynecology and Reproductive Sciences
Yale University School of Medicine
New Haven, CT, USA
Gary D. V. Hankins, MD
Professor
Department of Obstetrics and Gynecology
University of Texas Medical Branch
Galveston, TX, USA
Sonia S. Hassan, MD
Associate Professor
Director, Center for Advanced Obstetrical Care and Research
Perinatology Research Branch, NICHD, NIH, DHHS, Bethesda, MD, USA/Detroit, MI, USA
Director, PRB/WSU Maternal-Fetal Medicine Fellowship Program
Division of Maternal-Fetal Medicine and Ultrasound-Genetics
Department of Obstetrics and Gynecology
Wayne State University, School of Medicine, Hutzel Women’s Hospital
Detroit, MI, USA
Ursula Hiden, MSc, PhD
Junior Scientist
Department of Obstetrics and Gynecology
Medical University of Graz
Graz, Austria
Wolfgang Holzgreve, MD, MBA
Professor
Department of Obstetrics/Department of Biomedicine
University of Basel
Basel, Switzerland
and
Institute for Advance Study
Wallotstrasse, Berlin, Germany
Shahzya S. Huda, MBChB, MD, MRCOG, MRCP
Clinical Lecturer in Obstetrics and Gynaecology
Department of Reproductive and Maternal Medicine
University of Glasgow
Glasgow, UK
Joan S. Hunt, PhD, DSc(HON)
University Distinguished Professor
Department of Anatomy and Cell Biology
University of Kansas Medical Center
Kansas City, KS, USA
Berthold Huppertz, PhD
Professor of Cell Biology
Institute of Cell Biology, Histology and Embryology
Medical University of Graz
Graz, Austria
Aliya N. Husain, MD
Professor
Department of Pathology
University of Chicago
Chicago, IL, USA
Nicholas P. Illsley, DPhil
Professor
Department of Obstetrics, Gynecology, and Women’s Health
UMDNJ-New Jersey Medical School
Newark, NJ, USA
Daniel L. Jackson, MD
Resident
Department of Obstetrics and Gynecology and Women’s Health
Missouri Center for Reproductive Medicine and Fertility
University of Missouri-Columbia
Columbia, MO, USA
Cristiano Jodicke, MD
Fellow
Maternal-Fetal Medicine
Department of Obstetrics and Gynecology
Wayne State University
and
Perinatology Research Branch, NICHD/NIH/DHHS
Detroit, MI, USA
Helen H. Kay, MD
Professor
Division of Maternal-Fetal Medicine and Ultrasound-Genetics
Department of Obstetrics and Gynecology
Washington University School of Medicine
St. Louis, MO, USA
Chong Jai Kim, MD, PhD
Professor
Department of Pathology
Wayne State University School of Medicine
Detroit, MI, USA
and
Perinatology Research Branch, NICHD/NIH/DHHS
Bethesda, MD, USA
Douglas A. Kniss, PhD
Professor
Departments of Obstetrics and Gynecology
Division of Maternal-Fetal Medicine and Biomedical Engineering
and
Director
Laboratory of Perinatal Research
The Ohio State University
Columbus, OH, USA
Frederick T. Kraus, MD
Adjunct Professor
Department of Obstetrics and Gynecology
Washington University School of Medicine
St. Louis, MO, USA
Olav Lapaire, MD
Associate Professor
Department of Obstetrics/Department of Biomedicine
University of Basel
Basel, Switzerland
Fiona Lyall, BSc, PhD, FRCPath, MBA
Professor of Maternal and Fetal Health
Institute of Medical Genetics
University of Glasgow, Yorkhill Hospital
Glasgow, UK
Teng Ma, PhD
Associate Professor
Department of Chemical and Biomedical Engineering
Florida State University
Tallahassee, FL, USA
Chiara Mandò, PhD
Postdoctoral Fellow
Unit of Obstetrics and Gynecology
Department of Clinical Sciences, Hospital Luigi Sacco
and Centre for Fetal Research Giorgio Pardi
University of Milan
Grassi, Milan, Italy
Clifford W. Mason, PhD
Research Instructor
Department of Obstetrics and Gynecology
School of Medicine
University of Kansas Medical Center
Kansas City, KS, USA
Jennifer M. McNamara, MD
Fellow
Division of Maternal-Fetal Medicine and Ultrasound-Genetics
Department of Obstetrics and Gynecology
Washington University School of Medicine
St. Louis, MO, USA
Laura Meints, MD
Resident
Department of Obstetrics and Gynecology
Barnes-Jewish Hospital
Washington University School of Medicine
St. Louis, MO, USA
Kenneth J. Moise, Jr, MD
Professor of Obstetrics and Gynecology
Professor of Surgery
Division of Maternal-Fetal Medicine and Ultrasound-Genetics
Department of Obstetrics and Gynecology
Baylor College of Medicine
Texas Children’s Fetal Center
