Mechanisms responsible for parturition; the use of experimental models

Animal Reproduction Science 82–83 (2004) 567–581

Mechanisms responsible for parturition; the use of experimental models G. Jenkin∗ , I.R. Young Department of Physiology, P.O. Box 13F, Monash University, Melbourne, Vic. 3800, Australia

Abstract In this review, our knowledge, gleaned from a range of species, of what determines gestation length, how fetal maturation and birth are synchronized and how the uterotonic mechanisms are activated at birth are discussed. Accumulated data indicate that fetal glucocorticoids are involved in, but do not necessarily play a causative role in, the initiation of parturition in eutherian mammals generally. Present observations are consistent with a complex, positive regulatory interaction between estrogens, prostaglandins and oxytocin and are consistent with a role for prostaglandins as the final, common effector in myometrial activation. We are, however, left with the possibility that the initial mechanism for the timing of birth is encoded in the fetal genome and is closely linked to, and activated when, certain prerequisite developmental events have occurred in the fetus. Our understanding of these events in the sheep have led to its extensive use as an experimental model for the study of human clinical correlates of fetal maturation and development and the control of the initiation of parturition. © 2004 Elsevier B.V. All rights reserved. Keywords: Parturition; Pregnancy; Fetal maturation; Fetal development

1. Introduction Astute observations, by farmers as well as scientists, of a wide variety of anatomical and physiological aspects of reproductive processes have provided us with basic but significant knowledge of the physiology of parturition (see Liggins and Thorburn, 1994). More recently, such observations have been confirmed and extended by the use of both domestic and laboratory experimental animals. Our understanding of the mechanisms responsible for parturition, however, has been gained from studies undertaken in only a few species of animals. Despite a considerable body of literature relating to the few species that have been studied, the mechanisms responsible for the maintenance of pregnancy and the initiation of ∗ Corresponding author. Tel.: +61 3 9905 2500; fax: +61 3 9905 2547. E-mail address: [email protected] (G. Jenkin).

0378-4320/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.anireprosci.2004.05.010

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parturition have not been fully elucidated in any species. Significant variation has been, and continues to be, demonstrated as more orders and species of mammals are studied, although those studied in detail represent only the “tip of the iceberg” (Young, 2001). The diversity in these processes indicates that it is unlikely that a single uniting fundamental physiological process is involved. Thus, it is becoming manifestly clear that no one fundamental mechanism underlies the maintenance of pregnancy or the initiation of parturition. Attempts to relate physiological and experimental observations on the initiation of normal and induced parturition in experimental animals to events occurring in the human have made extensive use of the sheep as an experimental model. Such observations have been supplemented by a small number of studies in non-human primates and, where possible, the human. Animal models, however, have been used to great effect in the study of the development and the treatment of abnormal development in the human.

2. Gestation length The duration of gestation for an individual species of animals is remarkably constant, suggesting some sort of time measuring process. Such a process would, most likely, involve determining the number of cell divisions that have occurred since the time of fertilization; although experimental evidence for this is lacking. Alternatively, the process could involve measurement of the time elapsed since syngamy. This would require counting the repetitions of an isochronous process and could originate in the mother, the placenta, or the fetus. No link, however, has been made to a timing of gestation length or a circadian cycle-counting mechanism. Furthermore, the ovine fetus can signal its own time of birth, even after destruction of the optic nerves and suprachiasmatic nuclei (Poore et al., 1999) and maternal pinealectomy has been shown to abolish the diurnal melatonin rhythm, but does not affect the duration of gestation (McMillen and Nowak, 1989). Thus, photoperiodic or circadian information does not appear to be a necessary determinant of gestation length; although it has been shown to modulate the time of day when birth occurs in primates and rats (Bosc, 1990; Honnebier et al., 1991; Rowland et al., 1991; Honnebier and Nathanielsz, 1994). An alternative to a time measuring mechanism could be the development of the conceptus of each specific species at a genetically determined rate, alluded to above, and that birth occurs in response to a signal given when the fetus attains appropriate size and/or maturity. Such a signal could be transduced by the mother (e.g., uterine volume), the fetus (e.g., nutrient restriction), or the placenta (e.g., increased fetal demand for nutrients). In all of these cases, the duration of gestation would ultimately depend on the genetically determined growth rate of the conceptus. Uterine volume, once considered a determinant of gestation length, now seems unlikely to be so, although larger uterine volume, such as in multiple versus singleton ovine pregnancy, is associated with slightly shorter gestation length. Thus, in the case of multiple ovine pregnancy, birth occurs much closer to the time expected for singleton pregnancies (145–150 days) than to the time (about 120 days) when the combined fetal mass reaches that of a singleton pregnancy at term (Young, 2001). Furthermore, dysfunction or ablation of the fetal pituitary or adrenals in sheep are associated with prolonged gestation and continued fetal growth (see Liggins and Thorburn, 1994). In these cases, the ewe does not deliver the fetus but eventually dies of starvation because the

