Elsevier

Theriogenology

Volume 69, Issue 1, January 2008, Pages 55-67
Theriogenology

The pregnant sheep as a model for human pregnancy

https://doi.org/10.1016/j.theriogenology.2007.09.021Get rights and content

Abstract

Successful outcome of human pregnancy not only impacts the quality of infant life and well-being, but considerable evidence now suggests that what happens during fetal development may well impact health and well-being into adulthood. Consequently, a thorough understanding of the developmental events that occur between conception and delivery is needed. For obvious ethical reasons, many of the questions remaining about the progression of human pregnancy cannot be answered directly, necessitating the use of appropriate animal models. A variety of animal models exist for the study of both normal and compromised pregnancies, including laboratory rodents, non-human primates and domestic ruminants. While all of these animal models have merit, most suffer from the inability to repetitively sample from both the maternal and fetal side of the placenta, limiting their usefulness in the study of placental or fetal physiology under non-stressed in vivo conditions. No animal model truly recapitulates human pregnancy, yet the pregnant sheep has been used extensively to investigate maternal–fetal interactions. This is due in part to the ability to surgically place and maintain catheters in both the maternal and fetal vasculature, allowing repeated sampling from non-anesthetized pregnancies. Considerable insight has been gained on placental oxygen and nutrient transfer and utilization from use of pregnant sheep. These findings were often confirmed in human pregnancies once appropriate technologies became available. The purpose of this review is to provide an overview of human and sheep pregnancy, with emphasis placed on placental development and function as an organ of nutrient transfer.

Introduction

The establishment, maintenance and the successful outcome of pregnancy in the birth of a live, healthy offspring is the ultimate goal of the reproductive system. However, it has been estimated [1] that the likelihood of a woman conceiving during a given menstrual cycle is only 30%, and only 50–60% of these conceptions are expected to survive to 20 weeks of gestation [2]. Of the pregnancies lost, 75% can be attributed to implantation failure [2]. Furthermore, in the United States during 2004, 12.5% of live births were delivered premature [3] with 8.1% of live infants weighing less than 2500 g [3]. This represents an increase in the incidence of low birthweight of 11% since 1994. Worldwide, the incidence of low birth weight is estimated at 15% [4]. The definition of low birthweight in this context refers to live births weighing less than 2500 g, but is also defined as infants with ≤2 standard deviations of weight for the gestational age. By contrast, intrauterine growth restriction (IUGR) or fetal growth restriction (FGR) refer to infants that failed to reach their genetic growth potential in utero as determined by prenatal screening, many of which have low birthweight, but not all do. Approximately 30% of low birthweight infants result from clinically defined IUGR [5]. Low birthweight, IUGR and premature delivery are often interrelated, and the compilation of these adverse pregnancy outcomes result in increased infant mortality and morbidity [6], [7]. Furthermore, epidemiological studies provide evidence that adverse pregnancy outcomes predispose individuals to coronary heart disease, diabetes, hypertension and stroke later in life [8]. Consequently, an adverse conclusion of human pregnancy is a significant health issue worldwide.

While our knowledge of human fetal growth and development has increased significantly during the past 50 years [9], in conjunction with improved prenatal diagnosis and care, there are many questions regarding human pregnancy, especially complicated pregnancies, that have yet to be answered. For both ethical and practical reasons, many aspects of human pregnancy cannot be adequately investigated. Consequently, the use of animal models has played an integral part of our current understanding of both normal and complicated pregnancies [9]. A variety of animal species, spanning from laboratory rodents to domestic ruminants, have been used to investigate various aspects of normal and complicated pregnancies. All of the animal models used have merit, but most suffer from the inability to repetitively sample from both the maternal and fetal side of the placenta, limiting their usefulness in the measurement of placental or fetal physiology under steady-state conditions. While no animal truly recapitulates human pregnancy, the pregnant sheep has been used extensively over the past 40 years to investigate maternal–fetal interactions, in part due to the ability to surgically place and maintain catheters in both the maternal and fetal vasculature [10], [11], allowing repetitive sampling from non-anesthetized pregnant ewes. Since these early studies [10], [11], considerable insight on placental oxygen and nutrient utilization and transfer has been obtained using pregnant sheep, often confirmed in human pregnancies once appropriate technologies became available [9].