Houston, TX, USA
Leslie Myatt, PhD
Professor of Obstetrics and Gynecology
Co-Director, Center for Pregnancy and Newborn Research
Department of Obstetrics and Gynecology
University of Texas Health Science Center San Antonio
San Antonio, TX, USA
Tatiana N. Nanovskaya, DDS, PhD
Assistant Professor
Department of Obstetrics and Gynecology
University of Texas Medical Branch
Galveston, TX, USA
D. Michael Nelson, MD, PhD
Virginia S. Lang Professor and Vice-Chairman
Division of Maternal-Fetal Medicine and Ultrasound-Genetics
Department of Obstetrics and Gynecology
Washington University School of Medicine
St. Louis, MO, USA
J. Lee Nelson, MD
Professor
Department of Rheumatology
University of Washington School of Medicine
Seattle, WA, USA
and
Member
Fred Hutchinson Cancer Research Center
University of Washington School of Medicine
Seattle, WA, USA
Thinh Nguyen, MD
Fellow
Division of Maternal-Fetal Medicine and Ultrasound-Genetics
Department of Obstetrics, Gynecology, and Women’s Health
St. Louis University School of Medicine
St. Mary’s Health Center
St. Louis, MO, USA
Anthony O. Odibo, MD, MSCE
Associate Professor
Division of Maternal-Fetal Medicine and Ultrasound-Genetics
Department of Obstetrics and Gynecology
Washington University in St. Louis
St. Louis, MO, USA
Michael J. Paidas, MD
Associate Professor
Co-Director, Yale Women and Children’s Center for Blood Disorders
Co-Director, National Hemophilia Foundation-Baxter Clinical Fellowship
Program at Yale
Division of Maternal-Fetal Medicine and Ultrasound-Genetics
Department of Obstetrics, Gynecology and Reproductive Sciences
Yale University School of Medicine
New Haven, CT, USA
Ramesha Papanna, MD, MPH
Fellow
Division of Maternal-Fetal Medicine and Ultrasound-Genetics
Department of Obstetrics, Gynecology and Reproductive
Sciences, Yale University
School of Medicine
New Haven, CT, USA
Samuel Parry, MD
Professor
Director
Department of Maternal-Fetal Medicine
University of Pennsylvania
Philadelphia, PA, USA
Suzanne E. Peterson, MD
Fellow
Maternal-Fetal Medicine
Department of Obstetrics and Gynecology
University of Washington School of Medicine
Seattle, WA, USA
Margaret G. Petroff, PhD
Associate Professor
Department of Anatomy and Cell Biology
University of Kansas Medical Center
Kansas City, KS, USA
Roxane Rampersad, MD
Assistant Professor
Division of Maternal-Fetal Medicine and Ultrasound-Genetics
Department of Obstetrics and Gynecology
Washington University School of Medicine
St. Louis, MO, USA
Raymond W. Redline, MD
Professor of Pathology and Reproductive Biology
Case Western Reserve University School of Medicine
Cleveland, OH, USA
and
Co-Director
Pediatric and Perinatal Pathology
University Hospitals Case Medical Center
Cleveland, OH, USA
Gregory E. Rice, PhD, MHA, MAICD
Professor
Deputy Director (Translation)
Center for Clinical Research
University of Queensland, Royal Brisbane and Women’s Hospital Campus
Brisbane, QLD, Australia
John M. Robinson, PhD
Professor
Department of Physiology and Cell Biology
Ohio State University
Columbus, OH, USA
Wendy P. Robinson, PhD
Professor
Department of Medical Genetics
University of British Columbia
and
Child and Family Research Institute
Vancouver, BC, Canada
Roberto Romero, MD
Chief, Perinatology Research Branch
Program Director for Obstetrics and Perinatology
Intramural Division, NICHD, NIH, DHHS
Bethesda, MD, USA/Detroit, MI, USA
Professor of Molecular Obstetrics and Genetics
Center for Molecular Medicine and Genetics
Wayne State University, School of Medicine, Hutzel Women’s Hospital
Detroit, MI, USA
and
Professor of Epidemiology
Michigan State University
East Lansing, MI, USA
Michael G. Ross, MD, MPH
Professor and Chair
Department of Obstetrics and Gynecology
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Torrance, CA, USA
and
David Geffen School of Medicine at UCLA
Los Angeles, CA, USA
Yoel Sadovsky, MD
Scientific Director, Magee-Womens Research Institute
Elsie Hilliard Hillman Chair of Women’s Health Research
Professor of Obstetrics, Gynecology, Microbiology and Molecular Genetics
Department of Obstetrics, Gynecology, and Reproductive Sciences
University of Pittsburgh
