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Amino acids mobilizedfrom maternal carcass tissues McNeill et al., 1997 also may help sustain anincreased rate of hepatic gluconeogenesis during late pregnancy.. Incontrast, in ditocous

20 Pregnancy and Fetal Metabolism

Introduction

This chapter deals with quantitative aspects of macronutrient metabolism andits regulation in maternal and conceptus tissues in vivo, emphasizing data andconcepts generated or revised during the decade since publication of a similarchapter in the first edition of this book (see Bell, 1993) Recent findings on theregulation of nutrient partitioning among maternal tissues, the placentaand fetus(es) are highlighted, as is new information on placental transportmechanisms

Energy Cost of Pregnancy

Practical considerations

Meeting the nutrient requirements of pregnant females is important to ensure

an adequate nutrient supply for proper growth and development of the fetus, toensure that the female is in an adequate body condition for birth, lactation andrebreeding, and to provide immature females with adequate nutrients forcontinued growth Recognizing those needs, most feeding systems currently

in use for ruminants (e.g AFRC, 1990; CSIRO, 1990; NRC, 1996, 2001)recommend a factorial approach such that estimates of nutrient requirementsfor maternal maintenance, body weight gain and growth of gravid uterine(or conceptus) tissues are summed to derive total requirements for pregnantfemales This approach implies that fetal nourishment will be adequate ifmaternal body weight, condition and growth are maintained at suitable levels.Limited or no interaction among tissues (or nutrient needs) of the gravid uterusand maternal tissues is also implied by this approach

ß CAB International 2005 Quantitative Aspects of Ruminant Digestion

and Metabolism, 2nd edition (eds J Dijkstra, J.M Forbes and J France) 523

Recommended levels of feeding during late gestation range from about 1.7times maintenance in cows and ewes with single fetuses to 2.2 to 2.4 timesmaintenance for those with twins or triplets Unfortunately, these levels ofintake are frequently not achieved, especially by polytocous animals, duringlate gestation Inadequate consumption may result from inadequate availability

or quality of diet and from depressed voluntary intake of cattle and sheep duringlate gestation (Forbes, 1986) Under many production situations, maternalbody tissues must be mobilized during late gestation to sustain adequate nutrientsupply and growth of gravid uterine tissues (Robinson et al., 1999)

The increased energy used by the pregnant ruminant is reflected bygreater rates of heat production as compared to otherwise comparablenon-pregnant animals Brody (1945) described the increase in heat production

of pregnant animals relative to similar, well-fed non-pregnant animals as the

‘heat increment of gestation’ He concluded (p 429) that the heat increment ofgestation includes: (i) the energy expense of maintenance of the pregnantuterus; (ii) ‘work’ of growth; (iii) increased work of the maternal organism(including circulatory, respiratory and excretory activities); and (iv) endocrineinfluences on metabolism of the mother The physiological basis for thisincreased metabolism and its implications relative to apparent energetic effi-ciency of fetal growth are discussed in the following sections

Growth and energetic efficiency of the gravid uterus

Energy content of the gravid uterus (allantoic and amnionic fluids, fetus,placenta and uterus) or fetus increases exponentially in the sheep (Rattray

et al., 1974a) and cow (Ferrell et al., 1976a) Similar patterns are seen ingoats and other species This pattern of growth results in about 90% ofbirth weight of the calf or lamb being achieved during the last 40% of gestation.Thus, energy retention in gravid uterine tissues is small during early gestation(0.3 MJ/day at 130 days in the cow), but becomes relatively large nearterm (4.9 MJ/day at 280 days) In comparison, net energy required for main-tenance of a 550 kg cow is expected to be 36.6 MJ/day Several researchershave estimated the efficiency of utilization of dietary metabolizable energy(ME) for energy retention in the gravid uterus or conceptus to be about 0.13(AFRC, 1990; CSIRO, 1990; NRC, 1996) This value does not appear tovary much with stage of gestation (Rattray et al., 1974b; Ferrell et al., 1976b)even though absolute rates of fetal growth differ tremendously, but varies

to some extent with quality of diet (Robinson et al., 1980) Comparable

quality diets Estimates of the ME required for pregnancy during late gestation

in a 550 kg cow (37.5 MJ/day at 280 days) are about 72% of that requiredfor maintenance (52.2 MJ/day) The difference between ME requiredfor gestation and energy retained in the gravid uterus is reflected as heatproduction (or heat increment of gestation) Thus, about 87% of the

