The pregnant sheep as a model for human pregnancy
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)
- et al.
Estimates of human fertility and pregnancy loss
Fertil Steril
(1996) Management of preterm infants with intrauterine growth restriction
Early Hum Dev
(2005)- et al.
Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction. The Vermont Oxford Network
Am J Obstet Gynecol
(2000) Intrauterine growth restriction
Obstet Gynecol
(2002)- et al.
Human fetal growth and organ development: 50 years of discoveries
Am J Obstet Gynecol
(2006) - et al.
Angiogenesis and intrauterine growth restriction
Bailliere's Clin Obstet Gynecol
(2000) - et al.
Fetal microcirculation of abnormal human placenta. I. Scanning electron microscopy of placental vascular casts from small for gestational age fetus
Am J Obstet Gynecol
(1986) - et al.
Placental pathology of absent and reversed end-diastolic flow in growth-restricted fetuses
Obstet Gynecol
(1997) - et al.
Structural analysis of placental terminal villi from growth-restricted pregnancies with abnormal umbilical Doppler waveforms
Placenta
(1996) - et al.
Stereological investigation of placental morphology in pregnancy complicated by pre-eclampsia with and without intrauterine growth restriction
Placenta
(2003)
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
Angiopoietin-1 and angiopoietin-2 activate trophoblast Tie-2 to promote growth and migration during placental development
Am J Pathol
Placental development in normal and compromised pregnancies
Placenta
Relationship of fetal growth to duration of heat stress in an ovine model of placental insufficiency
Am J Obstet Gynecol
Fetal hypertension and abnormal Doppler velocimetry in an ovine model of intrauterine growth restriction
Am J Obstet Gynecol
Placental expression of VEGF, PlGF and their receptors in a model of placental insufficiency-intrauterine growth restriction (PI-IUGR)
Placenta
Longitudinal quantification of uterine artery blood volume flow changes during gestation in pregnancies complicated by intrauterine growth restriction
Br J Obstet Gynecol
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
Relationship of umbilical vein blood flow to growth parameters in the human fetus
Am J Obstet Gynecol
Simultaneous measurements of umbilical venous, fetal hepatic, and ductus venosus blood flow in growth-restricted human fetuses
Am J Obstet Gynecol
Blood flow and the degree of shunting through the ductus venosus in the human fetus
Am J Obstet Gynecol
Relationship of fetal oxygen consumption and acid-base balance to fetal hematocrit
Am J Obstet Gynecol
Effects of maternal anemia on uteroplacental and fetal oxidative metabolism in sheep
Am J Obstet Gynecol
Clinical significance of absent or reversed end diastolic velocity waveforms in umbilical artery
Lancet
Venous drainage of the human uterus: respiratory gas studies in normal and fetal growth-retarded pregnancies
Am J Obstet Gynecol
Development and mechanisms of fetal hypoxia in severe fetal growth restriction
Placenta
An evaluation of fetal glucogenesis in intrauterine growth-retarded pregnancies
Metabolism
Localisation of glucose transport in the ruminant placenta: implications for sequential use of transporter isoforms
Placenta
Glucose transporters in the human placenta
Placenta
Intrauterine growth retardation: morphometry of the microvillous membrane of the human placenta
Placenta
Asymmetrical transport of glucose across the in vitro perfused human placenta
Placenta
Transport of sugars across human placental membranes measured by light scattering
Placenta
The relationship of maternal and fetal glucose concentrations in the human from midgestation until term
Metabolism
Ontogenic changes in the nutritive function of the placenta
Placenta
Cordocentesis in the diagnosis of intrauterine starvation
Am J Obstet Gynecol
Incidence of early loss of pregnancy
N Engl J Med
Mothers, Babies and Health in Later Life
The diffusibility of oxygen across the sheep placenta
Q J Exp Physiol Cogn Med Sci
The effect of maternal oxygen inhalation upon fetal oxygenation
J Clin Invest
Fetal vasculogenesis and angiogenesis in human placental villi
Acta Anat
The physiological response to the vessels of the placental bed to normal pregnancy
J Pathol Bacteriol
A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies
Br J Obstet Gynecol
Vergleichende anatomie und entwicklungsgeschichte der eihaute und der placenta
Placental development in the sheep and its relation to fetal development. A qualitative and quantitative anatomic and histologic study
Bijdragen Tot De Dierkunde
A histological and histochemical examination of implantation and early placentome formation in sheep
J Reprod Fertil
Anatomy of the placental barrier
Placental vascular corrosion cast studies: A comparison between ruminants and humans
Micro Res Tech
Intrauterine growth restriction
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