The purpose of this review is to provide an overview of human and sheep pregnancy, with emphasis being placed on placental development and function as an organ of nutrient transfer to the fetus. Comparisons will be made between the two species, and where possible discussion of functional changes associated with FGR pregnancies will be provided. It is our aim to provide an appreciation for the utility of pregnant sheep as an investigative model of human pregnancy.

Section snippets

Placental development

Placental development begins quite early in human pregnancy, continues throughout gestation, and is closely tied to vascular development within the placenta, as increasing blood flow is required to meet the needs of the growing fetus. At the time of implantation, lacunae develop within the syncytiotrophoblast layer, coalescing to form the intervillous space that eventually fills with maternal blood. Between days 8 and 13 post coitus (p.c.) syncytiotrophoblast trabeculae separate the lacunae,

Placental transport of oxygen and nutrients

The placenta is not simply a quiescent transporter of fetal nutrients and hormones, but is a metabolically active organ that utilizes nutrients and oxygen at rates similar to the fetus for its own growth. There is a complex balance between placental utilization of substrates and oxygen for its own growth and the transfer of these nutrients to the fetus, allowing for fetal growth. The nutrient transfer capacity of the placenta, which is dependent on adequate placental development and growth,

Conclusions

In this review, we have provided an overview as to why the study of pregnancy and pregnancy outcome is important, reviewed placental development and function, and have compared human and sheep pregnancies. From the comparisons presented here, we recognize that sheep are not a perfect model for human pregnancy, but it has many commonalities with the human, especially from the standpoint of placental development, metabolic function and nutrient transport. Obviously, many of the questions yet

Acknowledgements

The authors wish to thank the faculty and staff associated with the Perinatal Research Facility, both past and present, who have contributed to the many studies of maternal–fetal physiology. Supported in part through National Institute of Child Health and Human Development Grant HD43089.

References (125)

  • F. Lyall et al.

    Placental expression of vascular endothelial growth factor in placentae from pregnancies complicated by pre-eclampsia and intrauterine growth restriction does not support placental hypoxia at delivery

    Placenta

    (1997)
  • C. Dunk et al.

    Angiopoietin-1 and angiopoietin-2 activate trophoblast Tie-2 to promote growth and migration during placental development

    Am J Pathol

    (2000)
  • T.R.H. Regnault et al.

    Placental development in normal and compromised pregnancies

    Placenta

    (2002)
  • H.L. Galan et al.

    Relationship of fetal growth to duration of heat stress in an ovine model of placental insufficiency

    Am J Obstet Gynecol

    (1999)
  • H.L. Galan et al.

    Fetal hypertension and abnormal Doppler velocimetry in an ovine model of intrauterine growth restriction

    Am J Obstet Gynecol

    (2005)
  • T.R.H. Regnault et al.

    Placental expression of VEGF, PlGF and their receptors in a model of placental insufficiency-intrauterine growth restriction (PI-IUGR)

    Placenta

    (2002)
  • J.C. Konje et al.

    Longitudinal quantification of uterine artery blood volume flow changes during gestation in pregnancies complicated by intrauterine growth restriction

    Br J Obstet Gynecol

    (2003)
  • E. Jauniaux et al.

    Evaluation of respiratory gases and acid-base gradients in human fetal fluids and uteroplacental tissue between 7 and 16 weeks’ gestation

    Am J Obstet Gynecol

    (2001)
  • A. Barbera et al.

    Relationship of umbilical vein blood flow to growth parameters in the human fetus

    Am J Obstet Gynecol

    (1999)
  • M. Bellotti et al.

    Simultaneous measurements of umbilical venous, fetal hepatic, and ductus venosus blood flow in growth-restricted human fetuses

    Am J Obstet Gynecol

    (2004)
  • T. Kiserud et al.