ME required to support pregnancy is dissipated as heat These observations

frequently have been interpreted to imply that gestation is energetically veryinefficient.

Reynolds et al (1986) reported that heat production of the gravid uterus incows was 1.37, 2.12, 4.87 and 8.57 MJ/day at 137, 180, 226 and 250 days

of gestation, whereas the heat increment of gestation at these times was 2.69,7.36, 12.34 and 14.95 MJ/day (Brody, 1945; Ferrell et al., 1976b) Thesedata were interpreted to indicate that 30% to 57% (mean 44%) of the heatincrement of gestation was attributable to the energy expenditure of the graviduterus It is implied that over 50% of the heat increment of gestation in the cowwas associated with metabolism of maternal tissues Freetly and Ferrell (1997)estimated that 49% of the heat increment of gestation in ewes was attributable

to gravid uterine tissues They showed that maternal hepatic oxygen tion increased during gestation in ewes and that increased hepatic metabolismaccounted for about 20% of the heat increment of gestation Rosenfeld (1977)observed that cardiac output increased about 75% during pregnancy in ewes,supporting the suggestion of Brody (1945) that increased heart work contrib-utes to the heat increment of gestation Increased energy expenditure ofother maternal tissues such as kidneys, pancreas, skin and mammary glandcontribute to the heat increment of gestation

consump-Gross efficiencies of energy accretion in the uteroplacenta and fetus can beestimated as energy accretion divided by the sum of energy accretion and heatproduction Resulting estimates of gross efficiency for the uteroplacenta andfetus were relatively constant across stage of gestation (Reynolds et al., 1986)and averaged 15.3% and 38.5%, respectively Fetal energetic efficiency wassimilarly constant at about 38% between mid- and late-gestation in sheep (Bell,1986) Gross efficiency of fetal growth compares favourably with grossefficiency of postnatal growth Estimates of the gross efficiency of uteroplacen-tal tissues were much lower The simple reason for the difference in efficiency isthat oxygen consumption or energy expenditure per kg of uteroplacentaltissues is nearly twofold that of the fetus, but rate of energy accretion isconsiderably less Some of the reasons for the high energy expenditure ofuteroplacental tissues will be discussed in subsequent sections Thus, althoughgrowth of the fetus itself is rather efficient energetically, the entire process ofproducing a calf or lamb is relatively inefficient because of the inefficiency ofenergy accretion of the uteroplacenta, which is required to support fetal growthdirectly, and because of the increase in maternal metabolism that is required tosupport fetal growth less directly

Maternal Metabolic Adaptations to Pregnancy

Patterns of macronutrient metabolism

During late pregnancy, ruminants generally increase their voluntary intake ofmedium- to high-quality diets (Forbes, 1986) and, thus, the liver’s access toglucogenic substrate of dietary origin (principally propionate and absorbedamino acids) However, hepatic gluconeogenesis increases in ewes during late

pregnancy even when feed intake is not increased above non-pregnant levels,

to an extent that is directly related to litter size and fetal demand (Freetly andFerrell, 1998) These results are consistent with earlier observations of theeffects of feed intake and pregnancy on whole-body glucose kinetics in sheep(see Bell, 1993) Part of this increased gluconeogenesis is supported by in-creased hepatic uptake of lactate (Freetly and Ferrell, 1998), apparently de-rived from uteroplacental metabolism and increased glycolysis in maternalperipheral tissues (Bell and Ehrhardt, 2000) A further portion is supported