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uterine volume compromises her ability to take in sufficient food (Van Kampen and Ellis, 1972). Thus, increased uterine volume alone appears to be insufficient to trigger birth in the sheep. It has been shown in the sheep, as well as in other species, that the rapid accumulation of fetal tissue in late gestation outstrips the ability of the placenta to supply substrates at the required rate, with the result that fetal substrate concentrations fall (Symonds et al., 2001; Ward et al., 2004). Such a stressor would activate the fetal hypothalamo-pituitary-adrenal (HPA) axis, which provides the signal for the initiation of parturition in some species (see below). Substrate limitation, however, would be expected to develop gradually, whereas the timing of birth is precise, mitigating against such a mechanism being important under normal circumstances. Acute substrate deprivation to the fetus is, however, known to precipitate parturition (Fowden et al., 1994; Fowden, 1997). We are, thus, left with the possibility that the mechanism for the timing of birth is encoded in the fetal genome and is closely linked to, and activated when, specific prerequisite developmental events have occurred in the fetus.

3. Synchronization of fetal development, fetal maturation and parturition The timely birth of a developmentally mature fetus appropriate for the species, requires that some mechanism synchronizes fetal development and maturation with the maternal mechanisms that effect the birth. In some species, particularly ruminants, the synchronizing factor has clearly been shown to be glucocorticoid, secreted by the fetal adrenal cortex. Glucocorticoid concentrations in fetal sheep plasma increase exponentially over the last month of gestation, a phenomenon known as the cortisol surge (Poore et al., 1998). In this species, in which the placenta is the principal source of progesterone for pregnancy maintenance, the increase in glucocorticoid not only directly accelerates the maturation of organ systems required for extrauterine life (Liggins and Thorburn, 1994), but also induces the expression of placental steroidogenic enzymes (specifically 17␣-hydroxylase-C-17,20 lyase) which redirect the steroidogenic pathway to favor the secretion of estrogens at the expense of progesterone (Anderson et al., 1975; Steele et al., 1976). The resultant increase in the estrogen/progesterone ratio activates prostaglandin G/H synthase in the placenta, synthesis of prostaglandins (PG) and, thus, increases myometrial activity and labor (Flint et al., 1974; Liggins et al., 1977; McLaren et al., 1996, 2000). Thus, the cortisol surge in the sheep constitutes the signal for parturition, as it does in other ruminants studied (Liggins et al., 1967; Liggins, 1968; Bassett and Thorburn, 1969). The goat, a close relative of the sheep, and the cow show an intriguing and significant difference from the sheep. In these species, as in the sheep, the fetal cortisol surge is essential for the initiation of labor (Currie and Thorburn, 1997a,b; Flint et al., 1978; Ford et al., 1998). However, the corpus luteum, and not the placenta, is the principal source of progesterone and removal of the corpus luteum at any time during gestation, at least in the goat, results in loss of the pregnancy. The caprine and ovine placentas synthesize similar amounts of progesterone, but the caprine placenta does not secrete sufficient progesterone to maintain the pregnancy because the progesterone is metabolized before it is secreted (Sheldrick et al., 1980, 1981). Despite this, induction of the placental 17␣-hydroxylase-C-17,20 lyase