Pittsburgh, PA, USA
Danny J. Schust, MD
Associate Professor
Department of Obstetrics, Gynecology and Women’s Health
Missouri Center for Reproductive Medicine and Fertility
University of Missouri-Columbia
Columbia, MO, USA
Christina Scifres, MD
Assistant Professor of Obstetrics, Gynecology, and Reproductive Sciences
Magee-Womens Research Institute
Department of Obstetrics, Gynecology, and Reproductive Sciences
University of Pittsburgh
Pittsburgh, PA, USA
Colin P. Sibley, PhD
Professor of Child Health and Physiology
Maternal and Fetal Health Research Centre
School of Biomedicine and Manchester Academic Health Sciences Centre
University of Manchester
St. Mary’s Hospital
Manchester, UK
Christina Stern, MD
Resident
Department of Obstetrics and Gynecology
Medical University of Graz
Graz, Austria
Toshihiro Takizawa, MD, PhD
Professor
Department of Molecular Medicine and Anatomy
Nippon Medical School
Tokyo, Japan
Methodius G. Tuuli, MD, MPH
Fellow
Division of Maternal-Fetal Medicine and Ultrasound-Genetics
Department of Obstetrics and Gynecology
Washington University in St. Louis
St. Louis, MO, USA
Ignatia B. Van den Veyver, MD
Professor
Department of Obstetrics and Gynecology
and
Department of Molecular and Human Genetics
Baylor College of Medicine
Houston, TX, USA
Marion S. Verp, MD
Associate Professor
Departments of Obstetrics and Gynecology, and Human Genetics
The University of Chicago
Chicago, IL, USA
Yuping Wang, MD, PhD
Professor
Departments of Obstetrics and Gynecology, and Molecular and Cellular
Physiology
Louisiana State University Health Sciences Center – Shreveport
Shreveport, LA, USA
Carl P. Weiner, MD, MBA
KE Krantz Professor and Chair
Professor, Molecular and Integrative Physiology
Department of Obstetrics and Gynecology
School of Medicine
University of Kansas Medical Center
Kansas City, KS, USA
Shu Wen, MD, PhD
Postdoctoral Associate
Department of Obstetrics and Gynecology
Baylor College of Medicine
Houston, TX, USA
Caroline Wright, MBBS
Obstetric Clinical Research Fellow
Maternal and Fetal Health Research Centre
School of Biomedicine and Manchester Academic Health Sciences Centre
University of Manchester, St. Mary’s Hospital
Manchester, UK
Stacy Zamudio, PhD
Senior Scientist, Director of Research
Division of Maternal-Fetal Medicine and Surgery
Department of Obstetrics and Gynecology
Hackensack University Medical Center
Hackensack, NJ, USA
Preface
The human placenta is central to the important events that influence not only development and growth of the fetus but also the risks for multiple adult diseases in both the mother and offspring. Diabetes mellitus, obesity, and cardiovascular disease, among others, have origins in utero where the placenta plays a pivotal role. Our goal as editors of The Placenta: From Development to Disease was to create a comprehensive, yet succinct, resource for new investigators and clinicians, while also providing a manual for senior investigators and experienced clinicians who mentor trainees at all educational levels.
With this ambitious goal in mind, we selected topics of interest to both clinicians and researchers. We first introduced the contemporary concepts about the placenta’s central position in the developmental origins of human adult disease (DOHAD) and in the cardiovascular health and maternal placental syndromes (CHAMPS). We then described the developmental biology of the placenta and the further dissection by molecular analyses for the structure and function of this organ, including assessments of metabolic, secretory and transport functions. We have highlighted key techniques used to study the placenta, both in the laboratory and in the clinical setting. Indeed, our authors provide some chapters with step-by-step instructions for study of the placenta by newcomers. From there we move to specific clinical disorders that influence pregnancy outcomes, underscoring the pivotal role the placenta plays in each. We conclude with topics that are at the forefront of clinical and research applications, including proteomics, stem cell development, and prenatal diagnosis by analysis of cell-free RNA and DNA from trophoblast.