by increased hepatic uptake of glycerol, especially if fat mobilization is creased as term approaches (Freetly and Ferrell, 2000) Amino acids mobilizedfrom maternal carcass tissues (McNeill et al., 1997) also may help sustain anincreased rate of hepatic gluconeogenesis during late pregnancy

in-Effects of pregnancy on the quantitative metabolism of amino acids haveyet to be studied systematically in ruminants However, the fractional rate ofhepatic protein synthesis increased by 45% during late pregnancy in dairycows, at a time when intake of dry matter and nitrogen was declining (Bell,1995) This is consistent with the moderate increase in hepatic protein accre-tion (McNeill et al., 1997), and an apparent decrease in hepatic deamination ofamino acids (Freetly and Ferrell, 1998) observed in late-pregnant ewes Incontrast, in ditocous ewes carefully fed to maintain zero energy and nitrogenbalance (CSIRO, 1990), there was a significant net loss of nitrogen fromcarcass tissues during late pregnancy, attributed largely to mobilization ofamino acids from skeletal muscle (Fig 20.1; McNeill et al., 1997)

Interpretation of putative pregnancy-specific adaptations in maternal lipidmetabolism in ruminants has been complicated by lack of experimental control

Fig 20.1 Crude protein deposition between days 110 and 140 of pregnancy in maternal tissuecomponents of ditocous ewes fed diets containing different levels of dietary crude protein Alldiets were designed to meet energy requirements Histograms are means for eight ewes Pooledstandard errors were 214 g for carcass, 84 g for organs and 44 g for mammary glands Withintissue components, means with different letters are significantly different (P< 0.05) Adaptedfrom the data of McNeill et al (1997) and reproduced from Bell and Ehrhardt (2000)

of nutrition and other environmental factors, such as photoperiod For ample, early suggestions of apparent upregulation of adipose tissue lipogenesisduring mid-pregnancy (Vernon et al., 1981) were later mostly attributed toseasonal (i.e photoperiod) effects (Vernon et al., 1985) Also, the extent towhich decreased lipogenic capacity and increased fatty acid release in adiposetissue during late pregnancy (Vernon et al., 1981) are due to pregnancy-specific factors has been unclear due to lack of data on accompanying changes

ex-in feed ex-intake and energy balance It is therefore notable that plasma trations of non-esterified fatty acids (NEFA), which are an excellent index of therate of mobilization of fatty acids (see Chapter 13), were moderately elevatedduring late pregnancy in ditocous ewes that had been fed to maintain energybalance in non-pregnant maternal tissues (Petterson et al., 1994) On the otherhand, there is little doubt that the decline in dry matter intake often observed incows and ewes close to term leads to an exaggerated increase in fatty acidmobilization and plasma NEFA concentrations (Grummer, 1993; Freetly andFerrell, 2000)

concen-Whole-body rates of entry and utilization of short-chain fatty acids, cially acetate, do not seem to be influenced by pregnancy beyond predictableeffects of the intake of rumen-fermentable organic matter (Bell, 1993).Similarly, pregnancy-related changes in the kinetics of ketone bodies, especially3-hydroxybutyrate, can be explained by changes in feed intake, energy balanceand the mobilization and hepatic catabolism of NEFA (see Chapter 13)

espe-Homoeorrhetic regulation of nutrient partitioning

General concept

The concept of homoeorrhesis as applied to regulation of nutrient partitioningduring different physiological states, such as pregnancy and lactation, recentlyhas been revised and updated by one of its original proponents (Bauman,2000) Key postulates of this concept include its simultaneous influence onmultiple tissues and functional systems, implying extracellular mediation, and itsoperation through altered tissue responses to homoeostatic effectors such asinsulin, at various levels of extracellular and intracellular signalling