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enzyme by glucocorticoid at term may act, as it does in the sheep, to redirect steroidogenesis from progesterone and its metabolites to estradiol synthesis and, thus, the initiation of parturition (Flint et al., 1978). A greater understanding of the mechanisms involved in the events leading to the initiation of parturition in the goat may enable the design of more effective strategies for manipulating the timing of parturition in other corpus luteum dependent domesticated species. This would be of economic benefit to producers and improve the welfare of their stock. For example, the physiology of parturition in the goat mostly parallels that in cattle. Increasingly, large dairy herds in developed countries use artificially assisted breeding programs which leads to some synchronization of calving. Nonetheless, there is still considerable variability in calving dates in such programs, resulting in significant costs to producers in terms of the labor needed to minimize and manage potential obstetrical mishaps. In species other than the sheep and goat, the role of the fetal HPA axis in the initiation of parturition is even less clear. For example, in the horse, the fetal cortisol profile increases only in the last 48 h before delivery and maternally administered glucocorticoid does not induce labor as it does in sheep and goats (Silver, 1990; Silver and Fowden, 1991). Similarly, there is little evidence for glucocorticoids as inducers of parturition in rodents. Mice lacking a functional corticoid releasing hormone (CRH) gene have atrophic adrenal cortices, yet are born at the normal time (Muglia et al., 1995); and the timing of birth in guinea pigs is unaffected by ablation of the fetal pituitary or maternal administration of the synthetic glucocorticoid, dexamethasone (Donovan and Peddie, 1973; Illingworth et al., 1974). Limited data available from other species are equivocal and, thus, it is probably unsafe to assume that fetal glucocorticoids play a causative role in parturition in eutherian mammals generally. Although glucocorticoids do not subserve the dual role of facilitating developmental maturation and initiation of the parturient process in all species, an increase in fetal glucocorticoid concentrations has been demonstrated in all species examined to date. In these species, they play an essential role in promoting organ maturation during late gestation. For example, in species such as the mouse, horse and human, which do not rely on a fetal corticoid signal to initiate birth, there still exists the possibility of a causal relationship between glucocorticoid-mediated maturation and the birth process. The link, most likely, involves PGE2, which is secreted in increasing amounts by the placenta or fetal membranes in many species during late gestation and the prelude to labor (Fowden et al., 1994). It is also a potent activator of the fetal HPA axis and glucocorticoid secretion (Louis et al., 1976; Hollingworth et al., 1995). Thus, the concentrations of glucocorticoids in fetal plasma may increase as a consequence of parturient mechanisms even in species that do not rely on them as the signal for birth. The universality of the fetal glucocorticoid surge preceding normal labor at term suggests that it may represent a fundamental signal common to all species. Since fetal glucocorticoids, to date, have been shown to signal birth in only a limited range of eutherian mammalian species, it is noteworthy that there is strong evidence for this phenomenon in a marsupial species, the tammar wallaby. Notwithstanding the distance of their phylogenetic relationship, the tammar conforms to the artiodactyl pattern in that the concentration of cortisol in fetal fluids increases in the last two days of the 27 day gestation period (Ingram et al., 1999). Exogenous glucocorticoid induces premature birth with maternal endocrine profiles closely matching those associated with spontaneous birth

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(Shaw et al., 1996), and inhibition of glucocorticoid synthesis may delay delivery (Renfree and Young, 1979). Whether this physiological homology between two widely separated groups is an example of convergent evolution or represents the persistence of a primitive condition which has been replaced in many other eutherian taxa is open to debate. In either case, the induction of labor as a result of the ubiquitous prepartum increase in fetal cortisol is not a highly conserved mechanism across taxa and, therefore, does not appear to be a fundamental one.