The chapters are designed to be reader friendly, and the clinical pearls, research spotlights, and teaching points are targeted at the novice. For seasoned investigators, we hope the overviews of topics outside their area of research and the technique chapters will be especially useful for training. For experienced clinicians, we aimed to heighten awareness of the diverse functions performed by the placenta and to provide insights into how the placenta can be a window to current and future disease(s).
Most importantly, The Placenta: From Development to Disease would not be possible without the committed efforts of the authors of the chapters. Clinicians and investigators; students, trainees, and postdoctoral fellows; and junior and senior investigators from around the world – all have contributed to this endeavor. We owe tremendous gratitude to each of them for their insightful contributions, their attention to deadlines, and their willingness to allow us to edit their chapters, sometimes brutally, for uniformity of style. Without these talented authors, we as editors would not have been able to produce a book with the breadth and depth, yet succinct writing style, that we feel has blossomed. Last but clearly not least, we thank the publishers at Wiley-Blackwell for their recognition of the importance of the placenta as a subject for a book and for their editorial support throughout this endeavor.
Sincerely,
Helen Kay
D. Michael Nelson
Yuping Wang
PART I
Fetal Origins of Adult Disease/Programming
Chapter 1
Maternal Undernutrition and Fetal Programming: Role of the Placenta
Introduction
What is developmental origins of health and disease (DOHaD)?
DOHaD is an area of research that emerged following retrospective cohort studies of David Barker and colleagues during the late 1980s. These investigators studied the association of geographical distribution of heart disease in the United Kingdom to a person's birthplace, irrespective of the place where individuals develop disease [1]. Their data suggested that environment in early life causes permanent changes in fetal physiology that predisposes the adult to disease later in life. Association of early undernutrition with low birth weight is a major component of fetal programming of the Barker hypothesis. The key contention of the Barker hypothesis is that the undernourished fetus is programmed to exhibit a “thrifty phenotype,” and this predisposes to a lifetime of increased food intake and fat deposition. Such individuals develop obesity, diabetes, and hypertension as adults, due to alterations in homeostatic regulatory mechanisms as a fetus.
The placenta is a multifunctional organ that synthesizes, metabolizes, and transports nutrients required by the fetus. The placenta is also a source of hormones that influence fetal, placental, and maternal metabolism and the course of fetal development. By virtue of these roles, the placenta plays a pivotal role in fetal programming.
Scope of problem
Four hundred thousand children in the United States alone are born annually with low birth weight resulting from intrauterine growth restriction (IUGR). IUGR is variably defined, but a common definition is a fetal weight below the 10th percentile for gestational age as determined by antenatal ultrasound (hence the phrase IUGR) or by newborn birth weight percentiles (hence the phrase small for gestational age). IUGR babies exhibit aberrant development and require higher neonatal intensive care. In addition to the short-term risks, the long-term risk of developmental programming includes metabolic disorders later in life. Up to 63% of adult diabetes, hypertension, and heart disease may be attributed to low-birth-weight conditions in conjunction with an accelerated newborn-to-adolescent weight gain and obesity. Therefore, the DOHaD field is increasingly recognized as an important contributor to the epidemic of obesity and metabolic syndrome in Western populations.
Why should we care?
We as scientists
The DOHaD field is now unequivocally established, yet still in its infancy. There is still a lack of specific mechanisms to explain the effects for most of the epidemiological observations described for adult human disease. Fetal growth is directly related to placental growth and placental phenotype, which are regulated by the genetic background. We as scientists have great potential to study the signals for fetal nutrient demand that control placental transfer capacity. Importantly, there are great opportunities to dissect molecular mechanisms that regulate placental nutrient transfer in early pregnancy and that program nutrient transfer closer to term.
We as clinicians
Clinicians should aim to identify IUGR placentas and fetuses early enough to institute appropriate monitoring, and ideally, interventions that can limit adverse outcomes for the offspring. Examination of the maternal diet prior to and during pregnancy together with early detection of “placental disease” may help improve outcomes in IUGR.
We as patients with a “placental disease”
Patients should improve life style, including a healthy diet, physical exercise, and prenatal care to optimize fetal and neonatal outcomes.