Altered tissue responses to insulin and catecholamines

In sheep, as in humans and laboratory animals, late pregnancy is associatedwith the development of moderate insulin resistance assessed by diminishedsensitivity to insulin of several variables of whole-body glucose utilization(Petterson et al., 1993; Ehrhardt et al., 2001) and decreased insulin respon-siveness of lipolysis and NEFA mobilization (Petterson et al., 1994) The tissuesites of pregnancy-induced insulin resistance in sheep have not been quantita-tively studied in vivo However, the whole-body responses described byapplication of the hyperinsulinaemic, euglycaemic clamp technique are con-sistent with observations of increasing refractoriness of in vitro lipogenicresponses to insulin in adipose tissue with advancing pregnancy (Vernon

et al., 1985; Guesnet et al., 1991) This phenomenon may be partly mediated

through decreased adipose expression of the insulin-responsive glucose port protein, GLUT-4, as demonstrated in underfed vs well-fed, late-pregnantewes (Ehrhardt et al., 1998) The latter study also demonstrated reducedexpression of GLUT-4 in skeletal muscle of underfed ewes This is consistentwith the diminished ability of insulin to promote glucose uptake by muscle

trans-in vivo trans-in lactattrans-ing vs dry ewes (Vernon et al., 1990), considertrans-ing the similarcharacteristics of whole-body insulin resistance observed in ewes during latepregnancy and early lactation (Ehrhardt et al., 2001)

In contrast, pregnancy appears to amplify the responses of adipose tissue

to lipolytic adrenergic agents This was most conclusively demonstrated

by in vitro studies in which lipolytic sensitivity and responsiveness to the

pregnancy advanced (Guesnet et al., 1987) This phenomenon has not beenstudied systematically in vivo but the increase in plasma NEFA concentrationprovoked by a single intravenous injection of epinephrine was significantlyincreased during late pregnancy in dairy cows (see Bell and Bauman, 1994).The degree to which altered metabolic responses to insulin andcatecholamines during late pregnancy are physiologically specific and notinfluenced by mild reductions in feed intake and energy balance requiresscrutiny It is notable that moderate undernutrition markedly exaggerated thedecrease in insulin-dependent glucose utilization in late-pregnant ewes (Petter-son et al., 1993) Energy deprivation also amplified the in vivo lipolyticresponse to various adrenergic agents in non-pregnant, non-lactating cattle(Blum et al., 1982)

Possible homoeorrhetic effectors

Several pregnancy-related hormones, including progesterone, oestradiol andplacental lactogen (PL) have been suggested as homoeorrhetic modulators ofobserved changes in tissue responses to insulin and catecholamines, and asso-ciated metabolic adaptations to the state of pregnancy in ruminants (Bell andBauman, 1994; Bell and Ehrhardt, 2000) A more recently suggested candi-date is leptin (Bell and Ehrhardt, 2000), whose adipose tissue expression andplasma concentration increase markedly in ewes during mid-pregnancy, inde-pendent of nutrition and energy balance (Fig 20.2; Ehrhardt et al., 2001).None of these putative regulators has been shown to have the integrative,pleiotropic influences that growth hormone (GH) has in lactating ruminants(Bauman and Vernon, 1993; Bauman, 2000) Possibly, the combinedinfluence of these hormones is more significant than their varying individualinfluences at different stages of pregnancy

indirectly to mediation of some metabolic adaptations, especially close toterm when there is a pronounced surge in plasma oestrogen concentrations

adipose lipogenesis and fatty acid re-esterification in vitro (Green et al.,1992) However, we were unable to discern any effect of a similar hormonaltreatment on responses of glucose or NEFA metabolism in vivo to insulin orcatecholamines, although basal plasma concentrations of glucose, NEFA and

glycerol were chronically elevated in treated animals (Andriguetto et al., 1995,1996) Oestradiol also may contribute indirectly to changes in lipid metabolismthrough its inhibitory effect on voluntary feed intake in late-pregnant ruminants(Forbes, 1986).