    Blood flow and the degree of shunting through the ductus venosus in the human fetus

    Am J Obstet Gynecol

    (2000)
  • D.I. Edelstone et al.

    Relationship of fetal oxygen consumption and acid-base balance to fetal hematocrit

    Am J Obstet Gynecol

    (1985)
  • M.E. Paulone et al.

    Effects of maternal anemia on uteroplacental and fetal oxidative metabolism in sheep

    Am J Obstet Gynecol

    (1987)
  • V.H. Karsdorp et al.

    Clinical significance of absent or reversed end diastolic velocity waveforms in umbilical artery

    Lancet

    (1994)
  • G. Pardi et al.

    Venous drainage of the human uterus: respiratory gas studies in normal and fetal growth-retarded pregnancies

    Am J Obstet Gynecol

    (1992)
  • T.R.H. Regnault et al.

    Development and mechanisms of fetal hypoxia in severe fetal growth restriction

    Placenta

    (2007)
  • A.M. Marconi et al.

    An evaluation of fetal glucogenesis in intrauterine growth-retarded pregnancies

    Metabolism

    (1993)
  • F.B. Wooding et al.

    Localisation of glucose transport in the ruminant placenta: implications for sequential use of transporter isoforms

    Placenta

    (2005)
  • N.P. Illsley

    Glucose transporters in the human placenta

    Placenta

    (2000)
  • F. Teasdale et al.

    Intrauterine growth retardation: morphometry of the microvillous membrane of the human placenta

    Placenta

    (1988)
  • H. Schneider et al.

    Asymmetrical transport of glucose across the in vitro perfused human placenta

    Placenta

    (2003)
  • A.N. Quraishi et al.

    Transport of sugars across human placental membranes measured by light scattering

    Placenta

    (1999)
  • P. Bozzetti et al.

    The relationship of maternal and fetal glucose concentrations in the human from midgestation until term

    Metabolism

    (1988)
  • H. Schneider

    Ontogenic changes in the nutritive function of the placenta

    Placenta

    (1996)
  • D.L. Economides et al.

    Cordocentesis in the diagnosis of intrauterine starvation

    Am J Obstet Gynecol

    (1989)
  • A.J. Wilcox et al.

    Incidence of early loss of pregnancy

    N Engl J Med

    (1988)
  • National Center for Health Statistics, final natality data. Retrieved July 10, 2007, from...
  • United Nations Children's Fund (UNICEF). The State of the World's Children 2007. Available online at:...
  • D.J.P. Barker

    Mothers, Babies and Health in Later Life

    (1998)
  • G. Meschia et al.

    The diffusibility of oxygen across the sheep placenta

    Q J Exp Physiol Cogn Med Sci

    (1965)
  • F.C. Battaglia et al.

    The effect of maternal oxygen inhalation upon fetal oxygenation

    J Clin Invest

    (1968)
  • R. Demir et al.

    Fetal vasculogenesis and angiogenesis in human placental villi

    Acta Anat

    (1989)
  • I. Brosens et al.

    The physiological response to the vessels of the placental bed to normal pregnancy

    J Pathol Bacteriol

    (1967)
  • J.W. Meekins et al.

    A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies

    Br J Obstet Gynecol

    (1994)
  • O. Grosser

    Vergleichende anatomie und entwicklungsgeschichte der eihaute und der placenta

    (1909)
  • J.H.J. Stegeman

    Placental development in the sheep and its relation to fetal development. A qualitative and quantitative anatomic and histologic study

    Bijdragen Tot De Dierkunde

    (1974)
  • D.P. Boshier

    A histological and histochemical examination of implantation and early placentome formation in sheep

    J Reprod Fertil

    (1969)
  • D. Steven

    Anatomy of the placental barrier

  • R. Leiser et al.

    Placental vascular corrosion cast studies: A comparison between ruminants and humans

    Micro Res Tech

    (1997)
  • R.K. Creasy

    Intrauterine growth restriction

  • Cited by (208)

    View all citing articles on Scopus
    View full text