Importance of maternal nutrients for fetal development
During normal pregnancy, the primary determinant of fetal growth is the concentration of nutrients in the maternal circulation and the blood supply to the placenta. Glucose, amino acids (AA), and fatty acids (FA) are among the nutrients vital for fetal growth and development. Collectively, the data show that deficiency of nutrients in the mother causes alterations in placental nutrient transport and reduced body weight in the offspring.
Glucose
The majority of fetal glucose derives from maternal metabolism of carbohydrate in the diet. Glucose supply to the fetus is a facilitated process mediated by members of the glucose transporter (GLUTs) family. Four isoforms GLUT1, GLUT3, GLUT4, and GLUT8 have been identified in human and rodent placentas. Glucose deprivation leads to hypoglycemia. This suggests that less glucose availability affects fetal growth. In rats, severe maternal glucose deprivation reduces placental transfer and fetal uptake of glucose, which results in fetal growth restriction.
AA
Fetal AA come from maternal AA pools derived from the diet. Fetal concentrations of nearly all AA are greater than maternal concentrations, suggesting that the placenta actively transfers AA from the maternal compartment to the developing fetus. Essential AA must be supplied in food, while nonessential AA are synthesized by the fetus from essential AA. Several AA transporter systems have been identified in human and rat placentas. Abnormalities in AA transport may be the reason that total AA concentrations are lower than controls in IUGR babies. AA transport by the placenta is downregulated following maternal protein deprivation and may contribute to fetal growth restriction.
Fatty acids
FA content and character in fetal plasma directly correlates with the FA composition of maternal plasma and with the maternal diet. Essential FA cannot be synthesized and are dietary essentials (e.g., linoleic and linolenic acid). Essential FA in human pregnancy are transported from maternal to fetal circulations as triglyceride-rich lipoproteins, which are hydrolyzed by placental lipases. This results in free FA (FF) release, which are transported by saturable plasma membrane FA-binding proteins, FA translocase, and a family of FA transport proteins. Low birth weight in both human and rat pregnancy correlates with low intake of essential FA.
Clinical Pearl
Balanced diets containing complex carbohydrates, essential AA, and essential FA optimize the substrates needed for normal fetal growth and development.
Factors affecting placental capacity for nutrient transfer
Multiple factors interact to influence the placental delivery of nutrients to the fetus. Size, histopathology, blood flow, transporter abundance, and organ consumption are factors responsive to environmental changes. Key studies address placental size, morphology, and transport abundance.
Size
Placental size affects the capacity for nutrient transport through changes in surface area, and placental weight correlates with fetal weight at term in many species. Timing, duration, and etiology of nutritional restriction yield variable phenotypes for placental mass. The Dutch Famine of 1944–45 reflects a highly cited example of this premise. Exposure to famine only during the first trimester of pregnancy enhanced placental weight at delivery without any impact on newborn weights when compared to control women, resulting in an increased placental-to-birth-weight ratio. In contrast, women subjected to starvation in their third trimester of pregnancy had reduced weight placentas and low-birth-weight newborns but an unaltered ratio of placental-to-birth-weight as compared with nonstarved women [1]. These results suggest that human placental adaptations in early pregnancy can overcome some environmental stressors such that fetal nutrition is maintained in late gestation. Collectively, these data suggest the placenta may compensate for insults to minimize fetal growth restriction. The histomorphology of the placenta ultimately determines placental function.
Histomorphology
Small placentas exhibit altered histopathology and ultrastructure compared to normal size placentas. Notably, the maternal undernutrition that yields IUGR in human pregnancy generates placentas with a reduced surface area for nutrient exchange, a lower volume density of trophoblasts, and increased placental apoptosis at term. In IUGR placentas, absent or reversed end-diastolic flow in the umbilical artery, as assessed by Doppler velocity waveform analysis, is indicative of poorly branched and capillarized villi, and thickened exchange barrier. In these placentas, vascular resistance occurs as a result of inadequate trophoblast invasion of the spiral arteries. In contrast, in less severe IUGR, positive end-diastolic umbilical artery flow is associated with a normal stem artery development, increased capillary angiogenesis, and adequate terminal villous development. Thus, the thicker placental exchange barrier and the increased placental vascular resistance in severe IUGR may correspond to alterations in placental structure directly involved in fetal programming of cardiovascular disease.