Definitive evidence of a homoeorrhetic role for PL remains elusive, butsuch a putative role is hard to dismiss, for several reasons First, this uniquelyplacental peptide cross-reacts with both GH and prolactin receptors in rumin-ant tissues (Gertler and Djiane, 2002) Its specific binding in ovine adiposetissue increases with advancing pregnancy, implying increased influence onlipid metabolism (N’Guema et al., 1986) Cross-reactivity with the GH receptorwould be consistent with the development of insulin resistance in adipose tissue

Pre-breeding

Mid-pregnancy

Late pregnancy

Early lactation

since GH is a potent homoeorrhetic effector of this response in ruminantadipose tissue (Etherton and Bauman, 1998) Second, moderate undernutri-tion enhances placental gene expression and secretion of PL in late-pregnantewes (R.A Ehrhardt, R.V Anthony and A.W Bell, unpublished), coincidentwith the decreased expression of GLUT-4 in maternal insulin-responsive tissues(Ehrhardt et al., 1998) and exaggeration of indices of whole-body insulinresistance (Petterson et al., 1993, 1994) Third, active immunization againstmaternal ovine PL increased lamb birth weight, possibly via enhancement ofthe bioactivity of PL and promotion of nutrient partitioning to favour theconceptus (Leibovich et al., 2000).

The apparently pregnancy-specific increase in leptin expression and tion by adipose tissue in sheep (Fig 20.2; Ehrhardt et al., 2001), together withincreasing evidence that leptin modulates the metabolic actions of insulin inrodents (Ceddia et al., 2002), suggests that this peptide should be added to thelist of putative homoeorrhetic effectors of metabolic adaptations to pregnancy

secre-In addition, the abundant placental expression of the physiologically relevantOB-Rb form of the leptin receptor (Ehrhardt et al., 1999) suggests that leptinmay act as a direct signal of maternal energy balance to the placenta

Metabolism of the Conceptus

Placental nutrient transport and metabolism

As recently reviewed by Bell and Ehrhardt (2002), the energy and proteinrequirements of the ruminant fetus are met mostly by placental transfer ofglucose and amino acids from the maternal to the fetal circulation, with theaddition of lactate produced by placental glycolysis Long-chain fatty acids andtheir keto-acid metabolites are poorly transported in sheep compared to spe-cies with haemochorial placentation Also, the maternal–fetal transfer of acet-ate makes only a small contribution to fetal energy requirements, notwithstanding the abundance of this metabolite in the maternal circulation (Bell

et al., 2005) Therefore, this section will consider only mechanisms for cental transport and metabolism of glucose and amino acids

pla-Placental transport mechanisms

Glucose is transported from the maternal to the fetal circulation by mediated, facilitated diffusion (see Bell and Ehrhardt, 2002) This process isstrongly dependent on the maternal–fetal plasma glucose concentrationgradient (Simmons et al., 1979; DiGiacomo and Hay, 1990a) The predom-inant glucose transporter protein isoforms in the sheep placenta are GLUT-1and GLUT-3 (Ehrhardt and Bell, 1997), mRNA and protein abundance ofwhich increase with gestational age, especially for GLUT-3 (Currie et al.,

at the apical, maternal-facing layer of the trophoblastic cell layer (Das et al.,2000), suggests that ontogenic changes in GLUT-3 expression and activitymay account for much of the fivefold increase in glucose transport capacity

of the sheep placenta in vivo between mid- and late-gestation (Molina

et al., 1991) Other factors must include remodelling and expansion of theplacenta’s effective exchange surface and the increasing maternal-fetal plasmaconcentration gradient (Molina et al., 1991)

