20
Pregnancy and Fetal Metabolism
A.W. Bell,
1
C.L. Ferrell
2
and H.C. Freetly
2
1
Department of Animal Science, Cornell University, Ithaca, NY 14853, USA;
2
USDA ARS, Meat Animal Research Center, Clay Center, NE 68933, USA
Introduction
This chapter deals with quantitative aspects of macronutrient metabolism and
its regulation in maternal and conceptus tissues in vivo, emphasizing data and
concepts generated or revised during the decade since publication of a similar
chapter in the first edition of this book (see Bell, 1993). Recent findings on the
regulation of nutrient partitioning among maternal tissues, the placenta
and fetus(es) are highlighted, as is new information on placental transport
mechanisms.
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, to
ensure that the female is in an adequate body condition for birth, lactation and
rebreeding, and to provide immature females with adequate nutrients for
continued 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 requirements
for maternal maintenance, body weight gain and growth of gravid uterine
(or conceptus) tissues are summed to derive total requirements for pregnant

et al., 1974a) and cow (Ferrell et al., 1976a). Similar patterns are seen in
goats and other species. This pattern of growth results in about 90% of
birth 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 near
term (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 researchers
have 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 to
vary 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
estimates of the efficiency of ME use for maintenance (k
m
) and postnatal
growth (k
g
) are typically about 0.70 and 0.40, respectively, for good
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 required
for maintenance (52.2 MJ/day). The difference between ME required
for gestation and energy retained in the gravid uterus is reflected as heat
production (or heat increment of gestation). Thus, about 87% of the
ME required to support pregnancy is dissipated as heat. These observations
524 A.W. Bell et al.
frequently have been interpreted to imply that gestation is energetically very
inefficient.
Reynolds et al. (1986) reported that heat production of the gravid uterus in
cows was 1.37, 2.12, 4.87 and 8.57 MJ/day at 137, 180, 226 and 250 days

energy accretion of the uteroplacenta, which is required to support fetal growth
directly, and because of the increase in maternal metabolism that is required to
support fetal growth less directly.
Maternal Metabolic Adaptations to Pregnancy
Patterns of macronutrient metabolism
During late pregnancy, ruminants generally increase their voluntary intake of
medium- to high-quality diets (Forbes, 1986) and, thus, the liver’s access to
glucogenic substrate of dietary origin (principally propionate and absorbed
amino acids). However, hepatic gluconeogenesis increases in ewes during late
Pregnancy and Fetal Metabolism 525
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 and
Ferrell, 1998). These results are consistent with earlier observations of the
effects 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 maternal
peripheral tissues (Bell and Ehrhardt, 2000). A further portion is supported
by increased hepatic uptake of glycerol, especially if fat mobilization is in-
creased as term approaches (Freetly and Ferrell, 2000). Amino acids mobilized
from maternal carcass tissues (McNeill et al., 1997) also may help sustain an
increased rate of hepatic gluconeogenesis during late pregnancy.
Effects of pregnancy on the quantitative metabolism of amino acids have
yet to be studied systematically in ruminants. However, the fractional rate of
hepatic protein synthesis increased by 45% during late pregnancy in dairy
cows, 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 of
amino acids (Freetly and Ferrell, 1998) observed in late-pregnant ewes. In
contrast, in ditocous ewes carefully fed to maintain zero energy and nitrogen