4. The role of progesterone and estrogen During gestation, the uterus grows to accommodate the increasing mass of its contents but remains relatively quiescent. As term approaches, the uterus is prepared for labor by increasing its ability to contract and expel the fetus. In common laboratory and domestic species such as the rat, mouse, rabbit, sheep, goat, cow, pig and dog, progesterone is required for the maintenance of pregnancy. It is secreted into the maternal circulation from the corpus luteum of pregnancy and, in some species, the placenta takes over this role at varying times during pregnancy (Heap et al., 1977). The high progesterone concentrations achieved during pregnancy generally favor myometrial quiescence (reviewed in Finn and Porter, 1975; Kuriyama and Suzuk, 1976; Parkington, 1983). Estrogens generally have opposing effects, favoring the synthesis of contractile proteins in myometrial cells and enhancing electrical coupling and the expression of oxytocin receptors, leading to well propagated, coordinated contractions. Prostaglandin F2␣ also induces myometrial contractile activity. The ability of PGF2␣ to increase intracellular calcium is opposed by progesterone, suggesting that the anti-uterotonic action of progesterone depends, at least partly, on its ability to antagonize PGF2␣ action (Csapo et al., 1977; Fu et al., 2000). In many species, the maternal plasma progesterone concentration decreases shortly before the onset of labor while progesterone withdrawal before term results in premature labor (Jenkin and Thorburn, 1985). In others, such as the guinea pig and human, plasma progesterone does not decrease before birth, but preterm treatment with antigestagens induces premature labor, at least under some conditions. This apparent paradox may be resolved in the case of the guinea pig by the observation that, although the circulating steroid concentrations do not change, the abundance of progesterone receptors decreases while estrogen receptors increase near term (Glasier and Hobkirk, 1993). This suggests that the actions of the steroids may be modulated at the level of the target organ rather than by their circulating concentrations (Mitchell and Wong, 1993; Karalis et al., 1996; Majzoub et al., 1999). In the common laboratory and domestic species, estrogens favor the synthesis of uterotonins including prostaglandins and oxytocin. They also promote the expression of receptors for prostaglandins and oxytocin in the myometrium. As such, they oppose progesterone action. The degree to which estrogens induce oxytocin receptors does, however, vary between species and Flemming et al. (2001) have elegantly shown that this depends on whether the oxytocin gene promoter contains estrogen response elements and whether the activated estrogen receptor binds to specific transcription factors and acts via specific response elements. While it is generally true that estrogens predispose the myometrium to contract, they are not essential for parturition in all species. Antagonism of estrogen action delays

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but does not abolish the birth process in rats (Fang et al., 1996) and pregnancy and parturition proceed in women when placental aromatase and, thus, estrogen, is absent (Shozu et al., 1991). Similarly, exogenous estrogen does not induce or accelerate labor in humans indicating that estrogens are not essentially linked to the onset of human labor (see review by Liggins and Thorburn, 1994). The classical roles of estrogen and progesterone in the physiology of parturition may not apply in the other species. In the horse, circulating progesterone concentrations are low in late gestation, while high concentrations of 5␣-reduced progesterone metabolites are observed (Holtan et al., 1975, 1991), suggesting that the estrogen/progesterone ratio is relatively unimportant in this species. In the tammar wallaby, there is no prepartum change in progesterone (Ward and Renfree, 1984; Renfree, 1994). Indeed, in this and related species, the duration of gestation and the estrous cycle are the same and the progesterone profiles in pregnancy and the cycle also do not differ. Further comparative studies are needed to determine whether progesterone, or related gestagens, play an obligatory role in the maintenance of pregnancy in mammals.

5. Interaction between prostaglandins, cytokines and oxytocin It has been suggested that the mechanisms initiating parturition represent an inflammatory response. Many of the changes observed in uterine and cervical tissues in the period surrounding the onset of labor resemble changes that typically occur in response to tissue damage (reviewed in Kelly, 1996; Romero et al., 2001; Grigsby et al., 2003). The case for inflammatory mediators as effectors in parturition is strengthened by the observation that stimuli, such as mechanical or chemical trauma or infection, that commonly induce the expression of these agents, are associated with premature delivery. Among the cytokines, interleukins (IL) 1, 6 and 8 and tumor necrosis factor (TNF) ␣ are implicated in myometrial activation, although they do not necessarily exert uterotonic effects directly (Romero et al., 1991; Romero and Tartakovsky, 1992; Elliott et al., 1998; Denison et al., 1999). Interestingly, more recent evidence suggests that IL-6 is secreted in response to tissue damage but acts to mitigate the inflammatory response (Xing et al., 1998) and its role in parturition needs to be carefully assessed. The role of the pro-inflammatory cytokines in the parturient process appears to be to promote the induction of PGHS-2 whose expression and activity increase at the onset of labor with consequent increases in prostaglandin production by intrauterine tissues. Prostaglandin F2␣ is secreted during labor in all species studied to date, including marsupials, and appears to act as a universal myometrial contractant. Similarly, direct infusion of PGF2␣ and, in some species, PGE2 induces labor, while pharmacological inhibition of the inducible prostaglandin synthase (PGHS)-2 inhibits labor (Thorburn et al., 1987; Poore et al., 1999). Furthermore, disruption of the genes encoding PGHS-2 or the prostaglandin F receptor is associated with disordered labor in mice (Dinchuk et al., 1995; Morham et al., 1995; Sugimoto et al., 1997). A positive feedback effect of prostaglandins on cytokine expression has also been demonstrated (Denison et al., 1999). Although it may not cause uterine contraction in all species, PGE2 is secreted in large amounts from the placenta in late gestation in many species