Most amino acids taken up by the placenta are transported against a fetal–maternal concentration gradient, implying the use of energy-dependent, activetransport processes (see Bell and Ehrhardt, 2002) Studies of isolated humanand rodent placental vesicles have confirmed that the transport systems inthe placenta are similar to those described for plasma membranes of othertissues (see Battaglia and Regnault, 2001) These include at least six sodium-dependent and five sodium-independent systems that have been classifiedsystematically on the basis of their affinity for neutral, acidic or basic aminoacids, and their intracellular location (Battaglia and Regnault, 2001) Recentresults from in vivo studies on sheep suggest that rapid placental transport ofneutral amino acids requires both sodium-dependent transport at the maternalepithelial surface and affinity for highly reversible, sodium-independent trans-porters located at the fetal surface (Jozwik et al., 1998; Paolini et al., 2001).These researchers also demonstrated major differences in placental clearanceamong the essential amino acids, with the more rapidly transported branched-chain acids, plus methionine and phenylalanine, apparently sharing the samerate-limiting transport system (Paolini et al., 2001)

Placental metabolism

Glucose entry into the gravid uterus and its component tissues is determined bymaternal arterial glucose concentration while glucose transport to the fetus isdetermined by the transplacental (maternal–fetal) concentration gradient (seeHay, 1995) In turn, the transplacental gradient is directly related to bothplacental and fetal glucose consumption, which are dependent on fetal arterialglucose concentration Thus, as fetal glucose concentration changes relative tothat of the mother, thereby changing the transplacental gradient, placentaltransfer of glucose to the fetus varies reciprocally with placental glucose con-sumption

In addition to its quantitative impact on placental transfer of glucose,placental glucose metabolism has a major qualitative influence on the pattern

of carbohydrate metabolites delivered to the fetus Rapid metabolism to lactate

uteroplacental glucose consumption in late-pregnant ewes, and was directlyrelated to placental glucose supply (Aldoretta and Hay, 1999) The fate of theremaining 44% of glucose metabolized by the placenta must include synthesis

of alanine and other non-essential amino acids (Timmerman et al., 1998),directly or via lactate (Carter et al., 1995)

Placental metabolism also affects the quantity and composition of aminoacids delivered to the fetus The significant net consumption by uteroplacentaltissues of glutamate, serine and the branched-chain amino acids (Liechty et al.,1991; Chung et al., 1998) implies catabolism or transamination of these acids

An additional, small fraction of this net loss of amino acids will be in the form ofsecreted peptides

The ovine placenta has very little enzymatic capacity for urea synthesis, butproduces considerable amounts of ammonia, much of which is released intomaternal and, to a lesser extent, fetal circulations (Holzman et al., 1977; Bell

et al., 1989) This is consistent with extensive placental deamination ofbranched-chain amino acids to their respective keto acids, which are releasedinto fetal and maternal bloodstreams (Smeaton et al., 1989; Loy et al., 1990),and with rapid rates of glutamate oxidation in the placenta (Moores et al.,1994) Transamination of branched-chain amino acids accounts for some ofthe net glutamate acquisition by the placenta, the remainder of which is taken

up from the umbilical circulation (Moores et al., 1994) That which is notquickly oxidized combines with ammonia to synthesize glutamine, which isthen released back into the umbilical bloodstream (Chung et al., 1998) Quan-titative aspects of ovine placental metabolism and fetal–placental exchanges ofbranched-chain amino acids, glutamine, glutamate and their metabolites aresummarized in Fig 20.3

NH3, ammonia From Loy et al (1990), Chung et al (1998), and Jozwik et al (1999); reproducedfrom Battaglia (2000) with permission of the American Society for Nutritional Sciences

Similarly, the placenta almost quantitatively converts serine, mostly taken

up from maternal blood, to glycine (Chung et al., 1998), reconciling thediscrepancy between the negligible net uptake of glycine by the uterus andsubstantial net release of this amino acid into the umbilical circulation (Belland Ehrhardt, 2002)

The complexity of interrelations among placental uptake, metabolism andtransport of amino acids was further illustrated by a study of alanine metabolism

in ewes during late pregnancy (Timmerman et al., 1998) Application of tracermethodology showed that negligible net placental consumption or production

of alanine masks an appreciable metabolism of maternal alanine entering theplacenta which exchanges with endogenously produced alanine Thus, most ofthe alanine delivered to the fetus is of placental origin, derived from placentalprotein turnover and transamination