526 A.W. Bell et al.
of nutrition and other environmental factors, such as photoperiod. For ex-
ample, early suggestions of apparent upregulation of adipose tissue lipogenesis
during mid-pregnancy (Vernon et al., 1981) were later mostly attributed to
seasonal (i.e. photoperiod) effects (Vernon et al., 1985). Also, the extent to
which decreased lipogenic capacity and increased fatty acid release in adipose
tissue during late pregnancy (Vernon et al., 1981) are due to pregnancy-
specific factors has been unclear due to lack of data on accompanying changes
in feed intake and energy balance. It is therefore notable that plasma concen-
trations of non-esterified fatty acids (NEFA), which are an excellent index of the
rate of mobilization of fatty acids (see Chapter 13), were moderately elevated
during late pregnancy in ditocous ewes that had been fed to maintain energy
balance in non-pregnant maternal tissues (Petterson et al., 1994). On the other
hand, there is little doubt that the decline in dry matter intake often observed in
cows and ewes close to term leads to an exaggerated increase in fatty acid
mobilization and plasma NEFA concentrations (Grummer, 1993; Freetly and
Ferrell, 2000).
Whole-body rates of entry and utilization of short-chain fatty acids, espe-
cially acetate, do not seem to be influenced by pregnancy beyond predictable
effects of the intake of rumen-fermentable organic matter (Bell, 1993).
Similarly, pregnancy-related changes in the kinetics of ketone bodies, especially
3-hydroxybutyrate, can be explained by changes in feed intake, energy balance
and the mobilization and hepatic catabolism of NEFA (see Chapter 13).
Homoeorrhetic regulation of nutrient partitioning
General concept
The concept of homoeorrhesis as applied to regulation of nutrient partitioning
during different physiological states, such as pregnancy and lactation, recently
has been revised and updated by one of its original proponents (Bauman,
2000). Key postulates of this concept include its simultaneous influence on
multiple tissues and functional systems, implying extracellular mediation, and its

increased during late pregnancy in dairy cows (see Bell and Bauman, 1994).
The degree to which altered metabolic responses to insulin and
catecholamines during late pregnancy are physiologically specific and not
influenced by mild reductions in feed intake and energy balance requires
scrutiny. It is notable that moderate undernutrition markedly exaggerated the
decrease in insulin-dependent glucose utilization in late-pregnant ewes (Petter-
son et al., 1993). Energy deprivation also amplified the in vivo lipolytic
response to various adrenergic agents in non-pregnant, non-lactating cattle
(Blum et al., 1982).
Possible homoeorrhetic effectors
Several pregnancy-related hormones, including progesterone, oestradiol and
placental lactogen (PL) have been suggested as homoeorrhetic modulators of
observed changes in tissue responses to insulin and catecholamines, and asso-
ciated metabolic adaptations to the state of pregnancy in ruminants (Bell and
Bauman, 1994; Bell and Ehrhardt, 2000). A more recently suggested candi-
date is leptin (Bell and Ehrhardt, 2000), whose adipose tissue expression and
plasma 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 combined
influence of these hormones is more significant than their varying individual
influences at different stages of pregnancy.
Among the sex steroids, oestradiol-17b (E
2
) may contribute directly or
indirectly to mediation of some metabolic adaptations, especially close to
term when there is a pronounced surge in plasma oestrogen concentrations.
Treatment of ovariectomized ewes with E
2

a
b
ab
a
4
3
2
1
0
Leptin mRNA, arbitrary units
a
b
ab
a
Fig. 20.2. Effects of physiological state on plasma concentration (upper panel) and adipose
tissue mRNA abundance of leptin (lower panel) in ewes fed to maintain relatively constant energy
balance and body fatness. Histograms are means for the same eight ewes studied at 20–40 days
before breeding (pre-breeding), 50–60 days of pregnancy (mid-pregnancy), 125–135 days of
pregnancy (late pregnancy) and 15–22 days postpartum (early lactation). Pooled standard errors
were 0.54 ng/ml for plasma leptin and 0.40 units for leptin mRNA abundance. Means with
different letters are significantly different (P < 0.05). Adapted from Ehrhardt et al. (2001).
Pregnancy and Fetal Metabolism 529
since GH is a potent homoeorrhetic effector of this response in ruminant
adipose tissue (Etherton and Bauman, 1998). Second, moderate undernutri-
tion enhances placental gene expression and secretion of PL in late-pregnant
ewes (R.A. Ehrhardt, R.V. Anthony and A.W. Bell, unpublished), coincident
with the decreased expression of GLUT-4 in maternal insulin-responsive tissues
(Ehrhardt et al., 1998) and exaggeration of indices of whole-body insulin
resistance (Petterson et al., 1993, 1994). Third, active immunization against
maternal ovine PL increased lamb birth weight, possibly via enhancement of