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(see above) and is effective in inducing cervical ripening. Thus, uterine activity and cervical compliance are affected simultaneously by the complementary actions of PGF2␣ and PGE2 . Such effects of prostaglandins appear to apply in all species studied to date. During established labor, oxytocin is secreted episodically from the posterior pituitary of most if, not all, species in response to cervico-vaginal stretch and acts on the myometrium to increase the frequency and force of contractions. Oxytocin does not normally induce preterm labor and, even at term, it is unreliable as an inducer of labor unless some procedure inducing tissue damage (such as amniotomy in the human) is also performed. Similarly, pharmacological inhibition of oxytocin action delays, but does not abolish, delivery in sheep, rats and guinea pigs and oxytocin-null mice deliver their pups spontaneously at the expected time of birth (Schellenberg, 1995; Nishimori et al., 1996; Young et al., 1996; Grigsby et al., 2000). The discovery that the oxytocin gene is expressed in the uterus has created considerable interest, raising the possibility that oxytocin synthesized within the uterus could participate in the initiation or the accomplishment of parturition (reviewed in Mitchell et al., 1998). The expression of oxytocin receptors in the pregnant uterus is increased at term in sheep, humans and rats (Meier et al., 1995; Wathes et al., 1996; Alexandrova and Soloff, 1980a,b,c; Fuchs et al., 1982, 1984). In the tammar wallaby, a similar increase has been reported in the concentration of receptors for mesotocin (8-Ile-oxytocin), the tammar equivalent of oxytocin (Parry et al., 1997) and oxytocin receptor inhibition delays parturition (Renfree et al., 1996). The induction of oxytocin receptors at term in the rat can be inhibited by blockade of PGHS (Chan, 1980), and this treatment is associated with prolonged gestation and dystocia (Chan and Chen, 1992). In the same study, specific oxytocin receptor blockade did not prolong gestation but interfered with the process of delivery whereas, in the sheep, oxytocin receptor blockade inhibits oxytocin induced, but not basal, PG release (Jenkin et al., 1994). Together, these observations suggest that prostaglandins are positive regulators of oxytocin receptor expression, that the uterotonic action of prostaglandins depends partly on oxytocin action, and that prostaglandins, but not oxytocin, are directly involved in the initiation of labor. The present observations are consistent with a complex, positive regulatory interaction between estrogens, PGHS and oxytocin (Fang et al., 1996) but are also consistent with the proposed role of prostaglandins as the final, common effector of myometrial activation.

6. The sheep as a model of fetal development and parturition The forgoing discussion indicates that a single uniting fundamental physiological process is unlikely to underlie the maintenance of pregnancy or the initiation of parturition. Despite this, the sheep has been used as a model for the study of mechanisms involved in fetal development, maturation and parturition since the pioneering work of two giants in the field, Graham (Mont) Liggins and Geoffrey Thorburn. As a result of their groundbreaking studies carried out in the 1960s and 1970s, the anatomy and physiology of pregnancy and fetal development in sheep have been well defined, and the chronically instrumented sheep is still considered to be one of the best models for addressing prenatal growth and