Fetal metabolism

Patterns of growth and nutrient accretion

Numerous studies on pregnant cows and ewes have described the energy andnitrogen requirements for pregnancy based on heat increment of gestation ofthe pregnant female and/or weight, energy, nitrogen (or crude protein) andmineral accretion of the fetus, conceptus or gravid uterus (see AFRC, 1990;NRC, 1996, 2001) Those studies have been extremely valuable for describingnormal patterns of growth of gravid uterine tissues and for the purposes ofestablishing general nutritional requirements of gestating ruminants

Weight, energy content and nitrogen content of bovine fetuses on differentdays of gestation (Ferrell et al., 1976a) are shown in Table 20.1 Estimateddaily accretion rates and accretion rates relative to fetal body weight (relativegrowth rate) are also shown In the bovine fetus, rates of accretion of weight,energy and nitrogen, increase during gestation (Ferrell et al., 1976a; Bell et al.,

Table 20.1 Weight (Wt.), energy (E) and nitrogen (N) accretion of bovine fetuses.a

1995), but may be constrained during late gestation by maternal factors related

to size or genotype (Ferrell, 1991; Ferrell and Reynolds, 1992) Maternalconstraint of fetal growth, resulting primarily from limitations in uteroplacentalfunctional capacity, has been more consistently reported, occurs earlier, and is

of greater magnitude, in sheep, especially with twin or multiple fetuses, than incattle (Rattray et al., 1974a; Mellor, 1983) In cattle, rate of accretion of fetalweight relative to fetal weight decreases during gestation, whereas energyaccretion relative to fetal weight increases until approximately 230 days, thendeclines (Table 20.1) Relative rate of N accretion increases throughout thelatter half of gestation Patterns of accretion of body tissues of the ovine fetus(Rattray et al., 1974a) are similar to those of the bovine, but as previouslyobserved, magnitudes of changes with advancing gestational age are generallygreater These differences in accretion patterns result in changes in fetal bodycomposition (e.g decreased water content), as noted by Bell et al (1995) andothers, and reflect changes in fetal metabolism, growth and development aspregnancy advances In addition to changes in gross chemical composition,proportions of metabolically active tissues such as the liver, heart, kidney andbrain decrease and those of less active tissues such as muscle, fat and bone,increase substantially during fetal development (Bell et al., 1987) These ob-servations also serve to point out that comparisons of data from differentspecies or different stages of development should be done cautiously In add-ition they indicate that alternative approaches are required to develop moredefinitive understanding of fetal growth and metabolism

Macronutrient uptake and metabolism

Numerous studies of pregnant ewes have described macronutrient metabolismand requirements of the fetus in terms of net umbilical exchange of oxygen,nutrients and metabolites, and net accretion of nutrients in growing tissues.Representative data from ewes and similar data from cows are summarized inTable 20.2 Oxygen consumption of the fetus provides a useful measure ofoxidative metabolism and provides a basis for establishing metabolic rate and

on an absolute basis due to the rapidly increasing mass of fetal tissue (Reynolds

et al., 1986; Bell et al., 1987) However, on a weight-specific basis, availabledata in cattle indicate little change during the latter half of pregnancy with heat

Somewhat higher values have been reported for sheep with typical valuesbeing about 240 kJ/kg/day (Bell et al., 1987) Reported values for heatproduction represent not only ‘maintenance’ costs but also energy costs asso-ciated with tissue accretion While these values are higher than observed forfasted adult cattle or sheep, they are similar to values for moderate- to well-fedpostnatal ruminants When expressed relative to fetal dry weight, however, asubstantial decrease in oxygen utilization rates during the latter half of gestation

in ovine fetuses has been noted (Bell et al., 1987) The decrease is likely due todecreased proportions of metabolically active tissues as gestation advances aspreviously noted, and to associated decreases in fractional protein syntheticrate (Kennaugh et al., 1987) Values of urea excretion of the fetus to the

placenta and subsequently to the maternal system are relatively high and areconsistent with high rates of amino acid deamination and oxidation by thebovine and ovine fetus As will be discussed in more detail subsequently, bothglutamate and serine are released from the fetal liver, taken up by the placentafrom fetal circulation, and metabolized within the placenta (Battaglia, 2002).