1997; Ehrhardt and Bell, 1997). This, together with its low K
m
and localization
at the apical, maternal-facing layer of the trophoblastic cell layer (Das et al.,
2000), suggests that ontogenic changes in GLUT-3 expression and activity
may account for much of the fivefold increase in glucose transport capacity
530 A.W. Bell et al.
of the sheep placenta in vivo between mid- and late-gestation (Molina
et al., 1991). Other factors must include remodelling and expansion of the
placenta’s effective exchange surface and the increasing maternal-fetal plasma
concentration 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, active
transport processes (see Bell and Ehrhardt, 2002). Studies of isolated human
and rodent placental vesicles have confirmed that the transport systems in
the placenta are similar to those described for plasma membranes of other
tissues (see Battaglia and Regnault, 2001). These include at least six sodium-
dependent and five sodium-independent systems that have been classified
systematically on the basis of their affinity for neutral, acidic or basic amino
acids, and their intracellular location (Battaglia and Regnault, 2001). Recent
results from in vivo studies on sheep suggest that rapid placental transport of
neutral amino acids requires both sodium-dependent transport at the maternal
epithelial 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 clearance
among the essential amino acids, with the more rapidly transported branched-
chain acids, plus methionine and phenylalanine, apparently sharing the same
rate-limiting transport system (Paolini et al., 2001).
Placental metabolism
Glucose entry into the gravid uterus and its component tissues is determined by

branched-chain amino acids to their respective keto acids, which are released
into 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 of
the net glutamate acquisition by the placenta, the remainder of which is taken
up from the umbilical circulation (Moores et al., 1994). That which is not
quickly oxidized combines with ammonia to synthesize glutamine, which is
then released back into the umbilical bloodstream (Chung et al., 1998). Quan-
titative aspects of ovine placental metabolism and fetal–placental exchanges of
branched-chain amino acids, glutamine, glutamate and their metabolites are
summarized in Fig. 20.3.
Uterine
circulation
Placenta Fetal
circulation
NH
3
NH
3
1.54.0
gln
5.73.5
glu
6.11.5
akg
TCA
bcaa
aka
18.9 10.9
Fig. 20.3. Net fluxes, measured in vivo, of the branched-chain amino acids, glutamine,

NRC, 1996, 2001). Those studies have been extremely valuable for describing
normal patterns of growth of gravid uterine tissues and for the purposes of
establishing general nutritional requirements of gestating ruminants.
Weight, energy content and nitrogen content of bovine fetuses on different
days of gestation (Ferrell et al., 1976a) are shown in Table 20.1. Estimated
daily accretion rates and accretion rates relative to fetal body weight (relative
growth 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
Day of
gestation
Fetus
b
Rate of gain
c
Relative growth rate
d
Wt. E N Wt. E N Wt. E N
100 0.48 0.76 5.01 17.9 38 0.2 37.05 78.14 0.415
130 1.37 2.99 16.30 45.1 130 0.6 32.82 94.61 0.437
160 3.45 9.96 47.28 98.6 372 1.6 28.57 107.76 0.463
190 7.63 27.97 122.6 185.8 883 3.6 24.34 115.68 0.472
220 14.86 66.32 283.6 298.6 1720 7.3 20.09 115.72 0.491
250 25.48 132.72 586.0 403.9 2695 12.9 15.85 105.75 0.506
280 38.47 224.18 1081.0 446.6 3285 19.8 11.61 85.39 0.515
a
From Ferrell et al. (1976a).
b
Fetal weight (kg), energy (kJ) and nitrogen (g).