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development in humans, as well as contributing to our understanding of the mechanisms involved in normal and premature parturition. In the sheep, normal term is at approximately 145–147 days of gestation, being much longer than that of many other laboratory species and, hence, closer to the duration of human pregnancy. The offspring are of similar weight to the human baby (Hecker, 1974) and the final stages of parturition that enhance uterine activity in the sheep are very similar to those that occur in the human. For example, the end stage of parturition for both sheep and humans is characterized by a substantial increase in prostaglandin concentrations (Challis and Lye, 1994) and oxytocin receptor concentrations leading to delivery (Fuchs et al., 1984; Meier et al., 1995; Wathes et al., 1996). Based on the similarities of fetal development between humans and sheep, many surgical techniques have been developed for chronic study of the sheep fetus. Clearly, the greatest advantage of the sheep model, in comparison with other laboratory species, is the ability to gain access to the fetal compartment and its uterine environment for the insertion of physiological monitoring and sampling devices. The sheep is also a species that recovers quickly and well from general anaesthesia and invasive surgery; and frequent fetal and maternal blood sampling is possible to measure various hormones and continually monitor fetal well-being, all without compromising the health of the mother or fetus. There is also a range of published evidence (reviewed by McMillen, 2001), which suggests that translation of results from the ‘sheep to the bedside’ is entirely feasible. In order to gain some quantitative understanding of the relative use of the sheep as a model in this area, the Medline database of world wide biomedical research publications was searched by McMillen (2001) for the number of papers in specific areas of biomedical research citing the use of the sheep for the period 1991–2000. The percentage of papers in most areas of biomedical research which cite the sheep varies between <1 and 8%. Several studies support the usefulness of the sheep model for the study of major physiological systems, such as the cardiovascular, respiratory, renal, reproductive and endocrine systems. There are three major areas, however, in which the sheep is much more frequently cited, these being: (i) fetal development, (ii) reproduction pregnancy and parturition, and (iii) endocrinology. The reason for the disproportionate use of sheep in fetal and developmental physiology is, in part, due to a consequence of the success of the translation of experimental work in the sheep to the antenatal clinic and the neonatal intensive care ward. For example, decades of studies on the developing sheep fetus have made a significant contribution to an understanding of the mechanisms underlying the critical role of endogenous glucocorticoids in maturing the lungs before birth (Ballard and Ballard, 1995), the timing of normal birth (Challis et al., 2000), and the impact of a suboptimal intrauterine environment on fetal development and the potential adverse consequences for adult health (Robinson et al., 2000). Given this background, perhaps it is not surprising that the sheep is still the model of choice for investigating many aspects of developmental physiology. 6.1. Lung maturation The result of studies in the sheep on the respiratory system (reviewed by Ballard and Ballard, 1995) demonstrated that glucocorticoid is needed for structural and functional maturation of the lungs. These observations rapidly led to the prophylactic use of

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glucocorticoid treatment in cases of threatened premature delivery in humans and, subsequently, to the development of synthetic surfactants for use in treatment of premature babies with respiratory distress syndrome (Morley, 1989). More recent evidence from studies on the development of the haematopoietic system suggests that glucocorticoids accelerate maturational changes, which are initiated by other means (Wintour et al., 1985; Zitnik et al., 1995; Wessely et al., 1997). Furthermore, the optimal degree of prenatal glucocorticoid exposure and its efficacy in severely growth retarded fetuses has been questioned. Because of the approximately 30-fold increase in cortisol concentration observed in fetal sheep in the month before birth, it might be assumed that this degree of exposure is required. Nonetheless, the cortisol concentration in human fetuses appears to rise more slowly and to a more modest extent. Infants born with defective cortisol synthesis, e.g., those affected by congenital adrenal hyperplasia, have low plasma glucocorticoid concentrations but do not usually come to clinical attention because of the immaturity of their vital systems (White and Speiser, 2000; New and Speiser, 1986). This observation suggests that the degree of glucocorticoid exposure required for organ maturation may be quite small. Prenatal glucocorticoid administration also alters vascular function, including cerebral circulation, which could result in permanent, harmful effects. In human growth retarded fetuses, placental vascular resistance is altered and end-diastolic flow in the umbilical artery is absent. It has been shown that maternal betamethasone treatment is associated with a transient return of end-diastolic flow (Wallace and Baker, 1999; Edwards et al., 2003). However, it is not known whether this treatment improves placental gas exchange in the long term, nor are the effects in the cerebral circulation well understood. Thus, the prophylactic use of betamethasone in threatened premature labor may need to be reviewed in the light of such concerns about the possible adverse consequences of inappropriate glucocorticoid exposure in growth retarded fetuses and in early in life (Seckl and Miller, 1997; Phillips et al., 1998; Huang et al., 1999; Quinlivan et al., 2000). 6.2. Premature parturition Challis et al. (2000) and Young (2001) have reviewed the contribution made by the sheep to our understanding of the mechanisms initiating parturition. Such studies have provided the background for the use of the sheep as a model to develop our understanding of the relationship between intrauterine infection and premature labor (Grigsby et al., 2003). Introduction of lipopolysaccharide to amniotic fluid of the late pregnant sheep provoked responses that were mainly restricted to the amniotic and fetal compartments, with no overt responses detected in the maternal circulation. Furthermore, these observations suggest that a fetal inflammatory response occurs rapidly following entry of endotoxins into the amniotic fluid, which may represent a survival mechanism to aid the fetus in the event of premature labor. This finding may also indicate a role for the amniotic fluid in protecting the fetus from endotoxin exposure during pregnancy. The experimental observation in the sheep, alluded to above, that prostaglandins and oxytocin act in concert to initiate and stimulate parturition have also resulted in the recent development of a new rational strategy for the treatment of premature labor in humans (Grigsby et al., 2000; Scott et al., 2001).