In cattle and sheep, 35–45% of the energy available to the fetus is taken up

as glucose and its fetal–placental metabolites, lactate and fructose A majorportion (40–45%) of the glucose is directly oxidized and utilized as a fetalenergy source (McGowan et al., 1995) As discussed earlier, energy is alsoprovided from maternal glucose indirectly via its placental metabolites, primar-ily lactate and fructose As a result, about 70% of the glucose carbon available

glucose carbon is utilized for fetal accretion and incorporated into compoundssuch as glycogen, glycerol and amino acids

During mid-gestation, the ovine placenta produces significant amounts of

maternal circulation (Carter et al., 1993) At that time, about 70% of fetal lactate

the remaining 30% of the carbon appearing primarily in non-essential aminoacids, especially glutamate, glutamine, serine and glycine (Carter et al., 1995)

Table 20.2 Fetal sources and disposal of energy and nitrogen in ewes

and cows during late pregnancy

Energy (kJ/kg/day) Nitrogen (g/kg/day)

d Char and Creasy (1976).

e Comline and Silver (1976).

f Holzman et al (1977).

g McNeill et al (1997).

h Ferrell et al (1976a).

i Lemons and Schreiner (1983).

During late gestation, the fetal placenta becomes a major net source of fetallactate, and a negligible contributor to fetal lactate disposal At both stages of

fructose Other reports have indicated the contribution of fructose to total fetaloxidative metabolism is no more than about 5% (Meznarich et al., 1987) Teng

et al (2002) observed high concentrations of inositol, erythritol, arabitol,sorbitol, ribitol and mannitol in fetal as compared with maternal blood suggest-ing production within the conceptus However, neither the site(s) of synthesisnor the biological reasons for the relatively high concentrations of these polyolcompounds in fetal blood have been elucidated Those authors also reported asmall, but perhaps important net transfer of mannose from maternal to fetalcirculation

Almost all of the nitrogen acquired by the bovine and ovine fetus is in theform of amino acids A small net umbilical uptake of ammonia is derived fromplacental deamination of amino acids during the latter half of gestation in thesheep fetus (Holzman et al., 1977; Bell et al., 1989) but, to our knowledge,this phenomenon has not been observed in cattle In both cattle and sheep,amino acids are taken up from the placenta in considerable excess of the fetalrequirements for accretion (Meier et al., 1981b; Lemons and Schreiner, 1984;Reynolds et al., 1986) About 60% of these amino acids are used for tissueprotein synthesis, which accounts for about 18% of fetal energy expenditure(Kennaugh et al., 1987) The remaining 40% are rapidly catabolized, account-ing for at least 30% of the oxidative requirements of the well-nourished sheepfetus (Faichney and White, 1987), or in the cases of glutamate and serine,taken up and metabolized by the placenta (Battaglia and Regnault, 2001;Battaglia, 2002) Thus, in total, 45–55% of the energy available to the fetusmay be provided as free amino acids

For 18 amino acids, Chung et al (1998) estimated that fetal uptake was40% greater than fetal accretion in the ovine Umbilical uptake of all essentialamino acids were two- to threefold greater than expected fetal accretion rates(Chung et al., 1998), suggesting that all essential amino acids were oxidized, invarying amounts, by the ovine fetus Fetal oxidation of leucine (Kennaugh et al.,1987; Loy et al., 1990; Ross et al., 1996), threonine (Anderson et al., 1997)and lysine (Meier et al., 1981a) have been confirmed by radioisotope method-ology In addition to the direct oxidation of essential amino acids, about 40% of