These structural alterations in the human placenta are mirrored in the guinea pig exposed to global maternal undernutrition compared to control diets. The nutrient deprived gestations exhibit a labyrinthine placenta with a 70% lower surface area and a barrier thickness 40% higher in late gestation. A reduction in the length of the labyrinthine vessels and decreased expression of vascular endothelial adhesion molecules in the murine placenta in response to maternal protein malnutrition are compatible with the possibility that alterations in maternal nutrition changes placental vascular function [2]. These histopathological changes predispose to lower nutrient transfer to the fetus. Our work in the rat exposed to maternal undernutrition showed enhanced apoptosis in junctional and labyrinthine zones of the placenta [3], suggesting that both hormone production and maternal–fetal exchange are impacted. Taken together, these data indicate that restriction of nutrients impairs the functional capacity of the placenta disproportionately compared to the reduction in placental weight alone.
Clinical Pearl
Doppler velocimetry techniques may be used to detect increased placental vascular resistance and predict adverse pregnancy outcome.
Transport abundance
Reductions in maternal–fetal nutrient transfer may derive from an inadequate maternal supply, inadequate placental blood flow, impaired placental transport, or a combination of these processes. Maternal nutritional status affects transporters in the placenta, which is time-dependent. For example, rats fed 50% less food during the last week of gestation have lower than control glucose levels in maternal plasma, a lower maternal-to-fetal glucose concentration gradient, and downregulation of GLUT3 expression, suggesting a mechanism for placental glucose transport dysfunction. These changes suggest that transport-mediated mechanisms may effectively reduce fetal levels of glucose.
Placental transport of AA is affected by the activity and location of AA transporter systems. In humans, circulating essential AA concentrations are decreased in growth-restricted human fetuses, likely from reduced AA transport activity. In rats, maternal protein restriction \nobreak{downregulates} placental nutrient transport prior to the onset of fetal growth restriction, suggesting that a reduced placental supply of AA is a causal factor for IUGR, not simply a consequence of this malady.
Undernourished women exhibit placental and offspring deficiency in essential FA, leading to altered placental FA metabolism and IUGR. These placentas not only have decreased levels of arachidonic acid and docosahexaenoic acid, but also show an altered ratio of both these FA relatives to their essential FA precursors, linoleic and α-linolenic, consistent with abnormal metabolism [4].
Taken together, these studies show the pivotal role played by the placenta in assuring that multiple nutrients are available to sustain normal fetal growth.
Placental nutrient synthesis and metabolism
Uteroplacental tissues in humans, ruminants, and equids metabolize glucose derived from the maternal circulation. Placental glucose consumption is reduced during short periods of maternal undernutrition, but this reduction has no effect on the partitioning of glucose between the uteroplacental and fetal tissues in humans [5]. Conversely, prolonged maternal hypoglycemia induces uteroplacental tissues to use less of the more limited supply of glucose available, thereby sparing glucose for the fetus. These adaptations correlate with reduced GLUT1 expression, offering a mechanism for the effect. The placenta metabolizes glucose to lactate during normal pregnancy [5], and this event increases the maternal-to-fetal concentration gradient for glucose. Placental lactate production decreases in response to maternal undernutrition in sheep, making glucose less readily available for fetal consumption [5].
The placenta synthesizes some of the AA required for fetal growth. For example, fetal glycine in sheep and human placentas are from endogenous synthesis. Serine derived from the fetus is converted in the placenta to glycine, and this AA is released back to the fetus. Interestingly, explant cultures from IUGR human placentas accumulate less serine in vitro than normal term villous explants. Besides placental synthesis of AA, uteroplacental tissues metabolize AA, supplying the fetus with essential AA [5].
The placenta synthesizes significant concentrations of FA in humans, sheep, and pigs. FA synthesis in term human placenta is lower than its oxidation. IUGR placentas commonly show a deficiency in oxidative enzymes, resulting in excess lipid peroxidation and free radical formation, both of which are harmful to maternal endothelial cells when released.
Collectively, these data show that placental nutrient synthesis and metabolism influence fetal growth and development.
Placental hormone synthesis and metabolism
The placenta releases hormones into both the maternal and fetal circulations, and synthesis and secretion of these hormones are responsive to environmental changes. Human placental lactogen, progesterone, insulin-like growth factors (IGF), and glucocorticoids play critical regulatory roles in fetal homeostasis.
Human placental lactogen and progesterone influence maternal metabolism to favor glucose delivery to the fetus [6]. Concentrations of both hormones are lower in undernourished mothers, and this may contribute to limited delivery of glucose to the fetus. This suggests that changes in placental endocrine dysfunction may be a cause and not a consequence of altered fetal growth.
Clinical Pearl
Maternal plasma concentration levels of lactogen and progesterone may be used to predict adverse outcomes for the offspring.