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6.3. Intrauterine growth retardation and fetal well-being The potential adverse consequences of intrauterine growth retardation (IUGR) for the fetus, the neonate and subsequent adult health have been reviewed by Jeffrey Robinson who pioneered the use of the sheep in such studies (Robinson et al., 2000). It is widely accepted that reduced oxygen availability (hypoxia) is a key feature of IUGR pregnancy and is the likely cause underlying late “unexplained” fetal death. Thus, the challenges facing clinical and basic scientists include being able to better predict which fetuses are at risk of hypoxia and subsequent growth restriction and to understand the adaptive mechanisms stimulated in IUGR fetuses so that, where possible, appropriate monitoring and protection of the “at risk” fetus can be initiated. Studies undertaken by us in the sheep have successfully adapted the model of single umbilical artery ligation (SUAL) to induce chronic placental insufficiency, resulting in a stressed, hypoxic fetus that enters labor prematurely. This animal model is now being used to make comparisons with human clinical studies, in which we can examine the mechanisms contributing to brain development and injury of IUGR fetuses. The model has been extended to study twin ovine pregnancies, in which one twin can be subjected to SUAL, and the second twin acts as an internal control. The SUAL twin demonstrates hypoxaemia and acidaemia and the content of activin A and PGE2 , which are increased in acute hypoxia in fetal serum and amniotic fluid (Jenkin et al., 2001; Loose et al., 2004), are distinctly altered. The SUAL model is being used to examine the possible stimulus for activin A production and secretion, and to determine whether activin A regulates other aspects of the intrauterine environment, such as PGE2 and cortisol. Such research will provide considerable knowledge relating to the mechanisms initiated in the chronically hypoxic fetus, which may impact upon management regimes, and may also provide theraupeutic and neuroprotective strategies in the treatment of IUGR pregnancies. 7. Conclusions It is apparent that there is a general requirement for antenatal exposure of the fetus to glucocorticoid which promotes the maturational changes needed for extrauterine life. The prepartum increase in glucocorticoid concentrations in fetal plasma only constitutes the signal for myometrial activation in a relatively small number of divergent species. Progesterone is required for the maintenance of uterine quiescence in many, but not all species. In such species, it is withdrawn at term by decreased secretion or receptor down regulation. Estrogens, in contrast, generally favor myometrial activation but, as for progesterone, they do not have an essential role in all species. Although there is considerable interspecies diversity in the ultimate determinants of parturition, the effector mechanisms at the level of the myometrium are more consistent. The prostaglandins PGF2␣ and PGE2 appear to be universally involved in direct activation of the myometrium and also in preparation of the cervix. Oxytocin also plays a role in inducing uterine contractions in most, if not all, species, although this role is not always essential.

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The chronically instrumented sheep is a useful model for the study of prenatal maturation and development and premature parturition in humans. It has also provided an insight to the acute and chronically hypoxic fetus, which may impact upon future therapeutic strategies in the treatment of IUGR pregnancies as well as premature parturition.

Acknowledgements The authors gratefully acknowledge the assistance of Jonathan Hirst, Peta Grigsby and Suzanne Miller in the preparation of the manuscript; Caroline McMillen for preparation of data on the use of sheep as a model for biomedical research and the late Geoffrey Thorburn for being a wonderful mentor and providing inspiration to the authors. G. Jenkin acknowledges the support of the Australian National Health & Medical Research Council (Program Grant No. 143786).

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