The IGF family of hormones modulates growth, cell division, and differentiation. The action of the IGFs is regulated by IGF-binding proteins (IGFBPs), and together may modulate fetal growth. IGF-I is mitogenic for placental stromal fibroblasts and has insulin-like effects to increase AA transport in human placental cells. The ovine placenta clears IGF-I from the umbilical circulation when fetal IGF-I concentrations are high but secretes IGF-I when fetal concentrations are low. Fetal IGF-I concentrations positively correlate with fetal body weight to suggest that hormone production, metabolism, or both adjust to conditions prevailing in utero to yield optimal fetal growth. IGF-II modulates trophoblast development at the feto–maternal interface. Disturbances in IGF-II expression and activity associate with IUGR in human pregnancy [7].
Research Spotlight
There are fetal sex differences in the IGF axis. IGF-II concentrations in umbilical cord serum from male neonates are significantly higher than those in female neonates, and cord plasma IGF-I and IGFBP-3 are higher in female neonates than in males.
Glucocorticoids are key regulators of organ development and maturation. The placenta is not a site for synthesis of glucocorticoids, but the placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) converts active glucocorticoids to inactive metabolites. This enzyme is affected by exogenous exposure to glucocorticoids and by fetal and maternal glucocorticoid concentrations. The human 11β-HSD2 enzyme is localized to the syncytiotrophoblast and is thus positioned to limit glucocorticoids transfer to the fetus. Extended periods of maternal undernutrition downregulates placental 11β-HSD2 activity, increasing placental exposure to glucocorticoids. This leads to feto–placental growth restriction and abnormalities in cardiovascular and metabolic function in the adult offspring. Therefore, changes induced by elevated glucocorticoids may have beneficial effects on the offspring viability, but they also impact negatively on fetal growth and development [8]. Thus, 11β-HSD2 enzyme plays a vital role to protect the fetus from exposure to excess maternal glucocorticoids.
Research Spotlight
Synthetic glucocorticoids such as dexamethasone and betamethasone are not extensively metabolized by placental 11β-HSD2, possibly due to protection from their 9-halogen group.
Collectively, these studies show that hormone synthesis and metabolism by the placenta are affected by maternal nutritional status and that the biological effects of the hormones influence fetal growth and development.
Mechanisms of placental programming
The placenta regulates fetal development by regulating nutrient transfer to the fetus and by controlling the bioavailability of specific hormones important to fetal growth and development. The placenta therefore plays a pivotal role in mediating the programming effects of suboptimal conditions during development. Mechanisms likely involved in programming the effects of maternal undernutrition include modulation of placental vascular resistance, regulation of the nutrient supply, epigenetic, gene imprinting, and metabolism of glucocorticoids.
Maternal undernutrition increases placental vascular resistance, and this subjects the fetal heart to an excess workload. This observation provides a direct link between altered placental structure and programming the risk for cardiovascular diseases in IUGR fetuses. The placenta functions as a nutrient sensor and directly regulates the nutrient supply available for fetal growth. Genomic imprinting is an epigenetic phenomenon whereby the expression of a gene depends on the parent of origin. For example, IGF-I is an imprinted gene and is crucial to fetal development as described above. IGF-I is downregulated in placentas exposed to nutrient restriction [7]. Moreover, a placenta-specific transcript (P0) for the IGF-II gene is expressed exclusively in the labyrinthine trophoblast of the mouse, and deletion of this transcript yields diminished placental growth, reduced placental nutrient transfer, and fetal growth restriction. Methylation of DNA restricts the genes available for transcription in cells. Maternal undernutrition affects the methylation status of the placental IGF-II gene and, in so doing, may control placental supply of maternal nutrients to the fetus. Imprinted genes in the placenta may be modified by perturbations of the maternal environment and altered fetal programming results. Moreover, the placenta strongly influences fetal endocrinology and metabolism. A well-documented example is rise in fetal glucocorticoid levels that follows decreased activity in placental 11β-HSD2. The adverse effects of excess fetal glucocorticoids on fetal development of the hypothalamic pituitary axis may program the fetus to be at higher risk for metabolic diseases as an adult.
Intervention strategies targeting the placenta to prevent altered fetal growth, fetal programming, or both should dissect in more detail how placental growth, nutrient transport function, and placental oxidative stress are modulated by maternal administration of IGFs or pharmacological levels of methyl donors. Targeted upregulation of the activity of placental 11β-HSD2 may also beneficially modulate feto–placental health.
Summary
Maternal nutrition during pregnancy is an important determinant of optimal fetal development, pregnancy outcome, and ultimately, life-long health. Barker's epidemiological studies have stimulated new ideas about both in utero development and risks for adult diseases. Animal models of programming have shown that most fetal organs are vulnerable to the effects of maternal undernutrition during critical periods of development. Importantly, these studies show that programming the placenta, as illustrated in , may mediate effects on the fetus.
Maternal undernutrition reduces fetal growth in part by impairing placental development and function. Placental alterations include decreases in placental weight, altered vascular development, reductions in glucose, AA, and FA transport, and hormone synthesis and metabolism. The plasticity of the placenta allows this pivotal tissue to respond to exogenous insults and to compensate for many environmental influences. Moreover, maternal diet may alter the placental genome through gene imprinting, an effect that may affect future generations. When the placental response is not sufficient to maintain fetal growth, IUGR results and suboptimal outcomes result (). The elucidation of further roles for the placenta in fetal programming will increase our understanding of DOHaD and hopefully will provide new strategies to prevent and treat suboptimal fetal development in the future.
Natural or Controlled Diet | Species | Adult Offspring Outcome |
Poor living conditions: Low-birth-weight baby | Human | Coronary heart disease, hypertension, obesity |
Twin pregnancies: The growth restricted baby | Human | Noninsulin-dependent type (II) diabetes mellitus |
Food restriction due to increased litter size | Pig | Hypertension, glucose intolerance |
Guinea-pig | Glucose intolerance, insulin deficiency | |
Global nutrient restriction | Ovine | Hypertension |
Sheep | Hypertension, smaller livers, females have reduced progesterone secretion during the luteal phase of their estrous cycles and markedly reduced fertility | |
Guinea-pig | Modification of pituitary–adrenal axis function | |
Rat | Glucose intolerance, hypertension, hypercholesterolemia, obesity | |
Rat-like hamster | Delay in physical and neurodevelopment | |
Protein deprivation | Rat | Glucose intolerance, relative insulin resistance, hyperinsulinemia, hypertension |
Mice | Longevity affected | |
Global mineral (calcium, copper, iron, magnesium, zinc) or vitamin restriction | Rat | Glucose intolerance, insulin resistance, obesity |
Chromium restriction | Rat | Obesity |
Low-sodium diet | Rat | Hypertension and reduced creatine |
Iron deficiency | Rat | Hypertension |
Teaching Points
1. Fetal programming may occur following natural or experimental environmental changes in both humans and animals.
2. Maternal undernutrition-mediated fetal programming results in different outcomes depending on species, sex, and type of diet. It is dependent on time and length of insult.
3. Placental development during pregnancy has a major impact on pregnancy outcome. Thus, small-for-gestational-age placentas are more likely to result in offspring with metabolic diseases later in life.
4. Genetic imprinting has a major role in placental development. Maternal undernutrition during pregnancy significantly decreases placental Igf2, which negatively affects placental growth.
5. Glucocorticoid treatment changes placental handling and fetal delivery of lactate and selected AA. Glucocorticoids also impact placental expression of GLUTs (GLUT1 and GLUT3) in a dose- and time-dependent manner in both human and rat placentas.
References
1. Barker DJP and Osmond C (1986) Infant mortality, childhood nutrition, and ischemic heart disease in England and Wales. Lancet 1: 1077–81.
2. Rutland CS, Latunde-Dada AO, Thorpe A et al. (2007) Effect of gestational nutrition on vascular integrity in the murine placenta. Placenta 28: 734–2.
3. Belkacemi L, Chen CH, Ross MG et al. (2009) Increased placental apoptosis in maternal food restricted gestations: Role of the Fas pathway. Placenta 30: 739–51.
4. Cetin I, Giovannini N, Alvino G et al. (2002) Intrauterine growth restriction is associated with changes in polyunsaturated fatty acid fetal--maternal relationships. Pediatric Research 52: 750–5.
5. Hay WW Jr (1995) Regulation of placental metabolism by glucose supply. Reproduction, Fertility and Development 7: 365–75.
6. Fowden AL and Forhead AJ (2004) Endocrine mechanisms of intrauterine programming. Reproduction 127: 515–26.
7. Fowden AL (2003) The insulin-like growth factors and feto-placental growth. Placenta 24: 803–12.
8. Fowden AL and Forhead AJ (1998) Glucocorticoids and the preparation for life after birth: Are there long-term consequences of the life insurance? Proceedings of the Nutrition Society 57: 113–22.